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f7320e7ce4a766fe9682c1d29609dd5802a2a336	pubmed	Development of a best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours in the UK	Development of a best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours in the UK Bleomycin, a cytotoxic chemotherapy agent, forms a key component of curative regimens for lymphoma and germ cell tumours. It can be associated with severe toxicity, long-term complications and even death in extreme cases. There is a lack of evidence or consensus on how to prevent and monitor bleomycin toxicity. We surveyed 63 germ cell cancer physicians from 32 cancer centres across the UK to understand their approach to using bleomycin. Subsequent guideline development was based upon current practice, best available published evidence and expert consensus. We observed heterogeneity in practice in the following areas: monitoring; route of administration; contraindications to use; baseline and follow-up investigations performed, and advice given to patients. A best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours has been developed and includes recommendations regarding baseline investigations, the use of pulmonary function tests, route of administration, monitoring and patient advice. It is likely that existing heterogeneity in clinical practice of bleomycin prescribing has significant economic, safety and patient experience implications. The development of an evidence-based consensus guideline was supported by 93% of survey participants and aims to address these issues and homogenise practice across the UK. # Background Bleomycin is a cytotoxic antibiotic with well-known anticancer activity. First discovered in 1966, [bib_ref] New antibiotics, bleomycin A and B, Umezawa [/bib_ref] FDA approval for Bleomycin was gained in 1973 and it is an important component of the curative treatment regimens for germ cell tumours and lymphomas. [bib_ref] Importance of bleomycin in combination chemotherapy for goodprognosis testicular nonseminoma: a randomized..., De Wit [/bib_ref] However, bleomycin can be toxic, with potential long-term complications, and in extreme cases can be fatal. [bib_ref] Fatal bleomycin pulmonary toxicity in the west of Scotland 1991-95: a review..., Simpson [/bib_ref] Due to its inclusion in curative regimens, minimising these effects is of utmost importance, but currently there is lack of consensus on how to prevent and monitor bleomycin toxicity. The most serious complications of bleomycin are pneumonitis (bleomycin-induced pneumonitis-BIP) and pulmonary fibrosis, but other lung pathology includes organising pneumonia and eosinophilic hypersensitivity pneumonitis. Immune-mediated hypersensitivity, with a potential genetic predisposition, is felt to play an important role in the pathogenesis and subsequent fibrosis that occurs in the later stages. [bib_ref] Bleomycin pulmonary toxicity: current status and future directions, Comis [/bib_ref] [bib_ref] Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the..., Eitzman [/bib_ref] [bib_ref] Inheritance of susceptibility to bleomycin-induced pulmonary fibrosis in the mouse, Haston [/bib_ref] [bib_ref] Role of repeated lung injury and genetic background in bleomycin-induced fibrosis, Chung [/bib_ref] [bib_ref] Mechanisms of bleomycin-induced lung damage, Hay [/bib_ref] In the case of germ cell tumours, bleomycin-induced pneumonitis is estimated to be around 10% and can be life threatening in up to 20% of these cases. [bib_ref] Fatal bleomycin pulmonary toxicity in the west of Scotland 1991-95: a review..., Simpson [/bib_ref] In patients receiving bleomycin for treatment of lymphoma, incidence of pulmonary toxicity has been reported as high as 18%, with 24% mortality of affected cases. [bib_ref] Bleomycin pulmonary toxicity has a negative impact on the outcome of patients..., Martin [/bib_ref] Other side effects from bleomycin include fever, rash, dermatographic pigmentation upon scratching, cutaneous nodules, alopecia and Raynaud's phenomenon, although skin changes are thought to be unrelated to lung toxicity. Diagnosis of BIP is made by combining systemic symptoms such as dry cough and shortness of breath with typical radiological changes on high resolution computed tomography (HRCT). Histological findings on biopsies or lavages and abnormal respiratory function tests can provide supportive, but not diagnostic evidence, and are important for exclusion of atypical infection and other pathologies. The role of pulmonary function tests (PFTs) in bleomycinassociated lung toxicity is controversial. Recent work has shown that abnormal PFTs pre-treatment do not predict the development of toxicity and are only associated with toxicity at the end of treatment. [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] However, PFTs have long been used as an indicator of toxicity and reduction in certain values may correlate with radiological changes and development of symptoms. [bib_ref] Bleomycin-induced pneumonitis, Sleijfer [/bib_ref] There is currently a lack of consensus regarding the use of bleomycin according to baseline PFTs. [bib_ref] Carbon monoxide diffusing capacity is a poor predictor of clinically significant bleomycin..., Mckeage [/bib_ref] Even though a cumulative dose has been well described as a cause for bleomycin toxicity, [bib_ref] Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours, O'sullivan [/bib_ref] it is still unclear whether bleomycin toxicity is fully dose-dependent and indeed BIP has been reported with lower doses. [bib_ref] Late pulmonary complications of treating Hodgkin lymphoma: bleomycin-induced toxicity, Jóna [/bib_ref] [bib_ref] Severe bleomycin-induced pneumonitis, White [/bib_ref] Severe reactions may be idiosyncratic with a number other factors likely to be important and BIP has been reported years after bleomycin treatment completion. [bib_ref] Delayed onset bleomycin-induced pneumonitis, Uzel [/bib_ref] [bib_ref] Lung fibrosis 10 years after cessation of bleomycin therapy, Tashiro [/bib_ref] Multiple studies have shown that patients over the age of 40 are at a much increased risk of BIP compared to patients under 40 in both the treatment of germ cell tumours 3 and lymphoma, 9 but the reasons remain unclear. Since bleomycin is mainly excreted by the kidneys (70%), concomitant use of cisplatin has been implicated in BIP due to renal toxicity by cisplatin, which may increase the halflife and toxicity of bleomycin. [bib_ref] Fatal bleomycin toxicity from a low cumulative dose in a patient with..., Mcleod [/bib_ref] [bib_ref] Bleomycin pulmonary toxicity: its relationship to renal dysfunction, Dalgleish [/bib_ref] Bleomycin can be given intravenously (IV), intramuscularly (IM) or subcutaneously (SC); there is currently no consensus regarding administration. Typical schedules involve weekly administration of bleomycin as an IV bolus or short IV infusion. While previous work suggested that the route of administration could potentially impact the level of toxicity [bib_ref] Prospective study of the pulmonary toxicity of continuously infused bleomycin, Cooper [/bib_ref] [bib_ref] Continuous infusion or bolus injection in cancer chemotherapy, Carlson [/bib_ref] and association between rapid IV infusion and higher BIP rates has been reported, [bib_ref] Pulmonary function in long-term survivors of testicular cancer, Haugnes [/bib_ref] the recentlypublished TE-3 trial-a phase III randomised study-found no significant difference in the incidence of CT assessed lung toxicity in patients receiving a continuous 72-hour infusion of bleomycin vs. patients receiving daily bolus infusions. [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] In this present study, we document the heterogeneity of bleomycin use among prescribing clinicians across the UK before suggesting a best-practice guideline intended to harmonise local practice and manage toxicity. # Methods Twenty-seven Core questions (supplementary information 1) were developed to assess how Bleomycin is used in the UK among prescribing clinicians in a range of cancer centres. The survey was performed to map current practice, describe heterogeneity and provide a rationale for guideline development-not to directly inform the guidelines themselves. All replies were from specialists in the UK who manage patients with testicular cancer and are experienced in the use of chemotherapy including bleomycin. ## Survey The survey was developed in survey monkey with a link emailed to clinicians. Email addresses were found using databases from the Association of Cancer Physicians (ACP), and several national testicular trials. In total responses were received from 63 individuals from 32 different cancer centres. # Survey analysis Responses were collected via survey monkey and downloaded to a spreadsheet. Analysis was performed using Microsoft Excel. Guideline development A best-practice guideline was developed based on a structured review of existing literature. In some areas, suitable literature is lacking and expert opinion, guided by an understanding of current practice, was used. Relevant literature was identified with MEDLINE searches performed independently by two authors (R.W., H.D.L.P.). Multiple iterations of guidelines were produced and refined based on expert consensus. # Results # Results of survey Responses were obtained from 63 individuals from 32 different cancer centres. Of the 63 replies there were 46 from named individuals and 17 remained anonymous. Fifty-one of these were treating adults with testicular cancer, 12 were looking after teenage and young adult patients. Of the 46 named individuals 44 were specialist clinicians and 2 were nurse specialists. ## Route of administration There was a wide variety in routes of administration of bleomycin both at day 2 and day 8/9 and 15/16. Sixty-eight percent of participants administer day 2 Bleomycin IV as infusion, 26% as IV bolus and 6% as IM injection [fig_ref] Figure 1: Method of administration of a day 2 bleomycin among those surveyed and... [/fig_ref]. However, IV infusion rate varied markedly from 30 min up to 18 h. Similarly, IV infusion was the most popular method of administration for day 8/9 and day 15/16, although IM injection and IV bolus were more likely to be used for these subsequent doses [fig_ref] Figure 1: Method of administration of a day 2 bleomycin among those surveyed and... [/fig_ref]. Use of bleomycin in those with pulmonary risk factors Fifteen percent of participants would use bleomycin in smokers, only 8% of participants would not and the majority (77%) would consider using it depending on individual circumstances. In hypoxic patients, 3% of participants would use bleomycin, 66% would never use it and 31% would consider it depending on individual patient circumstances. Regarding patients with history of lung disease, 17% of participants would never use bleomycin whereas 83% would consider using it [fig_ref] Figure 2: Willingness of participants to use bleomycin in patients with pulmonary risk factors [/fig_ref]. In those who would consider using bleomycin in some circumstances, the reasons for using it varied greatly with some suggesting they would be guided by pulmonary function tests, others basing their decision on smoking pack year history. Use of bleomycin in those with pre-existing co-morbidities Five percent of participants would use bleomycin in patients with poor renal function (eGFR < 50), 36% would never use it and 59% would consider it. Eleven percent of participants would use bleomycin in over 40-year olds, 74% would consider it. Fifty percent of participants would avoid bleomycin in patients who are already breathless [fig_ref] Figure 2: Willingness of participants to use bleomycin in patients with pulmonary risk factors [/fig_ref]. Use of baseline tests prior to bleomycin use Regarding baseline test to assess lung function, 85% of participants rely on clinical examination, 78% on staging CT (if available), 59% request pulmonary function tests (PFTs) and 7% request baseline HRCT [fig_ref] Figure 3: Tests done by participants prior to starting bleomycin [/fig_ref]. Sixty-four percent of participant complete a 'toxicity checklist' before bleomycin is authorised. However, 25% of these lists do not ask about cough and shortness of breath (SOB). Participants seem to agree with giving bleomycin with transfer factor (TLCO) values > 85. Thirty-four percent of participants would use bleomycin with TLCO levels > 75 < 85. Follow-up and monitoring Once bleomycin has been given at least once, 93% participants undertake patient clinical examination, 88% perform a symptom checklist, 74% request chest X-rays (CXRs) and 29% request PFTs prior to the next treatment. If patients complain of shortness of breath (SOB) post-bleomycin, 100% of participants perform clinical examination, 95% request CXR, 65% request PFTs and 54% request HRCT [fig_ref] Figure 3: Tests done by participants prior to starting bleomycin [/fig_ref]. If these tests are normal, 70% of participants continue with further bleomycin treatment and 12% stop using it. If a patient develops skin toxicity due to bleomycin, 65% of participants continue its use, whereas 7% stop it. Advice to patients Due to the oxygen-sensitive nature of bleomycin toxicity, patients should avoid inspiring oxygen at high concentrations, including anaesthesia and certain forms of scuba diving. Despite this, 18% of participants responded that they did not routinely give advice regarding anaesthetic and 20% reported that they do not routinely give advice about scuba diving to their patients [fig_ref] Figure 3: Tests done by participants prior to starting bleomycin [/fig_ref]. van Hulst et al. [bib_ref] To dive or not to dive with bleomycin: A practical algorithm, Van Hulst [/bib_ref] have published an algorithm to aid in risk stratification of scuba diving post-bleomycin and further advice can be sought from the UK Diving Medical Committee (www. ukdmc.org). ## A best-practice guideline Based on the significant heterogeneity demonstrated, and the fact that 93% of participants would support it, we have developed a best-practice guideline for the use of bleomycin in germ cell tumours in the UK [fig_ref] Table 1: Best-practice guidelines for the use of bleomycin in germ cell tumours in... [/fig_ref]. Baseline imaging Due to the fact that those of increasing age are at higher risk of developing bleomycin-associated lung toxicity, with those over the age of 30 having 4.8% higher grade ≥ 1 toxicity, [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] and those over the age of 40 having a twofold increased risk, we recommend performing a baseline CT in all those over the age of 40 receiving bleomycin. Expert consensus felt that a standard CT chest was as helpful as an HRCT for baseline imaging, and all patients are likely to have received this investigation as part of their staging. The role of PFTs The role and importance of PFTs in the monitoring of those receiving bleomycin, and those suspected of toxicity, has long been debated. Some authors have gone as far as advocating regular 3-weekly PFTs [bib_ref] The role of screening and monitoring for bleomycin pulmonary toxicity, Shippee [/bib_ref] and other studies have positively described the use of this test. [bib_ref] Bleomycin pulmonary toxicity: current status and future directions, Comis [/bib_ref] [bib_ref] Consortium de détection et prise en charge des atteintes pulmonaires induites par..., Biya [/bib_ref] However, other work has cast doubt on the utility of PFTs. [bib_ref] Role of carbon monoxide diffusing capacity in the early detection of major..., Bell [/bib_ref] [bib_ref] Routine pulmonary function tests during bleomycin therapy. Tests may be ineffective and..., Lewis [/bib_ref] Commentators disagree on the importance of the different components of PFTs, with diffusion factor (DLCO) felt to be most sensitive but lung capacity more specific. [bib_ref] Bleomycin-induced pneumonitis, Sleijfer [/bib_ref] [bib_ref] Bleomycin-induced pulmonary function abnormalities, Wolkowicz [/bib_ref] [bib_ref] Decrease in pulmonary function during bleomycin-containing combination chemotherapy for testicular cancer: not..., Sleijfer [/bib_ref] Much of the literature pre-dates an era of readily-available cross-sectional imaging, and, on the whole, consists of observational studies or is based on small sample sizes. A recent prospective phase III randomised study found that PFTs were only weakly correlated with increased toxicity and only at the end of treatment. [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] We consider this to be the highest level of available evidence and as such we do not recommend performing baseline PFTs with the aim of predicting those likely to develop toxicity. Further, in cases of suspected toxicity (based on symptoms), we consider it superior to investigate using HRCT. However, we recognise that many practitioners will see value in PFTs and they may be useful for corroborating CT findings or where there is diagnostic uncertainty. Further, PFTs are cheap, non-invasive and quick to perform and are favoured by respiratory physicians. As such, while we do not advocate using PFTs to predict those likely to develop pulmonary toxicity, we recommend performing baseline PFTs where possible, and considering their use (with particular attention paid to the DLCO) as part of the diagnostic process for suspected toxicity, especially in situations of diagnostic doubt. ## Contraindications to bleomycin We recommend that prescribers recognise that there are no absolute contraindications to use of bleomycin. However, caution should be exercised with increasing age, significant smoking history, reduced renal function and pre-existing lung disease (in particular pre-existing fibrosis or other symptomatic pathology); those with multiple risk factors are more at risk. [bib_ref] Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours, O'sullivan [/bib_ref] [bib_ref] The role of screening and monitoring for bleomycin pulmonary toxicity, Shippee [/bib_ref] [bib_ref] Consortium de détection et prise en charge des atteintes pulmonaires induites par..., Biya [/bib_ref] [bib_ref] Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours, O'sullivan [/bib_ref] [bib_ref] Bleomycin causes alveolar macrophages from cigarette smokers to release hydrogen peroxide, Lower [/bib_ref] Administration of bleomycin There is no evidence to support a bolus vs. continuous administration regimen for bleomycin. Typical administration schedules involve a weekly bleomycin bolus or short infusion; bleomycin can also be administered intramuscularly. We recognise that choice of regimen will depend on local centre capacity and preferences. However, we recommend that bleomycin should be administered under direct supervision of clinicians familiar with its use and toxicities. ## Development of bleomycin-related lung toxicity Bleomycin-related lung toxicity should be considered in all patients who develop new respiratory symptoms during systemic treatment with bleomycin. We consider cough to be the most sensitive symptom for predicting toxicity, [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] however, dyspnoea has also been associated. [bib_ref] Severe bleomycin-induced pneumonitis, White [/bib_ref] In cases of suspected toxicity, HRCT should be the investigation of choice, supported by clinical findings and possibly pulmonary function tests where there is diagnostic uncertainty. Volumetric chest CT can also be used to investigate suspected toxicity. This has the advantage of being able to detect lung metastases and, therefore, update staging, however it carries a higher radiation dose. Therefore, in younger patients where the primary aim is to investigate possible bleomycin toxicity, HRCT may be preferable. CXR has extremely low sensitivity and should not be used as an imaging modality to investigate suspected toxicity. If lung toxicity is confirmed, cessation of therapy may reverse lung damage and continuing bleomycin therapy may result in worsening toxicity. We recommend that the risks and benefits of stopping or continuing bleomycin treatment are thoroughly considered-including in an MDT setting with both oncologists and radiologists experienced in this condition-and discussed with the patient. To continue with bleomycin in the face of new symptoms of cough or dyspnoea should always be a consultant decision and we consider it safer to omit an individual dose in patients with new cough or dyspnoea than to risk exacerbating toxicity. Such decisions are likely to be guided by the amount and type of changes on CT scan, rapidity of change and the threat of progressive fibrosis and respiratory failure. It should be noted that Development of a best-practice clinical guideline for the use of. . . RA Watson et al. the changes seen on HRCT can be non-specific and hence the clinical picture needs to be carefully considered. There is limited evidence to suggest some benefit from highdose steroids in established cases of acute bleomycin-induced pneumonitis, 32,33 particularly considering the differential diagnosis that includes atypical pneumonia. In addition, infection should always be considered in cases of possible bleomycin lung toxicity and these can mimic, coexist and drive development of fibrosis. As such we recommend the use of steroids and a low threshold for antimicrobial therapy in acute bleomycin lung toxicity. Steroids are particularly effective in cases of hypersensitivity pneumonitis, but less so in established fibrosis and hence HRCT findings may guide treatment. We also recommend that referral to or discussion with a respiratory physician with an interest in interstitial lung disease is considered in cases of confirmed toxicity. If doses of bleomycin are omitted due to suspected toxicity, which is subsequently excluded following investigation, these doses can be added into treatment as a weekly dose following completion of the planned treatment cycles. This may prevent complete omission which can result in less favourable outcomes. Post-treatment monitoring All patients receiving more than 300 units of bleomycin should receive a post-treatment CT scan. We acknowledge that this is standard care for those receiving follow-up post-chemotherapy, however the fact that bleomycin was given, and the total dose, should always be included on the radiology request. This is particularly important as pulmonary nodules resulting from toxicity may rarely be mistaken for metastases. Further investigations (e.g., HRCT, pulmonary function tests) should be symptomled or considered in cases of diagnostic uncertainty. We consider a new cough to be the most important symptom. ## Symptom monitoring A 'toxicity checklist' should be used before and after every cycle of bleomycin. An example of this can be found in supplementary Pulmonary function tests Baseline PFTs can be a useful reference in the case of subsequent toxicity and should be considered where possible. ## Expert opinion (level 5) PFTs should not be used in isolation to aid in a decision as to whether or not to treat with bleomycin. [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] (Level 1b) PFTs should not be used as a first-line investigation for suspected lung toxicity. [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] (Level 1b) PFTs may aid in the diagnosis of suspected toxicity and may guide management of toxicity. Involvement of a respiratory physician should be considered. [bib_ref] Bleomycin-induced pulmonary function abnormalities, Wolkowicz [/bib_ref] (Level 1b) Expert opinion (Level 5) ## Contraindications to bleomycin There are no absolute contraindications to use but caution should be exercised with increasing age, significant smoking history, reduced renal function and preexisting lung disease (in particular pre-existing fibrosis or other symptomatic pathology) Expert opinion (Level 5) ## Administration of bleomycin There is no evidence to support a bolus vs. continuous administration regimen. Typical administration schedules involve a weekly bleomycin bolus or short infusion. [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] (Level 1b) 20 (Level 1b) ## Development of bleomycin-related lung toxicity Cessation of therapy may reverse lung damage and continuing bleomycin therapy may result in worsening toxicity. Continuation in the face of new symptoms should be a consultant decision. ## (level 1b) Cough is the most sensitive symptom for prediction of toxicity. Dyspnoea is also a significant symptom. [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] (Level 1b) 15 (Level 2a) All CT-confirmed diagnoses of bleomycin lung toxicity should be considered for oral Prednisolone (0.5 mg/kg) for 7 days and reduce [bib_ref] Severe bleomycin-induced pneumonitis. Clinical features and response to corticosteroids, White [/bib_ref] [bib_ref] Severe bleomycin lung toxicity: reversal with high dose corticosteroids, Maher [/bib_ref] (Level 4) Expert opinion (Level 5) HRCT chest is indicated if toxicity is suspected with referral to a respiratory physician with an interest in interstitial lung disease. ## Expert opinion (level 5) Infection should always be considered and treated, and may mimic, coexist with and drive bleomycin-related lung toxicity Expert opinion (Level 5) PFTs may have a role in cases of diagnostic uncertainty or high-risk groups (see text) Expert opinion (Level 5) ## Post-treatment monitoring All patients receiving more than 300 units of bleomycin should receive a posttreatment CT scan [bib_ref] Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours, O'sullivan [/bib_ref] (Level 2a) ## Expert opinion (level 5) Further investigations should be symptom-led. PFTs are only weakly correlated with increased toxicity at the end of treatment, with DLCO being most significant. ## (level 1b) Symptom monitoring A 'toxicity checklist' should be used before and after every cycle of bleomycin. An example of this can be found in supplementary information 2. ## Expert opinion (level 5) Renal function should be checked prior to every cycle of treatment. ## Expert opinion (level 5) Cough is the most important symptom and development of a new cough should trigger further investigation (with HRCT in the first instance). [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] Advice sheet Every patient receiving bleomycin should receive a post-treatment advice sheet. An example of this can be found in supplementary information 3. # Discussion This work used a qualitative survey to map the variation in practice in prescribers of bleomycin for germ cell tumours across the UK. Sixty-three participants from 32 different cancer centres responded to the survey. The results show marked heterogeneity in practice in route of administration, willingness to prescribe to those with lung and other co-morbidities, baseline and follow-up investigations performed and advice given to patients. As a result of this, we have produced a best-practice guideline based on current practice, published literature and expert consensus. Meaning of the study Our work has identified the large variation in practice across the UK, even among cancer centres that are in close geographical proximity. It is likely that this was a representation of a lack of a national consensus guideline, meaning that practices have evolved based on local preferences and experience. Many participants responded in the 'free comment' section that they have their own local protocols and guidance, particularly surrounding anaesthesia following bleomycin. Among our participants, 93% agreed that a standardised protocol for the use of bleomycin would be useful. It is, therefore, likely that the heterogeneity of practice observed is due to the lack of an accepted guideline, rather than the unwillingness of clinicians to follow it. Further, 90% of participants estimated the level of significant bleomycin toxicity in their practice is <10%. In the 'free comment' section of the questionnaire, a number of respondents stated that they felt that bleomycin toxicity is a rare and an unusual complication that they infrequently see in their own practice. The uncommon nature of this complication could explain why there is a variation in management and follow-up of these patients and may deepen the need for a standardised approach. However, the incidence of toxicity is likely to be higher than estimated by the respondents-indeed the TE3 study reported that by the end of three cycles, 70.5% of patients had CT evidence of parenchymal changes consistent with BIP (any grade). [bib_ref] A randomized phase III study of 72h infusional versus bolus bleomycin in..., Shamash [/bib_ref] It is unclear as to what the effect of the observed heterogeneity is in practice. However, it is likely that there are both patient safety and economic implications. For example 58% of participants request a chest X-ray before starting bleomycin, even though this has an extremely low sensitivity for detecting interstitial lung disease. [bib_ref] Bleomycin-related lung damage: CT evidence, Bellamy [/bib_ref] An evidence-based best-practice approach to working patients up for bleomycin could potentially save resources and prevent patients undergoing unnecessary tests. As a result of these findings, we have produced a best-practice guideline for the prescribing of bleomycin in germ cell tumours in the UK. Strengths and weaknesses of the current study This work is the first of its kind to map the variation in bleomycin use for germ cell tumours across the UK and propose an evidence-based best-practice guideline for use in this context. We received a high response rate and collected data from 32 different cancer centres, giving a wide spread and range of opinions. Participants were engaged in the work, many left free-text comments and a number were keen on being involved in future developments. However, we recognise that there are a number of limitations to the work. Regarding the survey, we accept that it is possible that invitations to participate were not received in every case and that there is likely to be some selection bias among participants. In addition, some questions were left unanswered and 'sometimes' was often given as a response, which prevents a more in-depth analysis. Finally, this survey was retrospective-so is at risk of recall bias-and is limited to UK practitioners. Regarding the guideline development, the literature was searched for relevant publications, but this was not exhaustive. Consensus was generated from experts (J.J., J.S., D.M., S.S., L.P.H., A.P.) but was not considered at a wider national level. Some of the recommendations are based on expert consensus and there is generally a lack of high-quality randomised or blinded research to support the recommendations and in some areas only the experience and judgement of the practitioner can guide practice. Finally, this current work is solely limited to the use of bleomycin in germ cell tumours. We had hoped to involve expert haematology opinion and circulate the survey to haemato-oncologists but to date this work has not involved haemato-oncologists. Future work regarding the use of bleomycin in UK haematology practice is planned through the expert haemato-oncology groups. Nevertheless, despite these limitations we are confident that our methods and approach has produced results that can confidently support our conclusion that there is significant heterogeneity in the use of bleomycin for germ cell tumours across the UK and that the guidelines produced represent current best-practice with the available evidence. ## Recommendations for practitioners The authors strongly support the introduction of this best-practice guideline for the use of bleomycin in germ cell tumours. We accept that some may resist this proposition and there are a wide variety of individual patient factors to take into consideration when deciding whether to proceed with, hold, dose-reduce or stop chemotherapy. We accept this, and it would be up to individual clinicians to use the guideline as they see fit and adapt it to their patients. However, for a relatively rare, but potentially very serious complication, such a wide variation in practice across the UK strongly supports the utility of a consensus guideline developed collectively by the community and available evidence. Ninety-three percent of our participants agreed that such a document would be helpful. We believe that further research needs to be conducted to more accurately ascertain what 'best-practice' looks like and to help further develop and refine the guideline. There is currently a lack of well-designed prospective randomised and blinded studies and while the TE3 trial has provided some evidence, further work is clearly needed. Further, patient involvement is vital in refining and developing information sheets that can give consistent and appropriate advice following bleomycin treatment. Finally, work to identify those at high-risk of bleomycin toxicity -not just through co-morbidities-but also via genetic, tumoural or phenotypical markers would be of great help in targeting higher intensity monitoring and investigations to those who are most likely to benefit. # Conclusions We have demonstrated marked heterogeneity in the clinical practice of bleomycin prescribers in the UK. The adverse effects of such variation are not clear, but we purport that there are significant economic, patient safety and patient experience implications. We have produced a best-practice guideline based on current practice, available published literature and expert consensus. [fig] Figure 1: Method of administration of a day 2 bleomycin among those surveyed and b day 8function (GFR <50) (n=58) [/fig] [fig] Figure 2: Willingness of participants to use bleomycin in patients with pulmonary risk factors (a) and willingness to use bleomycin in those with pre-existing co-morbidities (b) Development of a best-practice clinical guideline for the use of. . . RA Watson et al. [/fig] [fig] Figure 3: Tests done by participants prior to starting bleomycin (a) or routinely following at least one cycle of bleomycin or if the patient reports symptoms (b). Frequency of advice not routinely given to patients (c) [/fig] [fig] Level 1b: Expert opinion (Level 5)Advice sheetEvery patient receiving bleomycin should receive a post-treatment advice sheet. An example of this can be found in supplementary information 3.Expert opinion (Level 5)Levels of evidence are based on the Centre for Evidence-based Medicine Levels of Evidence. http://www.cebm.net/oxford-centre-evidence-based-medicinelevels-evidence-march-a new cough should trigger further investigation (with HRCT in the first instance), as should dyspnoea. Renal function should be checked prior to each new cycle of bleomycin due to increased risk of toxicity with declining renal function.11 [/fig] [table] Table 1: Best-practice guidelines for the use of bleomycin in germ cell tumours in the UK [/table]	None	https://www.nature.com/articles/s41416-018-0300-x.pdf	None
eb11ae4dd996ba644fc92cbe00c1c043dd512a50	pubmed	FIGO/ICM guidelines for preventing Rhesus disease: A call to action	FIGO/ICM guidelines for preventing Rhesus disease: A call to action The introduction of anti-Rh(D) immunoglobulin more than 50 years ago has resulted in only a 50% decrease in Rhesus disease globally owing to a low uptake of this prophylactic approach. The International Federation of Gynecology and Obstetrics, International Confederation of Midwives, and Worldwide Initiative for Rhesus Disease Eradication have reviewed current evidence regarding the utility of anti-Rh(D) immunoglobulin. Taking into account the effectiveness anti-Rh(D), the new guidelines propose adjusting the dose for different indications and prioritizing its administration by indication. ## \| introduc ti on In 1968, more than 50 years ago, anti-Rh(D) immunoglobulin was approved for use among Rhesus (Rh)-negative women to prevent sensitization to the Rh(D) blood group antigen after delivery.Subsequently, this approach was expanded to give anti-Rh(D) prophylaxis during pregnancy to prevent sensitization in the third trimester, as well as anti-D prophylaxis in the case of miscarriage, ectopic pregnancy, amniocentesis, bleeding or abdominal trauma during pregnancy, and/or external cephalic version for breech presentation. Recently in some countries, fetal Rh determination in maternal blood has been introduced in early pregnancy to prevent unnecessary immunoglobulin administration when the fetus seems to be Rh(D)-negative.This approach is highly effective and Rh disease has been more or less eradicated in most high-income countries. Nevertheless, recent data have shown that, in approximately 50% of eligible cases worldwide, anti-Rh(D) immunoglobulin is not administered.The reasons vary but include insufficient supply, cost considerations, ignorance (e.g., simply forgot to administer anti-Rh[D]), lack of access, and use of products that have not been tested for therapeutic efficacy.It has been estimated that Rh disease still results in more than 160 000 perinatal deaths and 100 000 cases of disability annually, representing only a 50% reduction relative to the era before immunoglobulin administration.Such a high burden of a preventable disease should be considered completely unacceptable. The aim of the present study was to summarize data on the prevention of Rh disease by immunoprophylaxis and provide guidelines that take into consideration the cost-effectiveness of the different dose regimens and prioritize the administration of anti-Rh(D) by indication. The guidelines are summarized in Box 1. ## \| b lood g roup and rh (d) t yping A pre-requisite for the prevention of Rh(D) sensitization is a priori knowledge of maternal Rh status. Although this is widely agreed This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. upon, it is not the case in many low-resource settings. The Rh(D) factor can be determined by collecting venous or capillary blood samples at local healthcare facilities and using classical or point-ofcare serologic methods. The Rh(D) type should preferably be determined in the first trimester, because indications for anti-Rh(D) immunoprophylaxis may arise early in pregnancy; for example, after a miscarriage or an ectopic pregnancy.According to one study, the median fetal-maternal transfusion at delivery is approximately 0.7 mL, with a transfusion exceeding 10 mL in only approximately 1% of cases. 8 Therefore, it has been suggested that an anti-Rh(D) dose of 500 IU (100 µg) would be sufficient. Nonetheless, the effectiveness of administering a higher standard dose has not been established,although a recent meta-analysis suggests that the 1500 IU regimen has slightly better efficacy.In some countries, it is policy to give a double dose of anti-Rh(D) after a cesarean delivery. However, this does not seem to be necessary because data from a large study in the Czech Republic did not show a greater volume of fetal-maternal transfusion after cesarean delivery.In case of uncertainty, a Kleihauer-Betke test may be performed to estimate the actual volume of fetal-maternal transfusion. It has been calculated that one vial of 1500 IU will prevent sensitization by 30 mL of fetal whole blood. This test is also reasonable in other settings where there is uncertainty regarding the size of a fetal-maternal hemorrhage (e.g., intrauterine fetal death). In the Kleihauer-Betke test, the percentage of fetal cells in maternal circulation is calculated by counting the number of fetal red cells in a maternal blood smear as follows: % of fetal red cells relative to maternal red cells × 50 = amount of fetal whole blood in maternal circulation (in mL). ## \| anti -rh (d) immunog lobulin adminis tr ation in preg nan c y Most cases of Rh(D) sensitization occur as a result of labor. Routine prenatal administration of anti-Rh(D) immunoglobulin to prevent sensitization resulting from fetal-maternal hemorrhage during pregnancy has been studied in a meta-analysis of two randomized controlled trials.These showed a 42% reduction in sensitization, although this reduction was not significant (95% confidence interval [CI], 0.15-1.62).However, a 'bias-adjusted' meta-analysis of data from 10 studies estimated a pooled odds ratio for a reduction in sensitization of 0.31 (95% CI, 0.17-0.56), which was highly significant.Therefore, prenatal administration seems to reduce sensitization further, from approximately 1.5%, achieved by administration of postpartum anti-Rh(D) immunoglobulin, to approximately 0.5%. Prenatal anti-Rh(D) immunoglobulin may be given intramuscularly or intravenously, with no clear difference in effectiveness. 14 It may be given once at 28-34 weeks of gestation (1500 IU), or twice at 28 and 32-34 weeks (625 IU or 1500 IU at each gestational age). Two recent meta-analyses and an additional randomized controlled trial showed that a single administration of 1500 IU resulted in the lowest proportion of women with detectable circulating anti-Rh(D) at delivery, suggesting that this is the optimal dose against sensitization during pregnancy. ## \| misc arriag e The risk for sensitization is most probably extremely low for spontaneous abortions before 10 gestational weeks; however, data are scarce. Based on the clinical expertise of the guideline committee from the UK's National Institute for Health and Care Excellence (NICE), it is suggested that prophylaxis should be given only to women who are having a spontaneous abortion or medical management of miscarriage after 10 0/7 gestational weeks. Moreover, for women who have surgical management, prophylaxis may also be considered before 10 gestational weeks.Given the low fetal blood volume during early gestation, an anti-Rh(D) immunoglobulin dose of 500 IU may be used, although there are no data to support this policy. In a complete molar pregnancy, organogenesis does not occur; thus, sensitization to Rh(D) should not occur. However, the situation is different in a partial molar pregnancy. Because differentiating between the forms of molar pregnancy may be difficult, it is generally advised to administer anti-Rh(D) immunoglobulin in this setting. 3 ## \| ec topi c preg nan c y A ruptured tubal pregnancy has been associated with a 24% incidence of alloimmunization to Rh(D) among Rh(D)-negative women.Therefore, anti-Rh(D) immunoglobulin administration is strictly advised for ectopic pregnancy. Because fetal blood volume is low in early gestation, the dose of anti-Rh(D) required may be low. ## \| chori oni c villus sampling or amni o cente s is Most countries advocate administering anti-Rh(D) immunoglobulin to Rh(D)-negative pregnant women after chorionic villus sampling or amniocentesis, although this recommendation is based on limited scientific evidence.In Denmark, by contrast, immunoprophylaxis is not provided in this setting because no differences in alloimmunization at 29 weeks were found between women with invasive testing and those without (900 cases would be needed to prevent one case of immunization). ## \| b leeding and ab dominal tr auma in preg nan c y Abdominal trauma may cause fetal-maternal transfusion, which might lead to Rh(D) alloimmunization. Although the exact risks are unknown, it is advised to administer anti-Rh(D) immunoglobulin as prophylaxis. The same holds for prenatal hemorrhage in the second and third trimester.The optimal dose of anti-Rh(D) immunoglobulin is not known (1500 IU is most commonly used). ## \| intr auterine fe tal de ath Because an intrauterine fetal death may have been caused by a large fetal-maternal hemorrhage, it may be useful to perform a Kleihauer-Betke test, both as a part of the workup of the fetal death and -among Rh(D)-negative women -to determine the amount of fetal-maternal hemorrhage to calculate the dose of anti-Rh(D) immunoglobulin needed. ## \| e x ternal cephali c ver s i on in b r e ech pr e s e ntati o n The risk of fetal-maternal transfusion during external cephalic version ranges from 2% to 6%; therefore, administration of anti-Rh(D) immunoglobulin is advised.However, the amount of transfusion is generally low. Based on a large Canadian study,it has been concluded that routine administration of prenatal anti-Rh(D) immunoglobulin at approximately 32 gestational weeks should be enough to prevent sensitization during a subsequent external cephalic version. ## \| noninva s ive fe tal rh (d) t yping in the fir s t trime s ter Non-invasive prenatal testing of cell-free DNA in the first trimester of pregnancy may be used to determine fetal Rh(D) status. Such a policy has recently been introduced into clinical practice in countries such as Denmark, the Netherlands, and the United Kingdom. A recent meta-analysis of 60 000 participants showed that it has a very high sensitivity (99.9%; 95% CI, 99.5%-100%) and specificity (99.2%; 95% CI, 89.5%-99.5%) as compared with testing newborn's blood.First-trimester non-invasive Rh(D) typing may therefore be used to prevent unnecessary administration of anti-Rh(D) immunoglobulin in the course of pregnancy (routinely or following amniocentesis, etc.). Although population-based cell-free DNA as a method to determine Rh status may not be currently cost-effective in all settings, 3 health policymakers should include this non-invasive test as a future option for combating Rh disease. ## \| dosag e of anti -rh (d) immunog lobulin Surprisingly little is known about the optimal dose of anti-Rh(D) immunoglobulin. Postpartum, a dose of 1500 IU may be slightly better than 500 IU, but financial restriction may prompt use of the lower dose. In early pregnancy, the amount of fetal-maternal hemorrhage is bound to be low; therefore, a dose of 500 IU should generally be enough. Prophylaxis in the third trimester should optimally consist of a dose of 1500 IU given once between 28 and 34 weeks. No ## Box 1 measures to prevent sensitization to rh(d) ## High priority Determine the maternal Rh factor, preferably in early pregnancy. For Rh(D)-negative women, determine the Rh factor of the newborn from umbilical cord blood. ## Middle priority Routine anti-Rh(D) prophylaxis during pregnancy: 1500 IU (300 µg) at 28-34 weeks. Anti-Rh(D) immunoglobulin prophylaxis (500 IU; 100 µg) after a surgical abortion or ectopic pregnancy (all gestational ages), or after spontaneous or medical abortion/miscarriage after 10 weeks. Anti-Rh(D) prophylaxis after bleeding, abdominal trauma in pregnancy, and/or fetal death (500 or 1500 IU; 100 or 300 µg) during the second or third trimester. Kleihauer-Betke test can be used to estimate the optimal dose. ## Low priority Anti-Rh(D) prophylaxis after amniocentesis, chorionic villus sampling, or external cephalic version (500 IU; 100 µg). information is available on the immunoglobulin dose that should be given after maternal vaginal bleeding, abdominal trauma, or fetal death. However, the Kleihauer-Betke test is very useful and provides dosing guidance for abdominal trauma or fetal death. Turkey, and Uruguay.There is still a long way to go. ## \| me a sure s to pre vent anti -rh (d) s en s itiz ati on ## Co n fli c t s o f i nte r e s t The authors have no conflicts of interest. ## Auth o r co ntr i b uti o n s GHAV wrote the manuscript, which was modified/amended by TT, GC DR, AN, and SLS and approved by the FIGO Safe Motherhood and Newborn Health Committee. ## M e m b e r s o f th e fi g o sa fe m oth e r h o o d a n d n e wb o r n h e a lth ## R e fe r e n c e s	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ijgo.13459	The introduction of anti‐Rh(D) immunoglobulin more than 50 years ago has resulted in only a 50% decrease in Rhesus disease globally owing to a low uptake of this prophylactic approach. The International Federation of Gynecology and Obstetrics, International Confederation of Midwives, and Worldwide Initiative for Rhesus Disease Eradication have reviewed current evidence regarding the utility of anti‐Rh(D) immunoglobulin. Taking into account the effectiveness anti‐Rh(D), the new guidelines propose adjusting the dose for different indications and prioritizing its administration by indication.
287f097ca11681331792fed4eb70738233cb901c	pubmed	Rational diagnostic strategies for Lyme borreliosis in children and adolescents: recommendations by the Committee for Infectious Diseases and Vaccinations of the German Academy for Pediatrics and Adolescent Health	Rational diagnostic strategies for Lyme borreliosis in children and adolescents: recommendations by the Committee for Infectious Diseases and Vaccinations of the German Academy for Pediatrics and Adolescent Health The varying clinical manifestations of Lyme borreliosis, transmitted by Ixodes ricinus and caused by Borrelia burgdorferi, frequently pose diagnostic problems. Diagnostic strategies vary between early and late disease manifestations and usually include serological methods. Erythema migrans is pathognomonic and does not require any further laboratory investigations. In contrast, the diagnosis of neuroborreliosis requires the assessment of serum and cerebrospinal fluid. Lyme arthritis is diagnosed in the presence of newly recognized arthritis and high-titer serum IgG antibodies against B. burgdorferi. The committee concludes the following recommendations: Borrelial serology should only be ordered in case of well-founded clinical suspicion for Lyme borreliosis, i.e., manifestations compatible with the diagnosis. Tests for borrelial genomic sequences in ticks or lymphocyte proliferation assays should not be ordered. When results of such tests or of serological investigations that were not indicated are available, they should not influence therapeutic decisions. Laboratories should be cautious when interpreting results of serological tests and abstain from giving therapeutic recommendations and from proposing retesting after some time without intimate knowledge of patient's history and disease manifestations. # Introduction Lyme borreliosis is caused by infection with Borrelia burgdorferi sensu lato and transmitted by the bite of the tick Ixodes ricinus [bib_ref] Lyme borreliosis, Stanek [/bib_ref]. In Europe, Lyme borreliosis may present as a variety of manifestations that are classified into early and late manifestations in children and adolescents [bib_ref] Childhood Lyme borreliosis in Europe, Huppertz [/bib_ref] [fig_ref] Table 1: Manifestations of Lyme borreliosis in children and adolescents [/fig_ref]. The correct diagnosis is made or is at least strongly suggested by history and physical examination. Borrelia-specific laboratory results confirm the clinical suspicion [bib_ref] Microbiological and serological diagnosis of Lyme borreliosis, Wilske [/bib_ref]. Besides the direct methods for detecting the infectious agents in body fluids or tissues, for example, by polymerase chain reaction (PCR), serological methods are usually used on blood and cerebrospinal fluid. Primarily, enzyme immunoassays, distinguishing between immunoglobulin M and G antibodies, are applied as screening tests. Because of their low specificity, (line) immunoblot assays, often with recombinant antigens, are used as confirmatory assays in case of a reactive (positive or borderline) enzyme immunoassay [bib_ref] Improvement of Lyme borreliosis serodiagnosis by a newly developed recombinant immunoglobulin G..., Goettner [/bib_ref]. A few antigens are especially helpful including VlsE and OspC for early disease and p83/100 for late borreliosis. By comparing antibody concentrations in serum and cerebrospinal fluid, it is possible to detect intrathecal antibody production [bib_ref] EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis, Mygland [/bib_ref]. These diagnostic strategies were established more than 10 years ago, and scientific progress, since then, is minimal. Although there are good review articles, for example, in the handbook of the German Society for Pediatric Infectious Diseases, diagnosing Lyme borreliosis continues to be difficult, and therefore, a rational strategy is presented here for everyday use. The diagnostic strategies discussed here apply to European, but not necessarily to North American Lyme borreliosis. ## Erythema migrans Erythema migrans is by far the most frequent manifestation of Lyme borreliosis in Europe, amounting to nearly 90 % of all cases [bib_ref] Incidence of Lyme borreliosis in the Würzburg region of Germany, Huppertz [/bib_ref]. Clinical presentation of erythema migrans is pathognomonic, and therefore, usually no laboratory tests are necessary for diagnosis [bib_ref] Lyme borreliosis, Stanek [/bib_ref]. Because serology is frequently negative at this stage, antibodies should not be determined. In rare cases of atypical erythema migrans, clinical diagnosis may be difficult. In these cases, the present extent of the erythema may be marked with a pen and should be reexamined 1-2 days later. If the erythema has expanded, the diagnosis of erythema migrans is most likely correct. PCR of skin biopsy is a good test to confirm a diagnosis of erythema migrans, and results are truly positive in about 70 % of cases when good biopsy and laboratory techniques are used [bib_ref] Comparison of PCR methods and culture for the detection of Borrelia spp...., Cerar [/bib_ref]. However, skin biopsy is seldom justified. Response to antibiotic treatment is only confirmed by disappearance of erythema migrans and not by serological means. ## Other manifestations When other manifestations of Lyme borreliosis are suspected, and erythema migrans is not present, serological assays should be performed [bib_ref] Microbiological and serological diagnosis of Lyme borreliosis, Wilske [/bib_ref]. ## Suspicion of early neuroborreliosis Lyme borreliosis should be considered in patients with cranial nerve palsy, in particular, seventh nerve palsy, and signs of meningitis with or without headache, lethargy, or irritability for about 9 days on average before admission [bib_ref] Lyme borreliosis: clinical case definition for diagnosis and management in Europe, Stanek [/bib_ref] [bib_ref] Prediction of Lyme meningitis based on a logistic regression model using clinical..., Tuerlinckx [/bib_ref]. Stiffness of the neck is often very mild or absent and must be searched for carefully. In contrast, patients with aseptic/viral meningitis usually display obvious nuchal rigidity and have a history of less than 6 days, often 1 or 2 days only [bib_ref] Validation of a clinical prediction rule to distinguish Lyme meningitis from aseptic..., Cohn [/bib_ref] [bib_ref] Prediction of Lyme meningitis based on a logistic regression model using clinical..., Tuerlinckx [/bib_ref]. Especially in the absence of cranial nerve palsy, the possible diagnosis of Lyme borreliosis is not being considered often enough. Patients with headache as a sole manifestation usually do not have neuroborreliosis. In comparison to patients with noninflammatory headaches of frequent and various causes, the headaches of patients with neuroborreliosis usually have a clearly indicated beginning and a short duration of less than a month [bib_ref] Prediction of Lyme meningitis based on a logistic regression model using clinical..., Tuerlinckx [/bib_ref]. To confirm neuroborreliosis, antibodies against Borrelia burgdorferi are assessed in serum and cerebrospinal fluid. In the case of early neuroborreliosis, there is lymphocytic pleocytosis in the cerebrospinal fluid, but often, intrathecal antibody production cannot yet be found [bib_ref] Lyme neuroborreliosis in children, Skogman [/bib_ref]. If cerebrospinal fluid yields pleocytosis with ≥90 % mononuclear cells, there are no other remaining causes apart from tuberculous meningitis. In very early stages of the disease, serological results in serum may still be negative [bib_ref] Validation of a clinical prediction rule to distinguish Lyme meningitis from aseptic..., Cohn [/bib_ref]. In typical cases, antibodies of the immunoglobulin IgM class against B. burgdorferi are found by enzyme immunoassay and are confirmed by two or more bands by IgM immunoblot. Later, IgG antibodies may be detected by enzyme immunoassay, and the number of bands in the IgG immunoblot increases gradually. Therefore, in case of a negative serology and continuing suspicion of neuroborreliosis, it may be useful to determine antibodies in serum again 2 or 3 or 4 weeks later to find seroconversion. PCR in cerebrospinal fluid often is positive only in very early cases when there are not yet antibodies against B. burgdorferi present. Although a positive PCR supports the diagnosis of neuroborreliosis, a negative PCR does not exclude it [bib_ref] EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis, Mygland [/bib_ref]. Therefore, PCR should not be used routinely to make a diagnosis of neuroborreliosis, but only in complex cases. ## Suspicion of late neuroborreliosis The neurological manifestations have usually been present for some time, and a number of different diagnoses have been considered, including multiple sclerosis, Guillain-Barré syndrome, pseudotumor cerebri, and cerebral vasculitis. The clinical presentation may be varying, including headache, lethargy, irritability, and focal neurological signs. Late neuroborreliosis is very rare in children. Lymphocytic pleocytosis is not necessarily found in cerebrospinal fluid, since it may occur intermittently. However, there is borrelia-specific intrathecal antibody production, usually of immunoglobulin G [bib_ref] EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis, Mygland [/bib_ref]. In addition, there are intrathecal oligoclonal bands and a high protein concentration in cerebrospinal fluid. In serum, there is a positive enzyme immunoassay for IgG antibodies against B. burgdorferi, confirmed by IgG immunoblot with a multitude of bands. ## Suspicion of lyme arthritis In the case of newly appearing arthritis, a borrelial serology should be obtained, especially in mono-or oligoarthritis, including the knee joint [bib_ref] Lyme disease, Huppertz [/bib_ref]. In case of Lyme arthritis, the enzyme immunoassay is highly positive for IgG antibodies against B. burgdorferi; the results of which are confirmed by immunoblot with a multitude of bands. PCR in synovial fluid may be positive. The rate of correctly positive results by PCR may be increased by using synovial tissue. However, the suspicion of Lyme arthritis is not sufficient justification for performing a synovial biopsy, and laboratory confirmation of the diagnosis primarily relies on serum antibody determination. ## Suspicion of further manifestations There is a variety of further rare manifestations of Lyme borreliosis. When there is a reasonable suspicion of Lyme borreliosis, diagnosis is supported by serology. The expected serological results vary with the stage of the disease, i.e., if the patient has an early or late manifestation of Lyme borreliosis. Eyes may be involved by keratitis, iridocyclitis, or uveitis intermedia. Cardiac involvement may appear as AV block or carditis. Acrodermatitis chronica atrophicans is a late skin manifestation of borreliosis and very rare in children. In borrelial lymphocytoma, usually found at earlobes, nipples, or testicular sacks, serology is not infrequently false negative. Therefore, diagnosis may be established exclusively by clinical means, as is the case for erythema migrans. The issue of summer flu, including fever, joint pain, and fatigue without signs of mucous membrane involvement is still unclear, although it may be a manifestation of early Lyme borreliosis. The clinical presentation is too varied, and serological examinations often are still negative, or false positive serological results lead to misdiagnosis and unnecessary treatment [bib_ref] Misdiagnosis of Lyme disease: when not to order serologic tests, Seltzer [/bib_ref]. The disease usually is self-limiting after a few days. ## Mental state disturbances and vague somatic symptoms (false manifestations of lyme borreliosis) Borreliosis is sometimes suspected in patients with functional problems or mental state disturbances. However, symptoms usually do not fit with known manifestations of Lyme borreliosis [bib_ref] Role of psychiatric comorbidity in chronic Lyme disease, Hasset [/bib_ref]. In case of chronic headache or diminishing academic achievements, often patients are not able to indicate when complaints started, which is not typical of neuroborreliosis. If suspicion of neuroborreliosis remains, lumbar puncture should be performed, which excludes neuroborreliosis if findings are normal, i.e., absence of pleocytosis and intrathecal antibody production. If antibody determination is only being done in serum, the result is without relevance for the cause of headaches, and frequently, serological results cannot be interpreted in the absence of results from cerebrospinal fluid [bib_ref] Lyme neuroborreliosis: aetiology and diagnosis of facial palsy in children from Tyrol, Brunner [/bib_ref]. In case of muscular and skeletal complaints, sometimes Lyme arthritis is suspected, although arthritis is missing, a sign which is necessary for the diagnosis of Lyme arthritis. If serology has been performed in spite of the absence of arthritis, the lack of antibodies of immunoglobulin G against B. burgdorferi excludes Lyme arthritis. If this determination of specific IgG antibodies is positive, anti-B. burgdorferi antibody production has been detected; however, the cause of musculoskeletal pain remains unclear in the absence of arthritis. This is due to the fact that the positive predictive value is low if the prevalence of the tested trait is low [bib_ref] Misdiagnosis of Lyme disease: when not to order serologic tests, Seltzer [/bib_ref]. Moreover, when assays for antibodies against B. burgdorferi are ordered in patients with an absence of objective signs of manifestations compatible with Lyme borreliosis, serology often cannot be interpreted. Therefore, in case of nonspecific complaints like headache, limb pain, or mental state disturbance, borrelial serology should not be performed. ## Recommendations by laboratories concerning the interpretations of serological results The interpretation of results of serology for B. burgdorferi may be difficult and sometimes is indeterminate. Interpretation should always be done in conjunction with complete clinical knowledge of the patient. Some laboratories recommend that borrelial serology be repeated after a few weeks or months. However, this only rarely leads to new evidence. An exception from this rule is early disseminated disease, including early neuroborreliosis. Therefore, serology should be repeated after an interval of time only in very few well-founded cases. Sometimes the interpretation of serology results by laboratories contains recommendations for treatment. However, this would require complete knowledge of clinical presentation and previous therapeutic measures. As these are usually not available in the laboratory, these recommendations often are inaccurate or wrong. In addition to these, other diagnostic strategies have been recommended: The analysis of ticks which have been removed from human skin for the presence of borrelia, and the assessment of the ability of lymphocytes from peripheral blood to proliferate after addition of borrelial antigens. Analysis for borrelia of ticks which have been removed from human skin Some laboratories recommend and advertise assessing ticks by PCR for borrelial genomic sequences when they have been removed from the skin of a human host. Laboratories report the presence of borrelia, sometimes also the genotype and the number of copies. In case of a positive result, these laboratories recommend either antibiotic prophylaxis or serological assessment immediately and a few weeks later to detect seroconversion. There are no convincing data, justifying the use of these tests in ticks removed from humans or patients. There are no data presented for false positive results. It is not known why the number of copies is relevant, since the minimal infectious dose of B. burgdorferi is not known [bib_ref] Low risk of developing Borrelia burgdorferi infection in the south-east of Sweden..., Fryland [/bib_ref]. If the genotype is not indicated, nonpathogenic genotypes may be included under the general term B. burgdorferi sensu lato, thus exaggerating the potential risk of transmission. In a study from Switzerland, a positive test result finding borrelia in removed ticks was not associated with the development of Lyme borreliosis [bib_ref] Risk of Borrelia burgdorferi infection in western Switzerland following a tick bite, Nahimana [/bib_ref]. The assessment of ticks for borrelial genomic sequences overestimates the importance of a single tick bite, since most tick bites are not recognized by the host, and most patients with Lyme borreliosis do not remember having been bitten by a tick [bib_ref] Prospective study on the incidence of infection by Borrelia burgdorferi sensu lato..., Huegli [/bib_ref]. When people recognize a tick on their skin and remove it early (i.e., within 24 h), most of the time, borrelia is not transmitted [bib_ref] Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated..., Warshafsky [/bib_ref]. The risk of transmission after a tick bite is given as 4 % [bib_ref] Maladie de Lyme: bases fondamentales à l'origine des measures preventives, measures de..., Guy [/bib_ref]. In a Swiss study, seroconversion occurred in 4.5 % of tick bites [bib_ref] EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis, Mygland [/bib_ref]. Most infections take an uneventful course without clinical manifestations [bib_ref] Risk of Borrelia burgdorferi infection in western Switzerland following a tick bite, Nahimana [/bib_ref]. Asymptomatic seroconversion and clinical infection are low in spite of a high percentage of infection by B. burgdorferi in ticks removed from these humans [bib_ref] Prospective study on the incidence of infection by Borrelia burgdorferi sensu lato..., Huegli [/bib_ref]. Up to 5 % of healthy blood donors display IgG antibodies against B. burgdorferi [bib_ref] Infections with Borrelia burgdorferi in Würzburg blood donors: antibody prevalence, clinical aspects..., Böhme [/bib_ref] ; healthy forest workers, up to 52 % [bib_ref] Foci of tick-borne diseases in southwest Germany, Oehme [/bib_ref]. In German children, this rate currently is 4.8 % [bib_ref] Seroprävalenz der Lyme-borreliose bei Kindern und Jugendlichen in Deutschland, Koch-Institut [/bib_ref]. The apparently low transmission rate and the high proportion of asymptomatic borrelia infections after tick bites do not justify the search for borrelial genomic sequences in a removed tick. In addition, a positive result does not allow a reasonable conclusion: prophylactic antibiotic treatment after a tick bite is not recommended in Europe the more so as this treatment may not prevent infection followed by clinical manifestations [bib_ref] Development of erythema migrans in spite of treatment with antibiotics after a..., Maraspin [/bib_ref]. Even if seroconversion is detected after a tick bite, found in paired serum assessments at an interval of 3-4 weeks, this finding is without consequences in the absence of clinical manifestation, since antibiotic treatment would only be recommended if the patient gets sick with borreliosis. In conclusion, the assessment of borrelial sequences or antigens in ticks removed from patients is without therapeutic consequence, and therefore, the test should not be performed [bib_ref] Zeckenstich und Lyme-borreliose. Eine epidemiologische untersuchung im raum Erlangen, Heininger [/bib_ref]. ## Assessment of the reaction of lymphocytes towards borrelia antigens Plasma cells producing antibodies are under the control of T cells during their development. Early attempts to assess the reactivity of T cells towards borrelial antigens used the lymphocyte transformation assay. In spite of refined tests and use of recombinant antigens, it was not possible to obtain the same specificity as in serological methods including enzyme immunoassay and immunoblot [bib_ref] The T-cell proliferative assay in the diagnosis of Lyme disease, Dressler [/bib_ref] [bib_ref] Lymphoproliferative responses to Borrelia burgdorferi in the diagnosis of Lyme arthritis in..., Huppertz [/bib_ref] [bib_ref] Cellular immune reactivity to recombinant OspA and flagellin from Borrelia burgdorferi in..., Krause [/bib_ref]. Consequently, the lymphocyte transformation assay has not been recommended for clinical use. Recently, there have been new attempts to introduce this test into the diagnosis of Lyme borreliosis [bib_ref] A novel lymphocyte transformation test for Lyme borreliosis, Valentine-Thon [/bib_ref] [bib_ref] Evaluation of the diagnostic significance of the lymphocyte proliferation test in patients..., Baehr [/bib_ref]. This was based on further technical improvements of the tests. In two publications, a good performance of these tests has been reported [bib_ref] A novel lymphocyte transformation test for Lyme borreliosis, Valentine-Thon [/bib_ref] [bib_ref] Evaluation of the diagnostic significance of the lymphocyte proliferation test in patients..., Baehr [/bib_ref]. Closer examination of these publications, however, shows that the patients had not been characterized, and the suspicion of the physician, sending the probe to the laboratory ("suspicion of borreliosis"), was taken as a diagnosis. Serological results were not communicated for all patients, and correct control groups were missing. Consequently, these publications are not able to contribute to the assessment of the validity of the lymphocyte transformation assay. Therefore, results of these tests cannot contribute to the management of patients. ## Conclusions of the committee The following consequences should be drawn: 1. The committee recommends that pediatricians order borrelial serology only when there is a well-founded clinical suspicion of Lyme borreliosis following the diagnostic strategy outlined above. Patients with chronic pain, fatigue, or mental state disturbances should not be tested for Lyme borreliosis. 2. The committee recommends that insurance companies do not pay for laboratory assessments that are not indicated. This includes serological tests without well-founded clinical suspicion, tests for borrelial antigens or genomic sequences in ticks, and lymphocyte transformation assays. 3. The committee strongly recommends that laboratories that offer serological examination for Lyme borreliosis should never add therapeutic recommendations when interpreting the laboratory results. Without close knowledge of clinical manifestations and previous therapeutic measures, it is not possible to reason about therapeutic consequences of serological results. 4. In addition, the committee asks laboratories not to recommend further serological assessments after a few weeks or months when interpreting serological results. In most cases, repetition of serology does not add useful new evidence. Only the attending physician with close knowledge of history, clinical manifestations, and previous treatments may decide on the usefulness of repeating the serology after 2 or 3 or 4 weeks in a given patient. [table] Table 1: Manifestations of Lyme borreliosis in children and adolescents (modified from Huppertz [12])Early manifestations can be observed after some days up to a few weeks after infection and are self-limiting. Assessment of antibodies in serum may still be unremarkable or show an early seroconversion including IgM antibodies and low-titer IgG antibodies against B. burgdorferi. Late manifestations show up months to years after infection, may become chronic and, in rare cases, lead to lasting organ damage. Serological results show high-titer IgG antibodies against B. burgdorferi; IgM antibodies may persist. EIA enzyme immunoassay, IB immunoblot [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs00431-012-1779-4.pdf	None
2d9442307361175c020da6d7829f05fdcc882e8d	pubmed	Position Paper of the Department of Hypertension of the Brazilian Society of Nephrology: Use of renin-angiotensin system blockers during the course of Covid-19 infection	Position Paper of the Department of Hypertension of the Brazilian Society of Nephrology: Use of renin-angiotensin system blockers during the course of Covid-19 infection ResumoEste posicionamento do Departamento de Hipertensão da Sociedade Brasileira de Nefrologia (SBN) trata da polêmica gerada em torno do uso ou da suspensão/ substituição dos bloqueadores do sistema renina-angiotensina-aldosterona (particularmente inibidores da enzima de conversão da angiotensina ou bloqueadores dos receptores AT 1 da angiotensina II) profilaticamente em indivíduos que utilizam esses medicamentos, devido à possibilidade de supostamente piorar o prognóstico de pacientes hipertensos infectados pelo SARS-CoV-2. O Departamento de Hipertensão da SBN recomenda a individualização do tratamento e a manutenção dessas medicações até que melhores evidências científicas estejam disponíveis.AbstRActThis position statement of the Department of Hypertension of the Brazilian Society of Nephrology (SBN) addresses the controversy surrounding the use or suspension/replacement of the renin-angiotensin-aldosterone system blockers (particularly inhibitors of the angiotensin-converting enzyme or angiotensin II AT1 receptor blockers) prophylactically in individuals using these drugs, due to the possibility of allegedly worsening the prognosis of hypertensive patients infected with SARS-CoV-2. The SBN Hypertension Department recommends individualizing treatment and maintaining these medications until better scientific evidence is available. ## Resumo # Abstract This position statement of the Department of Hypertension of the Brazilian Society of Nephrology (SBN) addresses the controversy surrounding the use or suspension/replacement of the renin-angiotensin-aldosterone system blockers (particularly inhibitors of the angiotensin-converting enzyme or angiotensin II AT1 receptor blockers) prophylactically in individuals using these drugs, due to the possibility of allegedly worsening the prognosis of hypertensive patients infected with SARS-CoV-2. The SBN Hypertension Department recommends individualizing treatment and maintaining these medications until better scientific evidence is available. ## Keywords: Coronavirus infections; Hypertension; Renin-Angiotensin System. Considering the correspondence called "Are patients with hypertension and diabetes mellitus at a higher risk of infection by Covid-19?" 1 , recently published in The Lancet, in which the authors suggest the association of renin-angiotensin-aldosterone system blockers (RAAS), particularly angiotensin-converting enzyme inhibitors or angiotensin II AT1 receptor blockers, in patients with heart disease, high blood pressure or diabetes mellitus at increased risk of severe Covid-19 infection, who should therefore be monitored. Based on this, and considering the beginning of speculations at a national and international level about the harm of maintaining these antihypertensive drugs in those infected with SARS-CoV-2, despite the lack of scientifical, clinical or experimental evidence; Furthermore, considering that arterial hypertension per se may not be directly correlated with the risk of infection or its worsening, there would be no indication for suspending these drugs or their preventive replacement in hypertensive patients during a pandemic outbreak; In addition, considering that, paradoxically, there are divergences between the recommendations of the publications available to date, with arguments in favor 2 and against its use 1 , even in hypertensive individuals proven to be infected; Moreover, considering that there is new data from observational studies concerning possible protection of the RAAS blockers against negative outcomes, including mortality, in those infected with SARS-CoV-2 using these antihypertensive classes;Finally, considering that the risk of cardiovascular and renal morbidity and mortality is directly associated with the lack of blood pressure control. The Department of Arterial Hypertension of the Brazilian Society of Nephrology, as well as other Societies of National 5,6 and Internationalmedical specialties, recommend the maintenance of these classes of drugs, even in those with suspected or confirmed Covid-19 infection, unless hypotension occurs due to sepsis or another cause, which would lead to the suspension of any and all antihypertensive drugs, and not specifically of RASS blockers, always taking into account the individualized treatment that results in the greatest possible benefit to the patient. This position statement may change in status at any time when better scientific evidence emerges.	None	https://www.scielo.br/j/jbn/a/CQQdZrqmB6LbcYswrvGzcYD/?lang=en&format=pdf	ABSTRACT This position statement of the Department of Hypertension of the Brazilian Society of Nephrology (SBN) addresses the controversy surrounding the use or suspension/replacement of the renin-angiotensin-aldosterone system blockers (particularly inhibitors of the angiotensin-converting enzyme or angiotensin II AT1 receptor blockers) prophylactically in individuals using these drugs, due to the possibility of allegedly worsening the prognosis of hypertensive patients infected with SARS-CoV-2. The SBN Hypertension Department recommends individualizing treatment and maintaining these medications until better scientific evidence is available.
839418e36e2e7d56daef6f0c203ed65e5322d86a	pubmed	EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis	EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis Objective To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficultto-treat rheumatoid arthritis (D2T RA). Methods An EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and nonpharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A-D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0-10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members. Results Two overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4-9.6). Conclusions These PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research. # Introduction Treatment options for rheumatoid arthritis (RA) have expanded with availability of biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs).The updated European League Against Rheumatism (EULAR, from 2021, European Alliance of Associations for Rheumatology) recommendations for the management of RA 2 focusing on pharmacological therapy are similar to those developed by other international organisations.Other recommendations and points to consider (PtCs) provide specific management support on cardiovascular disease (CVD) risk,comorbidities,imaging, 8 pain 9 and patient education.Together with implementation of treat-to-target and tight control strategies, specifically in the early phase of the disease, these have contributed to improved outcomes for the majority of patients with RA. However, some patients with RA do not reach low disease activity or remission and/or remain symptomatic after several cycles of conventional synthetic (cs) DMARDs, bDMARDs and/or tsDMARDs.Such patients may be referred to as having 'difficult-to-treat (D2T)' disease. Optimal management of these patients poses a significant challenge in clinical practice.Hitherto, no specific guidance has been developed for the management of this complex patient population. Therefore, an EULAR Task Force was convened to develop PtCs for the management of D2T RA. # Methods ## Steering committee and task force The convenor (GN) and co-convenor (JMvL) formed the Steering Committee and Task Force that followed the EULAR standardised operating procedures (SOPs).The Steering Committee included the (co-)convenors, a methodologist (DvdH), a co-methodologist (PMJW), a rheumatology postdoctoral fellow (Maria J H de Hair) and three fellows (NMTR, MK and AH). The Task Force comprised the Steering Committee members and another 18 rheumatologists (including 2 EMerging EUlar Network representatives), 3 patient partners, 1 rheumatology nurse, 1 rheumatology occupational therapist, 1 psychologist and 2 pharmacists. All rheumatologists were experienced in the treatment of RA, the majority with significant experience in clinical trials and some also in outcomes research and patient registries. All 34 Task Force members declared their potential conflicts of interest before the start of the project. Two of the Task Force members (Maria J H de Hair and Loriane Gutermann (pharmacist)) left the Task Force during the process, due to new positions, and did not attend the second and third Task Force meetings. ## Target audience In accordance with the EULAR SOP, the primary target audience of these PtCs is healthcare professionals (HCPs) and patients (and their carers).In addition, these PtCs may serve to highlight unmet needs in D2T RA and, therefore, also target policy-makers, pharmaceutical and health insurance companies. ## Definition As an initial step, a definition and a uniform term for the patient population had to be established. The Steering Committee proposed terminology and created a first draft of a definition, guided by the results of the international survey and a scoping literature review.These were discussed with the whole Task Force and amended during the first Task Force meeting (held in August 2018). The final terminology and definition were agreed by a voting process. All Task Force members agreed with 'D2T RA' as the term and the final definition (box 1). ## Clinical questions and systematic literature reviews The Steering Committee formulated the clinical questions for the systematic literature reviews (SLRs). Clinical questions focused on techniques for the confirmation of the diagnosis of RA and/or a relevant differential diagnosis (either as alternative (ie, misdiagnosis) or coexisting disease mimics). Additional questions centred around the assessment of inflammatory activity in patients with RA in general and in those with specific comorbidities, which may influence this assessment, adherence, pharmacological and non-pharmacological therapeutic strategies for different aspects of D2T RA: patients with limited DMARD choices because of adverse events, comorbidities or other contraindications; patients in whom at least two b/ tsDMARD with different mechanisms of action (MOA) failed; and patients with predominantly non-inflammatory complaints (not directly related to inflammation). In addition, the therapeutic role of lifestyle interventions, of goal setting between patients and HCPs and of self-management was assessed. All questions were discussed and finalised during the first Task Force meeting. SLRs on these questions were performed by the fellows (NMTR, MK and AH) under supervision of the co-methodologist (PMJW) in accordance with the EULAR SOP.As other ongoing EULAR projects were already focusing on adherence and lifestyle factors, it was decided not to perform separate SLRs on these topics, but to refer to the respective SLRs and PtCs. For the other questions, PubMed, Embase and Cochrane bibliographic databases were searched for relevant papers until December 2019, as well as EULAR and American College of Rheumatology (ACR) conference abstracts from 2017 up to and including 2019. Relevant papers were selected and critically appraised. Results were summarised, including assessment of risk of bias (RoB).Further details on the methodology and results of the SLRs are published separately. ## Consensus finding Based on the results of the SLRs, draft of overarching principles and PtCs were proposed. The results of the SLRs as well as the proposed overarching principles and PtCs were considered, then presented by the Steering Group and discussed at three consecutive online meetings (the second Task Force meeting was split into three different online meetings) of the Task Force in September 2020 and October 2020. Twenty-five, 30 and 27 Task Force members, respectively, participated in these online meetings. Thereafter, overarching principles and PtCs were discussed and amended. A voting process was applied per PtC. In round 1, a majority of at least 75% was required to accept the PtC. If this was not achieved, the PtC was discussed and amended and subjected to the second ballot. In round 2, a majority of at least 66% was required to accept the rephrased PtC. If this was not achieved, the PtC was discussed and amended again and subjected to the third ballot. In round 3, a majority of at least 50% was required to accept the rephrased PtC. If this was not achieved, the PtC was rejected. After the meeting, the level of evidence (LoE) and strength of recommendations (SoR) according to the Oxford Centre for Evidence-Based Medicine system were determined.The agreed overarching principles and PtCs were distributed among all Task Force members via email to assess their level of agreement (LoA) for each PtC. LoA was anonymously scored on a scale from 0 to 10 (0: completely disagree and 10: completely agree). LoA is shown as mean (SD) and as the proportion of Task ## Recommendation Force members with an LoA of at least 8. Additionally, a research agenda was created. All Task Force members reviewed the draft of the manuscript. Thereafter, the manuscript was submitted to the EULAR Quality of Care Committee and the EULAR Council for review and approval. A third virtual meeting was held in April 2021 to discuss the comments by the EULAR Council, with 30 Task Force members in attendance. The manuscript was revised and the final version was submitted to EULAR and subsequently to the journal. # Results ## General aspects Due to the scarcity of high-quality evidence (table 1), we prepared 'PtCs' for the management of D2T RA. Our PtCs complement current EULAR recommendations that also address elements of management of D2T RA.The SLRs and the formulation of the PtCs predominantly focused on topics not addressed previously and refer to several published 2 6-10 23-25 and ongoing EULAR projects where appropriate.The discussion of the Task Force resulted in 2 overarching principles and 11 PtCs (table 1). The LoE ranged from 3 to 5 and the SoR ranged from C to D, predominantly, because highquality evidence derived in the population of interest was scarce. The LoA was generally high and ranged from 8.4 to 9.6. The order of PtCs was presented in what was considered as logical sequence-in particular the first two PtCs, which serve as a basis for all subsequent items. The PtCs as presented can be used as a clinical roadmap (figure 1). Below, a point-by-point discussion is presented, explaining the reasoning behind the different topics and the supporting evidence. ## Overarching principles The Task Force formulated the following overarching principles. (A) These PtCs pertain to patients who fulfil the definition of D2T RA and are underpinned by the EULAR recommendations for the management of RA including the overarching principles (LoA: 9.6 (1.0)). This principle emphasises the relationship between these PtCs and the EULAR definition of D2T RA.All overarching principles and EULAR recommendations for the management of RA also apply to D2T RA.Patients who fail at least two b/ tsDMARDs with different MOA, and are, therefore, potentially classified as having D2T RA, fall in phase III of the management algorithm of the 2019 EULAR RA management recommendations. These D2T RA PtCs, therefore, provide further guidance on factors contributing to the D2T RA state. The Task Force unanimously agreed with this overarching principle (100% agreed, first round, n=27). (B) The presence or absence of inflammation should be established to guide pharmacological and non-pharmacological interventions (LoA: 9.5 (1.3)). The Task Force emphasised that confirming the presence of inflammatory RA disease activity is essential and should be done prior to adjustment of DMARD therapy. If the persistence of signs and/or symptoms is not caused by RA disease activity, DMARD therapy would in all probability be ineffective and may lead to apparent failure of multiple (b/ts)DMARDs. Concomitant fibromyalgia, osteoarthritis and/or psychological conditions, non-adherence, and comorbidities (eg, infections and malignancies) may contribute to the D2T state. Moreover, when the presence of inflammatory activity has been ascertained, the coexistence and role of these factors should be considered. It was agreed that in the absence of inflammatory activity, DMARD therapy should not be escalated (figure 1), and careful tapering might be considered. This overarching principle was accepted in the second round of the voting process (78% agreed, second round, n=24). ## Points to consider (1) If a patient has a presumed D2T RA, the possibility of misdiagnosis and/or the presence of a coexistent mimicking disease should be considered as a first step (LoE: 5, SoR: D, LoA: 9.3 . An accurate RA diagnosis is the cornerstone of appropriate management. In the SLR, very few studies could be identified on this clinically relevant item. Consequently, this PtC is based on expert opinion, reinforced by indirect evidence. Misdiagnosis (ie, an alternative disease mimic) may be more common in seronegative disease, but should be considered in all patients with D2T RA. Several diseases may mimic ongoing RA disease activity, such as: crystal arthropathies, polymyalgia rheumatica, psoriatic arthritis, spondyloarthritis, Still's disease, systemic lupus erythematosus, Rhupus (RA-lupus) syndrome, idiopathic inflammatory myopathies, vasculitis, remitting symmetric seronegative synovitis and pitting oedema, reactive arthritis (eg, parvo B19, rubella, Whipple's disease and hepatitis B virus (HBV) and hepatitis C virus (HCV) infections), paraneoplastic syndromes, osteoarthritis and fibromyalgia. Furthermore, such other conditions may coexist and underlie signs and/ or symptoms suggestive of active RA. Current RA management approaches may also lead to misdiagnosis. Based on the 'window of opportunity',EULAR and other international guidelines emphasise the importance of early diagnosis and immediate DMARD initiation to achieve optimal and sustained benefit. However, this raises the possibility of misdiagnosis.In this context, an RA treatment approach would inevitably lead to apparent inefficacy and unnecessary risk of toxicity. The Task Force unanimously agreed with this PtC (100% agreed, first round, n=24). (2) Where there is doubt on the presence of inflammatory activity based on clinical assessment and composite indices, ultrasonography (US) may be considered for this evaluation (LoE: 4, SoR: C, LoA: 9.2 . This PtC is linked closely to overarching principle B. In daily practice, composite indices (at patient level) and the clinical evaluation of a joint being swollen (at joint level) are most frequently used to assess the presence of inflammatory disease activity.However, in patients with D2T RA in whom there is a doubt about the presence of inflammation 37 (see also PtC #1), these traditional measures may be difficult to interpret. Limited (high-quality) evidence was found on diagnostics that can be used to assess the presence or absence of inflammatory disease activity in this patient group.When traditional measures are challenging, US appears to be the most feasible measure to detect inflammatory activity both in patients with D2T RA in general and in those with conditions that might compound assessment, such as obesity or concomitant fibromyalgia. In the general population of RA (where composite indices can be considered reliable), moderate-to-strong correlations were reported between US sum scores and composite indices on a group level.In a study in established patients with RA in whom there was explicit doubt about the presence of inflammation, only weak and non-statistically significant correlations between US sum scores and composite indices were found. 46 ## Recommendation This suggests that US may be better related to 'true' inflammatory activity in these patients and may have additional value in patients with D2T RA in whom a doubt about the presence of inflammatory activity exists. However, the minimal number of joints that should be included in an US assessment remains unclear,which hampers the use of a sum score to determine the overall level of disease activity in daily practice. Of note, no studies were found on tests in patients with comorbidities that may influence the assessment of disease activity. The evidence for biomarkers (eg, miR-146, fibrinogen, resistin, matrix metallopeptidase 3, interleukin 6 and multibiomarker disease activity score) and other imaging measures (eg, MRI or optical spectral transmission measures) is currently less convincing. The quality of this evidence was low to moderate and no evidence could be identified on their role in patients in whom there was explicit doubt about the presence of inflammatory activity resulting in indirectness. These limitations hamper the current use of these biomarkers and imaging modalities in daily practice. The Task Force unanimously agreed with this PtC (100% agreed, first round, n=24). ( . ## 3) composite indices and clinical evaluation should be interpreted with caution in the presence of comorbidities ‡, in particular obesity and fibromyalgia § , as these may directly heighten Although the Task Force was unanimous in its opinion that numerous comorbidities might influence the assessment of inflammatory disease activity, substantial evidence was only found for obesity and fibromyalgia. These two conditions may also frequently coexist, further complicating the precise assessment of inflammatory disease activity. Other comorbidities (especially those increasing acute phase reactants: eg, infections, malignancies or polymyalgia rheumatica) may lead to misclassification of inflammatory RA activity, although no substantial evidence was identified to support this. In addition, no evidence was identified regarding the impact of osteoarthritis, subluxation or joint dislocations on clinical evaluation of joints.It should be noted that the identification of synovitis and tenderness due to inflammation is generally more difficult in joints with destruction, since, for example, tenderness could be due to destruction rather than synovitis. The Task Force agreed that this PtC should refer to all potential comorbidities that may influence the evaluation of inflammatory disease activity. The Task Force unanimously agreed with this PtC (100% agreed, first round, n=24). (4) Treatment adherence should be discussed and optimised within the process of shared decision-making (LoE: 5, SoR: D, LoA: 9.5 (1.0)). In RA, drug non-adherence rates reportedly vary between 30% and 80% and these rates are indicated to be substantially higher in patients with D2T RA compared with patients with non-D2T RA.Suboptimal adherence is associated with higher disease activity levels, which may result in inappropriate treatment switches and reduced quality of life.In a patient with D2T RA, this could exhaust all currently available (b/ts) DMARDs. Therefore, the Task Force unanimously agreed that adherence should be addressed as a standalone PtC. Another EULAR project has recently provided detailed PtCs for the detection, assessment and management of non-adherence in people with rheumatic and musculoskeletal diseases (RMDs). We, therefore, refer to their SLR and PtCs. The Task Force agreed to concur with WHO definitions 74 and especially considered 'treatment adherence' instead of 'drug adherence', as the PtC also applies to non-pharmacological strategies. There is no gold standard for identifying non-adherence. Questionnaires or serum and/or urine drug level measurements may be used. If suboptimal adherence is present, this might be explained by various factors; both unintentional (eg, forgetting to take the prescribed drugs) and intentional non-adherence (driven by a decision not to take the prescribed drugs, eg, due to fear of side effects) are common in RA. The patient's evaluation of the risk-benefit ratio of the selected drug(s) is also of paramount importance. Therefore, discussions on adherence remain highly important. In addition to physicians, other HCPs, such as nurses experienced with patients with RA, psychologists and pharmacists, may also be involved in these discussions. Shared decision-making is clearly vital to optimise adherence. In this context, the quality of the relationship between the patient and the HCP is important. As non-adherence is a vulnerable topic, the patient should be made to feel safe and supported to discuss all aspects. In addition, appropriate education, especially in case of intentional non-adherence, would be useful and could strengthen the process of shared decisionmaking (see also PtCs ‡9 and 10). This PtC was accepted in the first round of the voting process (96% agreed, first round, n=28). (5) After failure of a second or subsequent b/tsDMARD ‡ and particularly after two tumour necrosis factor inhibitor (TNFi) failures § treatment with a b/tsDMARD with a different target should be considered ( ‡LoE: 4, SoR: C; § LoE: 3, SoR: C; LoA: 9. . Increasing numbers of b/tsDMARDs (with different MOA) are available for the treatment of RA.Switching within class as well as switching to a drug with a different MOA can be effective. However, a considerable proportion of patients with RA fail at least two b/tsDMARDs with different MOA, which may result in reaching criteria for D2T RA. In routine practice, a trial-and-error approach to DMARD cycling predominates when signs and/or symptoms suggestive active disease are present.In the SLR, only limited evidence was identified on pharmacological therapeutic strategies in patients with RA in whom at least two b/tsDMARDs (specifically with different MOA) failed.Several identified trials in patients with RA in whom multiple b/tsDMARDs failed did not clearly state reasons for previous DMARD failure (eg, toxicity, lack of efficacy or other factors). This resulted in the inclusion of heterogeneous patient populations, complicating interpretation of outcomes. After failure of at least two b/tsDMARDs, some evidence was identified regarding the beneficial effect of treatment with a b/tsDMARD with a different target.This evidence indicated that a third or fourth b/tsDMARD (ie, tocilizumab, tofacitinib, baricitinib, upadacitinib and filgotinib) is more effective than placebo.However, no preference can be given to any of these DMARDs. In patients with failure of at least one prior bDMARD, TNFi, abatacept and rituximab were more effective than placebo, although direct evidence was lacking about the efficacy as third and fourth bDMARD compared with placebo.Where a higher number of prior bDMARDs had been ineffective, the extent of the beneficial effect of several b/tsDMARDs (TNFi and the lower doses of tocilizumab, tofacitinib and baricitinib) was less. Furthermore, a tendency was identified for non-TNFis to be more efficacious than TNFis in patients in whom at least one bDMARD failed (predominantly if TNFi was failed). Our current PtC proposes to switch to a b/tsDMARD of different MOA, after failure of a second or subsequent b/tsDMARD and, particularly, after failure of two TNFis. This PtC was accepted in the first round of the voting process (96% agreed, first round, n=24). The Task Force emphasised that the current PtC is in line with the 2019 EULAR RA recommendation on b/tsDMARD switches. Our PtC adds the following: first, there is value in prescribing another b/tsDMARD after failure of a second or subsequent b/ tsDMARD; and second, a b/tsDMARD with a different MOA is preferred after failure of a second or subsequent b/tsDMARD.Concerning DMARD combination therapy, we refer to the 2019 RA EULAR recommendations, as no additional evidence was identified for D2T RA.(6) If a third or subsequent b/tsDMARD is being considered, the maximum dose, as found effective and safe in appropriate testing, should be used (LoE: 3, SoR: C, LoA: 8. . The extent of the beneficial effect of b/tsDMARDs was generally less in patients in whom a higher number of previous bDMARDs failed.This tendency was not so apparent for upadacitinib and filgotinib, and for the higher doses of tocilizumab (intravenously administered, 8 mg/kg), baricitinib (4 mg once daily) and tofacitinib (10 mg two times per day, although tofacitinib is not licensed at higher doses than 5 mg two times per day because of safety concerns). It should be noted, however, that baricitinib (4 mg once daily) should not be used in patients older than 75 years or those with reduced creatinine clearance (30-60 mL/min). ## Recommendation This suggests that the higher doses of intravenous tocilizumab, and tofacitinib and baricitinib may be preferred in patients in whom previously a higher number of bDMARDs failed. The evidence supports the use of higher doses from the beginning, excepting patients in whom contraindications for this higher dose are present. In addition, it was argued that this PtC might be more informative by including the names of the specific b/tsDMARD (baricitinib and tocilizumab, and not tofacitinib, as tofacitinib is not licensed at higher doses than 5 mg two times per day). The following wording was accepted (95% agreed, first round, n=22): 'If a second or subsequent b/tsDMARD has failed, and baricitinib or iv tocilizumab are being considered, the higher licensed dose should be used if appropriate'. However, it was also discussed that explicitly mentioning drug names (ie, baricitinib and tocilizumab) should be avoided in management PtCs as novel evidence may emerge for other drugs. Therefore, the Steering Committee initiated a new voting after the Task Force meeting regarding this PtC without explicit drug names. The Task Force members agreed to change the wording of the PtC and to exclude the drug names resulting in the current recommendation (94% agreed, second round, n=32).Comorbidities that impact quality of life either independently or by limiting RA treatment options, should be carefully considered and managed (LoE: 5, SoR: D, LoA: 9.3 (0.8)). In clinical practice, comorbidities may significantly limit treatment options, potentially contributing to the D2T state. The Task Force agreed to formulate a PtC on the importance of comorbidities (100% agreed, first round, n=28). We sought evidence about safe and efficacious therapies in patients with such contraindications.No studies were identified for patients with RA with HIV, gastrointestinal disease, latent tuberculosis and malignancies; only limited evidence was identified for patients with RA with extra-articular manifestations, hepatic disease, osteoporosis, psychological distress, pulmonary disease and renal disease. More than one study per intervention was identified only for patients with RA with HBV, HCV (see also PtC #8), CVD, before and during pregnancy and lactation, and obesity. Concerning venous thromboembolisms (VTEs), higher frequencies of VTEs were reported in patients with RA using tsDMARDs at high doses, and in whom risk factors for VTE are present.The Task Force unanimously agreed that in patients at risk for VTEs, tsDMARDs, specifically at high doses, should be used with caution and per drug label recommendations. As this item is covered in the 2019 EULAR RA management recommendations 2 and as the increased risk of VTEs is not specific for patients with D2T RA, the Task Force unanimously decided not to include this item as a standalone PtC (no formal voting). Nevertheless, the increased risk of VTEs should be considered as factor limiting treatment options, particularly for patients with D2T RA with VTE risk factors. Recommendations about safe DMARDs use before and during pregnancy and lactation are published as 2016 EULAR PtCs and as a 2020 ACR guideline. Few additional studies were identified, subsequently on these papers ; therefore, we refer to the existing guidance.Although obesity does not limit drug options per se, treatment efficacy might be different in obese patients. Intravenously administered infliximab may be less effective in patients with a body mass index (BMI) above 30 kg/m 2 compared with those with a BMI below 30 kg/m 2 . The Task Force voted whether this issue should be a standalone PtC. The first vote did not clearly indicate the preference of the Task Force (formulate a separate PtC on this item 58%, n=24). Further discussion noted that evidence for several other comorbidities was lacking or very limited. Two studies of relevance had a high RoB.The repeat vote indicated not to formulate a separate PtC on this item (formulate a separate PtC on this item: 12%, n=24). Clinically meaningful contraindications of some therapies may result in limited treatment options, for example, tocilizumab in case of diverticulitis or janus kinase (JAK) inhibitors in case of repeated herpes zoster infections.However, no substantial clinical evidence was identified about safe and/or efficacious therapies for patients with these conditionsand, therefore, no specific PtCs were formulated. A broad range of comorbidities and coexisting conditions were discussed at the Task Force meeting but are not explicitly part of the PtCs due to the lack of evidence. 21In patients with concomitant HBV/HCV infection, b/ tsDMARDs can be used ‡ and concomitant antiviral prophylaxis or treatment should be considered in close collaboration with the hepatologist § ( ‡LoE: 4, SoR: C, § LoA: 5; SoR: D, . Substantial evidence was identified related to HBV and HCV infections prompting a standalone PtC.TNFi, abatacept and tocilizumab may be considered in patients with HBV,and TNFi in patients with HCV. Furthermore, no evidence was identified regarding other b/tsDMARDs, but this does not indicate that these b/tsDMARDs are unsafe to use. Therefore, the Task Force voted not to include specific b/tsDMARDs in the PtC (83% agreed, n=24). Furthermore, the Task Force agreed that concomitant antiviral prophylaxis should be considered,and that the treatment should be conducted in close collaboration with the hepatologist. The Task Force unanimously agreed with this PtC (100% agreed, first round, n=24). It should be noted that concomitant antiviral prophylaxis is appropriate for HBV infection in case of HCV infection, antiviral treatment is necessary. (9) In addition to pharmacological treatment, nonpharmacological interventions (ie, exercise ‡, psychological § , educational ‡ and self-management interventions †) should be considered to optimise management of functional disability, pain and fatigue ( ‡LoE: 3, SoR: C; § LoE: 4, SoR: C; LoA: 9.4 (1.2)). A wide spectrum of factors may contribute to the persistence of signs and/or symptoms, although these are not always directly related to inflammation (eg, functional disability, pain and fatigue). Individually tailored non-pharmacological interventions are also important components of the management of D2T RA. The SLR focused on non-DMARD interventions to improve non-inflammatory complaints in patients with RA who do not clearly have active inflammatory disease.It is not always possible to disentangle inflammatory and non-inflammatory symptoms in clinical practice. Non-pharmacological interventions should also be considered in all patients with D2T RAand not only in those patients without inflammatory RA activity. Evidence emerged regarding the beneficial effect of exercise, education, psychological and self-management interventions to improve pain, fatigue and functional disability in RA, while substantial evidence regarding the role of non-pharmacological interventions to improve quality of life was lacking.Benefit of exercise in RA is well establishedand was specifically found to improve physical functioning. A wide range of physical activities might be advised in accordance with the patients' status, for example, aerobic exercises, water-based dynamic exercises, muscle strengthening or hand exercises.Psychological interventions could be applied, specifically to reduce pain and fatigue, for example, cognitive behavioural therapy and interventions focusing on stress management. Furthermore, patient education can assist patients in learning about their disease and management options (see also PtCs #4, 9 and 10)and was specifically found to improve physical functioning.Education can be provided one on one, but also in group sessions promoting patients to learn from each other. Lastly, selfmanagement programmes can be applied. These programmes are typically a combination of different non-pharmacological interventions (eg, exercise and education) and were found to optimise the management of pain, fatigue and functional disability (see also PtCs #9 and 10). Ideally, a package of care (ie, multimodal treatment) should be considered in accordance with the patient's needs and preferences. This individually tailored multimodal treatment can be provided by different members of the rheumatology team (eg, rheumatologists, rehabilitation physicians, nurses experienced with patients with RA, physiotherapists, occupational therapists, psychologists, pharmacists and podiatrists). The Task Force unanimously agreed with this PtC (100% agreed, first round, n=29). (10) Appropriate education and support should be offered to patients to directly inform their choices of treatment goals and management (LoE: 4, SoR: C, LoA: 9.4 (1.2)). Setting treatment goals is central in the management of RA. In the current EULAR RA management recommendations, clinical remission or at least low disease activity is the ideal target with adjustment of therapeutic strategies if there is no improvement at 3 months or if the treatment target is not achieved at 6 months (recommendation #3).These treatment targets may be unrealistic to achieve for patients with D2T RA, considering their disease history, accrued joint damage and other factors that may contribute to the D2T RA state,and lead to unnecessary DMARD switches. Accordingly, in D2T RA, treatment goals should be tailored to the individual patient. Discordance in a given set target between the patient and HCP could negatively impact disease outcomes.The SLR did not find a diagnostic method to identify a mismatch in treatment goals (between HCP and patient with RA).Treatment goals should be discussed to be able to identify a mismatch in treatment goals and to optimise goal setting in shared decision-making. Web-based education tools improve patients' knowledge and certainty in treatment decisions. Such tools could be used in addition to providing information via usual discussions. As perceptions on treatment goals and management may change over time continuous education between patients and HCPs remains important. This PtC was accepted in the first round of the voting process (89% agreed, first round, n=28). . Self-efficacy refers to patients' ability to control or manage various aspects of their disease and has a major role in the well-being of patients.Self-efficacy beliefs determine how individuals think, feel and act, and are an important aspect of self-management. People with low self-efficacy quickly give up their goals when faced with difficulties and are at higher risk of worse levels of pain, fatigue, depression, anxiety and stress.All this may contribute to the D2T RA state. In contrast, a strong sense of self-efficacy improves human performance and well-being in several ways, promotes the accomplishment of challenging goals and supports commitment to them.Improved self-efficacy may not only improve disease outcomes such as mental well-being but may also improve many aspects of health behaviour, including treatment adherence and willingness to change lifestyle factors. Therefore, strengthening self-efficacy is specifically important in D2T RA. The Arthritis Self-Efficacy Scale (ASES), a tool to measure perceived self-efficacy to cope with the disease,was found as the most reliable measure of self-efficacy. However, the ASES is perhaps too general to evaluate self-efficacyand cutoffs for suboptimal self-management are not well-validated, so a standalone PtC regarding its application was not pursued (89% agreed, n=27). There was consensus that the ASES may be used as a screening instrument and to assess the change in self-efficacy over time. The Task Force considered it challenging to clearly define what constituted a suboptimal level of self-efficacy and agreed that offering interventions to improve self-efficacy could be beneficial for all patients with D2T RA. The SLR identified self-management programmes, educational interventions and psychological interventions to have a beneficial effect on self-efficacy.Some evidence suggested patients would like more education on disease processes. Educational interventions, for example, individual education, a group education programme or education through a mobile app, specifically improved self-efficacy and RA knowledge. Psychological interventions, for example, cognitive behavioural therapy or relaxation therapy, not only improve self-efficacy, but may also reduce symptoms related to anxiety and depression. Self-management programmes (ie, typically a combination of different nonpharmacological interventions) were also found to be effective in improving self-efficacy. In addition, mobile health applications may improve self-management.The Task Force thoroughly debated if these interventions should be offered to every patient (mandatory) or should be considered only (optional). The Task Force agreed that selfmanagement programmes should be optional (agreed 82%, n=28). If a patient wishes to improve their self-efficacy, a shared decision-making that captures the patient's status and preferences should decide the type of intervention. This PtC was accepted in the first round of the voting process (96% agreed, first round, n=28). ## Research agenda The Task Force created a research agenda containing research questions that are considered most relevant to address. # Discussion The term 'D2T RA' has recently been defined to characterise a heterogeneous group of patients with RA with persistent signs and symptoms. While the typical patient with D2T RA is characterised by longstanding disease and structural damage in whom (b/ts)DMARDs have been ineffective (multidrug resistant or 'true refractory' RA), this only represents a subgroup of this heterogeneous patient population. Identification of all factors potentially contributing to D2T RA warrants a holistic management approach and is essential in order to tailor management strategies to the individual patient. D2T RA constitutes an area of unmet need, which motivated our Task Force to develop a roadmap for clinical decision-making by HCPs and patients laid out in the current PtCs on diagnostic challenges and pharmacological and non-pharmacological therapeutic strategies (summarised in . The PtCs promote individually tailored treatment interventions by addressing specific aspects of b/tsDMARD selection (including in patients with comorbidities and coexisting conditions) and non-pharmacological interventions to improve Recommendation adherence, functional disability, pain, fatigue, goal setting and self-efficacy. Although some of these PtCs may seem self-evident, our purpose in offering this PtC is to promote the need to address each of them in D2T RA management strategies. This approach mitigates against both overtreatment as well as undertreatment. Although the Task Force aimed to cover all potential aspects of D2T RA, not all relevant topics were addressed in the SLRs because of overlap with previous or ongoing EULAR projects (eg, treatment non-adherence, lifestyle factors, pain syndromes and osteoarthritis, see below). Joint replacement and reconstructive surgery, both of which may have relevance in D2T RA, were not included in the systemic literature search, as these were considered out of scope. There was no substantial evidence identified regarding non-steroidal-anti-inflammatory drugs and analgesics in the context of D2T RA.For a few topics, the Task Force members considered a theme particularly relevant in the context of D2T RA as to merit highlighting herein. For instance, education is already addressed in separate EULAR recommendations 10 but is crucial in the management of D2T RA ( § 4 and 9-11). Additionally, treatment non-adherence is common in patients with RMDs and may also contribute to the D2T RA state ; therefore, it has also been addressed in the D2T RA PtCs (#4). Additional guidance on treatment non-adherence can be found in the recently published EULAR PtCs for the detection, assessment and management of non-adherence in people with RMDs.Furthermore, lifestyle factors, including diet, lack of exercise, smoking and alcohol consumption, might also be associated with D2T disease. Therefore, the management of lifestyle factors in patients with D2T RA was raised as a clinically relevant issue at our first Task Force meeting and resulted in the formulation of a research question on this topic. However, an ongoing EULAR project is focusing on lifestyle behaviour PtCs to prevent progression of RMDs and will be published soon. The Task Force, therefore, decided to refer to these PtCs for the management of these factors, as evidence in patients with D2T RA specifically was expected to be lacking. Concomitant fibromyalgia and other pain syndromes as well as osteoarthritis may coexist in patients with D2T RA and may (partly) explain the persistence of signs and/or symptoms suggestive of active disease. Because previous EULAR projects focused on these conditions, it was decided to refer to their recommendations. Guidance on the management of these coexisting conditions can be found in the 'EULAR revised recommendations for the management of fibromyalgia','EULAR recommendations for the health professional's approach to pain management in inflammatory arthritis and osteoarthritis','2018 update of the EULAR recommendations for the management of hand osteoarthritis'and 'EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis'.One of the main conclusions of the SLRs was the scarcity of high-quality direct evidence regarding D2T RA. This is not surprising, considering the recent establishment of the EULAR definition of D2T RA.However, indirect evidence (ie, in patients with RA in whom at least two b/tsDMARDs failed, especially with different MOA) was also scarce and the quality was generally low to moderate. This lack of (high-quality) direct evidence can be seen as a limitation of these PtCs, but also as a stimulus for future studies to address patients with D2T RA specifically. Importantly, the heterogeneity of D2T RA should be considered when conducting such studies, as not all management strategies will be helpful in all patients with D2T RA. Selecting the appropriate patient population will, therefore, be crucial in order to obtain relevant results (see also table 2). As new evidence regarding D2T RA emerges, the PtCs on the management of D2T RA will need to be updated. In summary, the evidence as identified in the SLRs together with expert opinion have resulted in a comprehensive set of overarching principles and PtCs for the management of D2T RA, promoting a holistic management approach and individually tailored pharmacological and non-pharmacological therapeutic strategies. Although high-quality evidence was scarce, these PtCs can be seen as a clinical roadmap and will provide assistance to HCPs and patients in the management of D2T RA. A research agenda was created to support future research in this emerging field. 14 What is the role of therapeutic drug monitoring to in the management of DT RA? *For example, infections (HIV and TB); malignancies; lung disease (fibrosis, asthma and COPD); CVD (hypertension and cardiomyopathy); hyperlipidaemia; chronic kidney dysfunction; chronic liver dysfunction; liver enzyme elevation; osteoporosis; diabetes mellitus; thrombosis; depression and anxiety. b/tsDMARDs, biological or targeted synthetic disease-modifying antirheumatic drugs; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; D2T, difficult-totreat; RA, rheumatoid arthritis; TB, tuberculosis.	None	https://ard.bmj.com/content/annrheumdis/81/1/20.full.pdf	Objective To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA). Methods An EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A–D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0–10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members. Results Two overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4–9.6). Conclusions These PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research.
49ab1e26b2baf0594658783cff6eca86c36ac2a7	pubmed	Management of lateral skull base cancer: United Kingdom National Multidisciplinary Guidelines	Management of lateral skull base cancer: United Kingdom National Multidisciplinary Guidelines This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition.Recommendations- All patients with more than one of: chronic otalgia, bloody otorrhoea, bleeding, mass, facial swelling or palsy should be biopsied. (R) - Magnetic resonance and computed tomography imaging should be performed. (R) - Patients should undergo audiological assessment. (R) - Carotid angiography is recommended in select patients. (G) - The modified Pittsburg T-staging system is recommended. (G) - The minimum operation for cancer involving the temporal bone is a lateral temporal bone resection. (R) - Facial nerve rehabilitation should be initiated at primary surgery. (G) - Anterolateral thigh free flap is the workhorse flap for lateral skull base defect reconstruction. (G) - For patients undergoing surgery for squamous cell carcinoma, at least a superficial parotidectomy and selective neck dissection should be carried out. (R)Assessment and stagingClinical examination Confirmation of diagnosis is mandatory before treatment and is gained by biopsy of the pinna, skin, EAM or ME. Advanced parotid cancers should be diagnosed through cytopathology or, occasionally if necessary, incision biopsy. Tumours of the infratemporal fossa often will require a surgical biopsy via access superior or inferior to the zygoma as necessary. Cytology is possible, but, as many tumours here are sarcomas, histopathology is required. The differential # Introduction Primary cancers of the temporal bone (TB) and lateral skull base are comparatively rare, accounting for 0.2 per cent of all head and neck cancers. They consist of different sites of cancer with a range of pathologies. Consequently, there is little evidence as to best practice. Over ten times more frequent are cancers of the skin and parotid invading the TB. Despite this there is even less evidence of best practice. Lateral skull base cancer can be considered to comprise any of the entities described in [fig_ref] TABLE I ENTITIES: THAT COME UNDER THE CATEGORY OF LATERAL SKULL BASE CANCER [/fig_ref]. ## Clinical presentation Late diagnosis of patients with cancers of the external auditory meatus (EAM) and middle ear (ME) is not uncommon and this should be considered in any patients with: chronic otalgia, bloody otorrhoea, bleeding, mass, facial swelling or palsy. [bib_ref] Squamous cell carcinoma of the temporal bone: outcomes of radical surgery and..., Leong [/bib_ref] Clinical findings of excoriation, ulceration and granulation tissue should be considered as suspicious. Some patients may have a long history of chronic middle or external ear infection, which can be a pre-disposing factor. Skin cancers present as visible or itchy skin and/or pinna lesions. Tumours of the infratemporal fossa may present with a subtle mass or fullness immediately above the zygoma or with pain (which can be easily misdiagnosed as temporal mandibular joint pain). diagnosis is myriad, but care must be taken to exclude pseudotumoral skull base osteomyelitis of the TB (also called necrotising otitis externa) and inflammatory diseases such as granulomatosis with polyangiitis. ## Imaging considerations In most cases, both computed tomography (CT) and magnetic resonance imaging (MRI) should be used. Computed tomography (fine cut, high resolution) is essential for external auditory canal (EAC) erosion, extent of middle ear and mastoid involvement, spread into jugular bulb, carotid canal, tegmen, temporomandibular joint (TMJ), parotid and beyond. It can also stage the neck. Magnetic resonance differentiates mucosal swelling or mastoid fluid from tumour; is superior at ascertaining dural or brain involvement; and gives more detail of parapharyngeal space and infratemporal fossa involvement. Despite high-resolution scanning using both modalities, both over and under estimation of the extent of the tumour occurs. Patients should be prepared for more extensive surgery or abandoning surgery if the scans prove wrong. Depending on the pathology of the tumour, imaging of the thorax (squamous cell carcinoma (SCC)) or whole body may be required (sarcomas, melanoma). Carotid angiography and balloon occlusion are occasionally required to assess ipsilateral carotid artery involvement. If a tumour is thought unresectable without internal carotid artery sacrifice, then a temporary balloon occlusion test can be performed. If successful, permanent pre-operative occlusion via coils can be performed (ideally two weeks pre-operatively). ## Audiology Pure tone audiogram of both ears should be performed pre-operatively. ## Pre-treatment staging There is no Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) staging system for cancers of the TB or lateral skull base. However, many use the revised Pittsburgh staging system [fig_ref] TABLE I ENTITIES: THAT COME UNDER THE CATEGORY OF LATERAL SKULL BASE CANCER [/fig_ref]. The standard UICC staging is used for neck and distant metastases. ## Recommendations - All patients with more than one of: chronic otalgia, bloody otorrhoea, bleeding, mass, facial swelling or palsy should be biopsied (R) - Magnetic resonance and CT imaging should be performed (R) - Patients should undergo audiological assessment (R) - Carotid angiography is recommended in select patients (G) - The modified Pittsburg T-staging system is recommended (G) Treatment planning and prognosis There should be a specific multidisciplinary team (MDT) dealing with skull base cancers. For sarcomas, there should be liaison with the sarcoma MDT, and, for paediatric sarcomas, with the paediatric oncology MDT. Most patients with operable cancer of the lateral skull base are treated with primary surgery, with the exception of some sarcomas. Given the low incidence of lateral skull base cancer, the variety of precise sites of origin, heterogeneity of tumour pathology and individual circumstance, it is difficult to generalise treatment guidelines. The commonest scenarios are of SCC arising in the ear or TB (ME and/or EAM) and advanced parotid cancers. The situation of advanced cutaneous SCC invading the TB is not materially different. [bib_ref] Lateral temporal bone resection in advanced cutaneous squamous cell carcinoma: report of..., Essig [/bib_ref] Cancers arising in the temporal bone General principles For cancer arising in the TB, the most favourable survival rates are achieved with an en bloc extended TB resection and post-operative radiotherapy (RT). [bib_ref] Guidelines for treating temporal bone carcinoma based on long-term outcomes, Bacciu [/bib_ref] [bib_ref] Squamous cell carcinoma of the temporal bone: clinical outcomes from radical surgery..., Masterson [/bib_ref] [bib_ref] Cancer of the external auditory canal and middle ear in Denmark from, Madsen [/bib_ref] The influence of ME involvement on prognosis is critical. T1 and T2 lesions lateral to the tympanic membrane have cure rates near to 100 per cent with true enbloc resections without breach of the tumour. The majority of T3 tumours are also cured with disease specific survival rates over 70 per cent, whereas T4 five-year survival results vary between 30 and 50 per cent. [bib_ref] Squamous cell carcinoma of the temporal bone: outcomes of radical surgery and..., Leong [/bib_ref] [bib_ref] Squamous cell carcinoma involving the temporal bone: lateral temporal bone resection as..., Lassig [/bib_ref] [bib_ref] Analysis of 95 cases of squamous cell carcinoma of the external and..., Yin [/bib_ref] Nodal metastasis has a major influence on prognosis. [bib_ref] Squamous cell carcinoma of the temporal bone: clinical outcomes from radical surgery..., Masterson [/bib_ref] [bib_ref] Primary squamous cell carcinoma of the external auditory canal: surgical treatment and..., Mazzoni [/bib_ref] Equally critical for prognosis is a histologically-proven complete microscopic resection. [bib_ref] Guidelines for treating temporal bone carcinoma based on long-term outcomes, Bacciu [/bib_ref] [bib_ref] Analysis of 95 cases of squamous cell carcinoma of the external and..., Yin [/bib_ref] Extension superiorly through the tegmen leads to dural and cerebral involvement. Dural involvement is an adverse prognostic indicator, but around one-third of such patients are curable with the appropriate surgery. [bib_ref] Squamous cell carcinoma of the temporal bone: clinical outcomes from radical surgery..., Masterson [/bib_ref] Cerebral involvement rarely confers any chance of cure. On the other hand, T4 tumours that are T4 by virtue of anterior invasion to the TMJ and/or pre-auricular tissue have a much better prognosis than other T4 tumours. [bib_ref] Primary squamous cell carcinoma of the external auditory canal: surgical treatment and..., Mazzoni [/bib_ref] Resection of the intra-petrous carotid is possible. Some patients can benefit from pre-operative radiological permanent occlusion of the carotid artery, subject to successful balloon occlusion. However, the cancer-mortality in this group of patients with petrous apex involvement is high, due to difficulties achieving full microscopic resection around this area, and the post-operative morbidity is high due to, amongst other things, multiple cranial nerve deficits from a resection of this extent. Thus, for patients with a combination of high morbidity with low chance of surgical cure, consideration should be given not to offer primary surgery. [bib_ref] Squamous cell carcinoma of the temporal bone: clinical outcomes from radical surgery..., Masterson [/bib_ref] Temporal bone surgery Lateral temporal bone resection (LTBR) should be regarded as the minimum oncological operation for T1 and T2 lesions [bib_ref] Squamous cell carcinoma of the temporal bone: clinical outcomes from radical surgery..., Masterson [/bib_ref] [bib_ref] Evidence-based surgical management of T1 or T2 temporal bone malignancies, Zhang [/bib_ref]. Essential elements of LTBR are (1) excision lateral to facial nerve; (2) conchal bowl resection; and (3) bony cuts: mastoid to middle fossa dura (or leaving a thin layer of bone), anteriorly into zygomatic aircells and TMJ, inferiorly to stylomastoid foramen, hypotympanum to TMJ. Additional options include (see below): resection of entire pinna and periauricular skin; condyle/mandible, parotid, extension of resection into parapharyngeal space and infratemporal fossa, neck dissection, facial nerve sacrifice and cable graft. Extended temporal bone resection (ETBR) is required for more extensive tumours involving the middle ear [bib_ref] Treatments and outcomes of malignant tumors of external auditory canal, Chang [/bib_ref]. The essential elements of EBTR are (1) facial nerve sacrifice; (2) posterior and middle craniotomy; (3) labyrinthectomy; (4) transection of internal auditory canal; (5) resection of petrous tip; (6) exposure of intra-petrous portion of the carotid; and (7) total parotidectomy. Additional options include: craniectomy (squamous TB; sphenoid wing, posterior fossa); mandibulectomy; parapharyngeal and/or infratemporal fossa resection; extension to jugular foramen; lower cranial nerve sacrifice; internal carotid artery; dura; brain. ## Recommendation - The minimum operation for cancer involving the temporal bone is a lateral temporal bone resection (R) ## Resection of other structures in tb surgery Parotid gland. When performing TB resections for TB cancers and advanced skin cancers, the parotid gland may be either involved directly by tumour or be harbouring intra-parotid lymph node metastases (it may contain the primary echelon lymph node). The former may be suggested by pre-operative scans. Therefore, for all resections, at least a superficial parotidectomy should be carried out. [bib_ref] Evidence-based surgical management of T1 or T2 temporal bone malignancies, Zhang [/bib_ref] For advanced T3/T4 TB SCCs, total parotidectomy should be carried out, which also facilitates access to the parapharyngeal space, infratemporal fossa and masticator space. For basal cell carcinoma (BCC) without evidence of direct invasion into or near the parotid gland, parotidectomy can be omitted. Temporo-mandibular joint/mandible. The standard anterior bony cut in a lateral TB resection goes into the TMJ. There is therefore some degree of disruption of TMJ function as a consequence. If there is involvement of or near the TMJ/condyle, it is recommended that a partial mandibulectomy is carried out, which may range from condylectomy to resection from mandibular notch to angle. If the latter is done, the inferior alveolar nerve should be preserved, if oncologically sound to do so. There is, however, no need for routine resection to include the TMJ in lateral temporal bone resection (LTBR). 5 ## Temporal bone resection in parotid cancers Almost all parotid cancers abutting the TB are easier to remove if an inferior TB resection is done to get medial and posterior to the tumour rather than finding the facial nerve outside the stylomastoid foramen and getting too close to the tumour. This improvement in surgical access both improves prognosis and ease of facial nerve grafting if required. [bib_ref] Outcomes of temporal bone resection for locally advanced parotid cancer, Mehra [/bib_ref] [bib_ref] Parotid metastatic disease from cutaneous squamous cell carcinoma: prognostic role of facial..., Shao [/bib_ref] For parotid tumours with EAM or TB involvement, at least a lateral TB resection will be required. ## Facial nerve Facial nerve involvement by tumour is a significant adverse prognostic factor. Pre-operative facial nerve dysfunction due to facial nerve involvement by tumour requires sacrifice of the nerve as part of the resection required. For some patients with normal function pre-operatively, it may be technically impossible to resect a tumour without nerve sacrifice if the nerve is totally encased by tumour, bearing in mind the aim of surgery is complete, preferably monobloc, tumour resection with margins. When the facial nerve is sacrificed, the proximal stump at the limit of the sacrifice should be sent for frozen section pathology. In cases in which nerve sacrifice is necessary, one or more of the following steps should be considered detailed below. It should be borne in mind that the best time to perform many of these interventions is at the time of tumour resection, as virtually every patient in this group will go on to have post-operative RT. A cable graft from ME facial nerve to intra-parotid branches can be performed if (a) there is enough proven tumour-free proximal facial nerve (otherwise a facial-hypoglossal anastamosis can be considered) and (b) if the peripheral branches can be identified (this may be difficult when a radical en-bloc parotidectomy with overlying skin is performed). Useful donor nerves include greater auricular nerve, sural nerve or lateral cutaneous nerve of thigh (easily available if harvesting an anterolateral thigh free flap). If an alternative lengthening of telomeres (ALT) free flap is to be employed, this can be used as a chimaeric flap, with separate components for volume restoration and facial function and vascularised interposition nerve grafting. Otherwise, either static procedures can be employed such as fascia lata sling for oral commissure/cheek suspension or dynamic procedures such as lengthened temporalis myoplasty (e.g. Labbé type I or II), if the deep temporal nerve and artery are preserved. Oculoplastic interventions (e.g. gold weight, canthoplasty) can be performed at the time of tumour resection or later on. ## Recommendation - Facial nerve rehabilitation should be initiated at primary surgery (G) ## Reconstruction The aims of reconstruction of lateral skull base defects can be considered hierarchically: - Protection for the brain when the dura mater is breached. - Skin defect. - Auricular defect. - Tissue volume defect and mandible defect. - Functional defect-facial nerve. Dural defects are normally repaired with non-vascularised tissue such as autologous fascia lata grafts, pericardial xenografts or synthetic materials. Reconstruction of the skin defect should be considered with the volume defect, this being determined by extent of temporal bone resection, parotidectomy and mandibulectomy in particular. [bib_ref] Comprehensive management of temporal bone defects after oncologic resection, Hanasono [/bib_ref] For smaller skin defects without much volume loss, options include radial forearm free flap, cervicofacial rotation flap, temporalis flap and supraclavicular artery island flap. These can be used to reconstruct small skin/auricle defects with modest volume loss. For most defects after temporal bone resection, the anterolateral thigh free flap offers optimal reconstruction, offering bulk (variable by the inclusion of vastus lateralis), and enough skin for most defects (which can be reduced by de-epithelialisation if the auricle is not resected). 14 It is reliable, has the requisite tissue and minimal donor site morbidity. It allows vascularised fascia lata to be used for static facial resuspension or the lateral cutaneous femoral nerve for either sensory innervation of the flap or an interpositional facial nerve graft. Also, the accessible donor site allows for concomitant flap harvest and tumour ablation. Alternative flaps include latissimus dorsi, rectus abdominis or deep inferior epigastric artery perforator, radial forearm, medial sural artery and lateral arm flaps. In a vessel-depleted neck or in a patient unsuitable for microvascular surgery, lower trapezius muscle island flap (if the transverse cervical vessels are intact) or superior trapezius flap (when a radical neck dissection has been performed) can be used. The use of pectoralis major or delto-pectoral flap is suboptimal as the lateral skull base is at or beyond the limits of rotation in many cases. It is feasible to leave selected condylar resections unreconstructed accepting minor dental occlusal disturbance. Where mandibular reconstruction is required, a composite microvascular flap such as a chimeric thoracodorsal artery perforatorscapular osteomusculocutaneous flap can restore a large mandibular and lateral skull defect. ## Recommendation - Anterolateral thigh free flap is the workhorse flap for lateral skull base defect reconstruction (G) ## Neck dissection Up to 20 per cent of patients with temporal bone SCC will have lymph node metastases. The need for neck dissection depends on the pathology. As for any head and neck cancer, clinically or radiologically staged N + necks require comprehensive neck dissection, but level 1a (submental) can be spared. In the setting of N0 neck, it is also recommended that neck dissection (levels 1b, 2-5) is performed for all temporal bone SCC. [bib_ref] Nodal disease in temporal bone squamous carcinoma, Rinaldo [/bib_ref] The same applies to advanced parotid carcinomas with temporal bone involvement. JJ HOMER, T LESSER, D MOFFAT et al. ## S122 ## Recommendation - For patients undergoing surgery for squamous cell carcinoma, at least a superficial parotidectomy and selective neck dissection should be carried out (R) ## Radiation therapy Post-operative RT Most T2-T4 SCCs will require post-operative RT, 5 as will advanced parotid cancers requiring temporal bone surgery. T1 and selected T2 SCCs without adverse histological features (particularly peri-neural infiltration) and with proven clear margins may not require adjuvant therapy. Dosimetry with electrons is unpredictable due to tissue heterogeneity and photon therapy is preferred using three-dimensional conformal or intensity modulated techniques (IMRT). The clinical target volume is determined from pre-operative imaging and further informed from MDT feedback on operative and histopathological findings. Conformal RT is computer planned and the target volume often resembles a transaxial triangular shape with the base laterally. A simple pair of horizontal wedged lateral oblique fields may suffice, with beams exiting on either side of the contralateral parotid. An additional lateral field with vertical wedging may improve homogeneity longitudinally. Intensity modulated techniques may well reduce dose to the ipsilateral cochlea (if this is separate from the tumour volume) and oral cavity. Chronic otomastoiditis and TB necrosis following RT can be reduced by restricting the volume of bone treated to high dose as far as possible. The contralateral parotid, bilateral submandibular glands, oral cavity, mandible, cochlea as well as central nervous system (CNS) structures should be routinely contoured and given constraint doses. Post-operative doses used for head and neck cancer are 60 Gy in 30 fractions for moderate risk and 66 Gy in 33 fractions for high risk; these doses can potentially be applied for lateral skull base cancers, but the normal tissue (particularly CNS) complication rate is clinically significant at doses above 60 Gy. Synchronous postoperative treatment with cisplatin can be also considered. [bib_ref] Chemoradiation therapy for squamous cell carcinoma of the external auditory canal: a..., Takenaka [/bib_ref] Primary RT When primary surgery is not considered possible, or too morbid, definitive RT may be used, with overall cure rates of just under half of patients overall. [bib_ref] Chemoradiation therapy for squamous cell carcinoma of the external auditory canal: a..., Takenaka [/bib_ref] Clinical target volume is based on staging imaging, preferably with both CT and MR imaging (MRI). Higher biological doses are used compared with the post-operative setting so that optimal conformality is essential to reduce treatment complications. Standard IMRT doses can be used: 66 Gy in 30 fractions for macroscopic disease, 60 Gy for high risk microscopic areas and 54 Gy for moderate risk microscopic areas; these doses may be modified according to the volume of CNS tissue in the clinical target volume. In view of the emphasis on conformality, there may well be a role for proton beam therapy in some cases. Synchronous treatment with cisplatin can be considered; an alternative strategy is to use cetuximab. Other lateral skull base cancer operations Tumours of the infratemporal fossa are more rare and heterogeneous and thus need an individualised operative approach. Examples include facial translocation, sub-temporal pre-auricular, orbito-zygomatic and trans-TB (Fisch) approaches. [bib_ref] Subtemporal-preauricular infratemporal fossa approach to large lateral and posterior cranial base neoplasms, Sekhar [/bib_ref] [bib_ref] Craniofacial disassembly in the management of skull-base tumors, Nuss [/bib_ref] [bib_ref] Facial translocation approach in the management of central skull base and infratemporal..., Suarez [/bib_ref] [bib_ref] Preauricular transmandibular and transzygomatic approach for tumors of the infratemporal fossa revisited, Timoshenko [/bib_ref] Post-operative care issues In addition to VII nerve issues, all lower cranial nerves essential for swallowing and voice (IX, X, XII) are at risk of injury or sacrifice in surgery for advanced tumours. Care of the patient in this situation must include close involvement of speech and language therapy. Interventions include either pre-or postoperative percutaneous gastrostomy; naso-gastric tube; tracheostomy if aspirating on saliva. Later interventions include vocal cord medialisation and cricopharyngeal myotomy. Ipsilateral total or total conductive hearing deficit is an inevitable outcome of TB resection. Pre-operative audiological assessment of the contralateral ear will identify patients with a pre-existing deficit. This may be corrected or improved with appropriate aiding in either the pre-or post-operative period. Total conductive hearing loss can be rehabilitated through an osseointegrated bone anchored hearing aid (BAHA). Total hearing loss can be rehabilitated through either a BAHA or a bilateral contralateral routing of signals (BI-CROS) aid. Post-operative vertigo is expected if there is resection of a functioning labyrinth. If vestibular compensation is protracted and incomplete, referral for vestibular rehabilitation services should be considered. ## Palliative care The local issues that affect patients when tumours are inoperable or recur are generally pain (particularly through dural involvement) and fungation. Therefore, the instigation of a comprehensive analgesic regimen is required. Fungation can be a particular problem, made worse by the prominent site of the cancer. Radiotherapy can be given for palliative intent, if not already given, and can be useful for both pain and fungation. Short fractionation schedules may well be appropriate in these situations using, for example, 30 Gy in 10 fractions and a single lateral megavoltage photon field. If RT has previously been given and there is a reasonable interval (more than 12 months), then reirradiation is sometimes beneficial. ## Key points - Cancer of the lateral skull base is rare and constitutes a heterogeneous group of cancers and sites of origin - Most cancers are treated with primary surgery and post-operative radiotherapy - For temporal bone cancers, the boundary of the tympanic membrane is paramount in prognosis. Most T1 and 2, and many T3 cancers are cured - The minimum operation for a temporal bone cancer should be a lateral temporal bone resection - Lateral temporal bone resection should be considered in advanced parotid cancers - Achieving clear microscopic margins at surgery is critical - Salvage surgery is often not successful: the best, and usually only, chance of cure is at initial surgery - For patients with advanced cancers, particularly at the petrous apex or with dural or facial nerve involvement, cure rates drop considerably - For patients with advanced cancers undergoing surgery, there are many rehabilitation issues - The anterolateral thigh free flap is the workhorse for reconstruction. [table] TABLE I ENTITIES: THAT COME UNDER THE CATEGORY OF LATERAL SKULL BASE CANCER [/table]	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/51BD36080E19C45C30146CEF7B29CA33/S0022215116000542a.pdf/div-class-title-management-of-lateral-skull-base-cancer-united-kingdom-national-multidisciplinary-guidelines-div.pdf	Abstract This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition. Recommendations • All patients with more than one of: chronic otalgia, bloody otorrhoea, bleeding, mass, facial swelling or palsy should be biopsied. (R) • Magnetic resonance and computed tomography imaging should be performed. (R) • Patients should undergo audiological assessment. (R) • Carotid angiography is recommended in select patients. (G) • The modified Pittsburg T-staging system is recommended. (G) • The minimum operation for cancer involving the temporal bone is a lateral temporal bone resection. (R) • Facial nerve rehabilitation should be initiated at primary surgery. (G) • Anterolateral thigh free flap is the workhorse flap for lateral skull base defect reconstruction. (G) • For patients undergoing surgery for squamous cell carcinoma, at least a superficial parotidectomy and selective neck dissection should be carried out. (R)
4bc6d3b17436e3580b56ea05d0ed01921a3e76f4	pubmed	KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors	KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors # Introduction Living kidney donation has become essential in increasing the donor pool as kidney transplant waiting lists continue to grow and organ shortage increases. [bib_ref] Shifting paradigms in eligibility criteria for live kidney donation: a systematic review, Ahmadi [/bib_ref] [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] The use of living kidney donors varies widely around the world. Among countries with active kidney transplant programs, the proportion of kidney transplants from living donors varies from less than 5 percent in countries such as Finland, Poland, Ireland, Spain, and Hungary to more than 70 percent in countries such as South Korea, Japan, Turkey, Saudi Arabia, Iran, Jordan, [bib_ref] Global trends in the rates of living kidney donation, Horvat [/bib_ref] and Mexico.Living kidney donation represents between one-third and one half of all kidney transplants in the United Kingdom, United States and Australia. [bib_ref] Screening and follow-up of living kidney donors: a systematic review of clinical..., Tong [/bib_ref] In most cases, transplantation with kidneys from living donors leads to better outcomes for transplant recipients compared to kidneys from deceased donors. Far less is understood about how donation affects the long-term health of donors. Assessment of potential long term harms has primarily been studied by comparing donor data to data available on samples of non-donors collected for other purposes (i.e. NHANES). [bib_ref] Screening and follow-up of living kidney donors: a systematic review of clinical..., Tong [/bib_ref] These types of comparisons are subject to confounding from known and unknown factors and do not account for lifelong outcomes. These comparisons have been used to demonstrate the low risk associated with living kidney donation. While the comparisons are not ideal to draw this conclusion, they do suggest a low prevalence of major negative outcomes correlated with donation in the overall donor population. Far less is known about specific subgroups of living kidney donors, especially subgroups defined by sex and race. Our need for improved understanding of long-term donor outcomes becomes more urgent as living kidney donation increases and eligibility criteria expand to accept kidneys from individuals with higher risk for negative health outcomes compared to traditional donors. These expanded donor criteria include accepting kidneys from older individuals and those with isolated medical abnormalities (overweight and obese, hypertension, reduced kidney function, etc.). [bib_ref] Recipient outcomes for expanded criteria living kidney donors: the disconnect between current..., Iordanous [/bib_ref] Guidelines are beginning to address the acceptance of kidneys from expanded criteria donors and the long-term care of donors. However, there is a great deal of variation among guidelines on how and if these issues are addressed. A recent systematic review of existing guidelines addressing living kidney donation concluded: "Multiple major guidelines for living kidney donation have been published, resulting in unnecessary duplicative efforts. Most do not meet standard processes for development, and important recommendations about thresholds for exclusion based on comorbidities are contradictory. There is an urgent need for international collaboration and coordination to ensure, where possible, that guidelines for living donation are consistent, evidence based, and comprehensive to promote best outcomes for a precious resource." [bib_ref] Screening and follow-up of living kidney donors: a systematic review of clinical..., Tong [/bib_ref] In an effort to address these shortcomings, the Kidney Diseases Improving Global Outcomes (KDIGO) assembled a Work Group to develop comprehensive guidelines addressing the evaluation and care of living kidney donors (LKD). We conducted this systematic review to synthesize and assess the currently available evidence on the topic. Full-text screening also identified trials and observational studies. ## Systematic reviews, randomized controlled trials, and observational studies Full-text screening identified studies with total sample sizes (donor and comparator combined over 50; Data were extracted from studies with total sample sizes over 100. Duration of Follow-up Systematic reviews with outcomes measured at 0 to 90 days postnephrectomy were extracted. Full-text screening identified studies with outcomes measured up to one year. Full-text screening identified studies with outcomes measured one year or more post-donation; Data was extracted from studies with a mean duration of 5 years or more post donation. a -Healthy non-donor comparison groups must have matched or controlled for demographic and health characteristics to be considered 'healthy nondonor' comparisons. ## Literature searches and article selection We searched Ovid Medline, Ovid Embase, and the Cochrane Library to identify previous systematic reviews, randomized controlled trials, and observational studies published and indexed in bibliographic databases through September of 2014. Our search strategy included relevant medical subject headings and natural language terms for the concept of living kidney donation (Appendix A). These terms were combined with filters to select RCTs, systematic reviews and observational studies. Bibliographic database searches were supplemented with backward and forward citation searches of highly relevant systematic reviews. Two independent investigators reviewed titles and abstracts of search results published after 2003 to identify systematic reviews, trials and observational studies relevant to the topic. We relied on citation searching of relevant systematic reviews to identify relevant studies published prior to 2004. Citations deemed eligible by either investigator underwent full text screening. Two investigators independently screened full text to determine if PICODDs criteria were met. Discrepancies were resolved by a third investigator. We documented the inclusion and exclusion status of citations undergoing full-text screening. We often revisited the screening process as the Work Group identified new outcomes or subgroups not included in the original PICODDs. Screening criteria were liberal. We did not extract data from all eligible studies. In an effort to capture the highest quality and most relevant and meaningful data as efficiently as possible, we extracted data only from previous systematic reviews for peri/post-operative outcomes (KQ 1-3) and from systematic reviews and select observational studies for long-term outcomes (KQ 4-7). We extracted long-term outcomes data from observational studies with sample sizes over 100 and mean follow-up time of at least 5 years. Studies reporting long term outcomes had to have an adequate comparison group. For studies comparing living kidney donors to non-donors, we required that the non-donor comparison group have health characteristics suggesting eligibility for kidney donation. Studies comparing living kidney donors to the general population were not eligible. ## Data extraction We extracted data from relevant comparisons in recent systematic reviews to replace the de novo extraction process for all peri/post nephrectomy outcomes. We extracted relevant narrative information from systematic reviews that did not provide meta-analyses. We extracted pooled results from previous meta-analyses. We extracted data from observational studies for long term outcomes. One investigator extracted relevant study, population demographic, and outcomes data from studies eligible for extraction. In several cases, many comparisons were made within the same published study. In these cases, we extracted relevant comparisons but did not extract ineligible comparisons. Data fields extracted included author, year of publication, setting, donor and comparison inclusion and exclusion criteria, donor and comparison characteristics, followup duration, descriptions, and results of outcomes. Relevant data were extracted into tables for descriptive analysis. ## Assessment of previous systematic review quality and individual study risk of bias We assessed the quality of eligible systematic reviews using modified AMSTAR criteria. We assessed risk of bias for observational studies using an instrument developed using the Research Triangle Institute Item Bank for assessing risk of bias and confounding in observational studies of interventions or exposures.Overall summary risk of bias is based upon the collective risk of bias inherent in each domain and confidence that results are believable given study limitations. We used overall summary risk of bias assessments when grading evidence quality as described below. ## Evidence profiles A structured approach (GRADE) was used to grade the quality of the overall evidence [fig_ref] Table 2: Evidence Quality Assessment Criteria [/fig_ref]. ("Methods for Guideline Development," 2011) Evidence profiles were used to facilitate this process. The GRADE approach is prescriptive in how evidence quality is assessed. The study design suggests the initial quality of evidence; high for randomized controlled trials and low for observational studies. Evidence quality is then lowered by one level if the studies in the evidence base for a particular comparison have serious risk of bias and by two levels with very serious risk of bias. Evidence quality is also lowered when results across studies are inconsistent or very inconsistent, if the relationship between the intervention and the outcome is indirect or if the outcome does not directly influence patient well-being. Additionally, evidence quality is downgrade when estimates are imprecise and publication bias is likely. Evidence quality improves with a large effect size. A large effect size includes a relative risk confidence interval lower limit of at least 2; a very large effect size includes a relative risk confidence interval lower limit of 5. Evidence quality is also increased when an effect is demonstrated after all plausible confounding has been addressed. # Results # Search results Our search identified 4,530 citations, of which 417 required full text review after title and abstract screening. We identified an additional 70 references via supplemental citation searching for a total of 484 references undergoing full text review . Studies excluded after full text review are listed in Appendix B along with exclusion reasons. ## Figure 2. literature flow diagram We extracted study characteristics; conducted systematic review quality assessments and risk-of-bias assessments; and extracted relevant outcomes into evidence tables for all studies eligible for extraction (Appendix C for peri/post-operative studies; Appendix D for longterm outcomes studies). We grouped results by Key Question:  Key Question 1: Peri/Post Nephrectomy Outcomes: surgical approach  Key Question 2: Peri/Post Nephrectomy Outcomes: demographic subgroups  Key Question 3: Peri/Post Nephrectomy Outcomes: isolated medical abnormalities  Key Question 4: Long-term Living Kidney Donor Outcomes: comparison to healthy nondonors  Key Question 5: Long-term Living Kidney Donor Outcomes: demographic subgroups (i.e., comparison to healthy non-donors from the same demographic subgroup or donors of different demographic subgroups)  Key Question 6: Long-term Living Kidney Donor Outcomes: isolated medical abnormalities (i.e., comparison to non-donors with similar medical status or donors without IMA)  Key Question 7: Long-term Living Kidney Donor Outcomes: pregnancy-related ## -key question 1: peri/post-nephrectomy outcomes: surgical approach Four recently published systematic reviews addressed peri and post-nephrectomy outcomes by surgical technique. (C. H. [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] [bib_ref] Comparison of the laparoscopic versus open live donor nephrectomy: an overview of..., Fonouni [/bib_ref] C1. Three reviews compared open versus laparoscopic nephrectomy. [bib_ref] Comparison of the laparoscopic versus open live donor nephrectomy: an overview of..., Fonouni [/bib_ref] [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] All RCTs included in were also included in [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Fonouni et al. report results from previous systematic reviews and RCTs searching PubMed through 2013 and included 11 reviews including the reviews by Wilson and Yuan and 4 RCTs (3 of which were included in . One recent high quality systematic review compared right versus left laparoscopic donor nephrectomy. [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] The literature search through July 2013 identified 29 studies (one randomized controlled trial and 28 comparative studies) and analyzed 32,426 live kidney donors. ## 1a -open versus laparoscopic nephrectomy Three reviews present evidence in the comparison of open living donor nephrectomy versus laparoscopic donor nephrectomy (Appendix [fig_ref] Table 3: Key Question 1 Evidence Profile 1a [/fig_ref]. [bib_ref] Comparison of the laparoscopic versus open live donor nephrectomy: an overview of..., Fonouni [/bib_ref] [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] We assessed the quality of evidence on several outcomes including perioperative complications, operative time, blood loss, reoperation, length of hospital stay and time to return to work [fig_ref] Table 3: Key Question 1 Evidence Profile 1a [/fig_ref]. ## Peri/post-operative complications Four trials presented peri-/post-operative complications, variably defined. [bib_ref] Comparison of the laparoscopic versus open live donor nephrectomy: an overview of..., Fonouni [/bib_ref] [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] ## Operative time Operative time was measured in 26 studies of 2188 donors in a systematic review by [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] The open group had significantly shorter operative time than the laparoscopic group [weighted mean difference (WMD): 50.5 minutes; 95% CI: 32.7 to 68.4]. [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] There was substantial heterogeneity across studies (I 2 =96%). Wilson et al. did not pool results, but showed that laparoscopic procedures took longer than open nephrectomy in five of six trials.(C. H. [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] Mean surgery times ranged from 101 to 164 minutes with open and 152 to 270 minutes with laparoscopic across six trials. Laparoscopic nephrectomy requires longer surgery time than open nephrectomy (low quality evidence). ## Intraoperative blood loss Yuan et al. included 11 studies that reported blood loss in 917 donors. [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Meta-analysis showed significantly greater blood loss with open compared with standard laparoscopic nephrectomy (WMD: -99.64 mL; 95% CI: -165.90 to -33.37) or hand-assisted laparoscopic group . [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] [bib_ref] Laparoscopic versus open nephrectomy for live kidney donors, Wilson [/bib_ref] Rates of reoperation with either approach were low (0.7% with open and 2.2% with laparoscopic). Open and laparoscopic nephrectomy had similar rates of reoperation (moderate quality evidence). ## Length of hospital stay Hospital stay (in days) was reported in 18 of the studies (1851 donors) included in the Meta-analysis showed significantly fewer hospital days with laparoscopic group than open group (WMD: -1.27; 95% CI: -1.72 to -.82). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] There was substantial heterogeneity among trials (I 2 =93%). Wilson et al. reported data from five trials comparing open to laparoscopic nephrectomy and did not pool data. Three of five trials showed a statistically significantly shorter hospital stay with laparoscopic. Mean hospital stay was between 4 and 7 days with open and 2 and 6 days with laparoscopic. Length of hospital stay is longer with open nephrectomy than laparoscopic (low quality evidence). ## Return to work Time to return to work (in days) was reported in one systematic review; data from nine studies including 1016 donors. Pooled results show significantly less time to return to work with laparoscopic than open (WMD: -16.35 days; 95% CI: -23.0 to -9.7). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] There was substantial heterogeneity among trials (I 2 =78%). Mean time to return to work varied from 10 to 66 days with laparoscopic and 27 to 91 days with open. Return to work is sooner with laparoscopic than open nephrectomy (high quality evidence). ## 1b -standard laparoscopic versus hand-assisted laparoscopic nephrectomy Yuan et al. compared standard living donor laparoscopic nephrectomy and handassisted laparoscopic nephrectomy. [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Peri/post-Operative Complications There was no statistical difference in peri-/post-operative complications when comparing standard versus hand-assisted laparoscopic techniques (OR: 0.62; 95% CI:0.27 to1.39). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Complication rates were below 15% with both techniques (7.5% with hand-assisted and 12% with standard). Complication rates are similar with hand-assisted and standard laparoscopic nephrectomy (low quality evidence). ## Operative time There was no difference in operating time between standard and hand-assisted laparoscopic nephrectomy (WMD: -24.55 minutes; 95% CI:-50.81 to1.71). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] There was substantial heterogeneity among studies (I 2 =92%). Mean operative times varied across studies and ranged from 121 to 269 minutes with hand-assisted and 180 to 311 minutes with standard. Standard and hand-assisted laparoscopic techniques have similar operating times (very low quality evidence). ## Intraoperative blood loss There was no difference in blood loss between standard and hand-assisted nephrectomy (WMD: -20.65 mL; 95% CI: -43.88 to 2.57). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] There was little heterogeneity among studies (I 2 =0.8%). Blood loss was similar with standard or hand-assisted laparoscopic nephrectomy (very low quality evidence). ## Length of hospital stay Six studies comprising 320 donors compared standard laparoscopic versus handassisted laparoscopic with respect to length of hospital stay. [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Donors undergoing standard laparoscopic nephrectomy had significantly shorter hospital stays than those undergoing hand-assisted laparoscopic nephrectomy (WMD: 0.33 days; 95% CI: 0.10-0.56). [bib_ref] The safety and efficacy of laparoscopic donor nephrectomy for renal transplantation: an..., Yuan [/bib_ref] Mean length of stay ranged from 2 to 7 days with both techniques; statistical difference may not be clinically important. Standard laparoscopic has statistically significantly longer hospital length of stay, but the difference is not clinically meaningful (low quality evidence). ## 1c -left versus right laparoscopic live donor nephrectomy One systematic review comprising one trial and 28 observational studies including a total of 32,426 donors. [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] assessed the evidence comparing right-with leftlaparoscopic live donor nephrectomy. Evidence profile for left versus right laparoscopic nephrectomy shows very low quality evidence for several outcomes [fig_ref] Table 5: Key Question 1 Evidence Profile 1c [/fig_ref]. ## Peri/post-operative complications There was no difference in the rate of complications with left or right laparoscopic nephrectomy (perioperative complications: OR: 1.31; 95% CI: 0.89 to 1.94; postoperative complications OR: 1.27; 95% CI: 0.86 to 1.88). [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] Data necessary to calculate absolute rates was not provided in the systematic review. Complication rates are similar with right-or left-nephrectomy (very low quality evidence). ## Operative time Operation time (in minutes) in the 14 studies (2656 donors) reporting, was no different with left and right laparoscopic nephrectomy (WMD: 1.35 minutes; 95% CI: -11.73 to 14.44). [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] Mean operative times for each included study was not provided. Left and right nephrectomy have similar operating times (very low quality evidence). showed no difference in blood loss (in mL) between donors undergoing left or right nephrectomy in 15 studies reporting (3033 donors) (WMD: 4.36mL; 95% CI: -19.83 to 28.55). [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] Mean blood loss for each included study was not provided. Left and right living donor nephrectomy have similar blood loss (very low quality evidence). ## Intraoperative blood loss ## Length of hospital stay Mean length of hospital stay (in days) in 11 studies (1730 donors) was no different between those undergoing left and right nephrectomy (WMD: 0.05 days; 95% CI: -0.08 to .019). [bib_ref] Maximizing the donor pool: left versus right laparoscopic live donor nephrectomy--systematic review..., Liu [/bib_ref] Mean length of stay for each included study was not provided. Left and right living donor nephrectomy have similar lengths of hospital stay (very low quality evidence). Standard laparoscopic nephrectomy has longer length of stay than hand-assisted, but difference is not clinically meaningful. ## Low ## -key question 2. peri/post nephrectomy outcomes by demographic subgroups: age One systematic review examined peri/postoperative outcomes by donor demographic groups. [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] We did not identify systematic reviews that analyzed peri/post-operative outcomes by race or sex. ## 2a -older versus younger donors We identified one systematic review that examined peri-/post-surgical outcomes by age. [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Young et al. included twenty-two articles comprising 987 donors (mean age: 66 years old; range: 60-85 at donation). Older donors were most commonly defined as ≥60 years. However, other definitions were used including: ≥61, ≥65 and ≥66 years. Young et al. pooled operating time, blood loss, and length of hospital stay by age group (Appendix C, table C6). The evidence profile for peri/post nephrectomy outcomes for older versus younger donors shows very low quality evidence for several outcomes [fig_ref] Table 6: Key Question 2 Evidence Profile 2a [/fig_ref]. ## Operative time Operative time was reported by 3 studies comprising 339 donors. Most were retrospective observational studies. There was no significant difference in operative time (minutes) between older and younger donors (WMD: 11 minutes; 95% CI: -3.0 to 25). [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Mean operative time ranged from 134 to 238 minutes with older donors and 128 to 203 minutes with younger donors. Operative time is similar in older and younger donors (very low quality evidence). ## Intraoperative blood loss Young et al. included two studies (146 donors) reporting blood loss (mL) by age. No statistical difference by age was found (WMD: 6.0 mL; 95% CI: -91.0 to 103.0). [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Reported mean blood loss was 157 and 192 mL for older donors and 112 and 248 in younger donors in the two included studies. Blood loss is similar in older and younger donors (very low quality evidence). ## Length of hospital stay Young et al. included three studies (339 donors) reporting length of hospital stay (in days) by age. In meta-analysis, no statistical difference by age was found (WMD: 0.0; 95% CI: -1.0 to 1.0). [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Mean length of stay ranged from 3 to 10 days with older donors and 3 to 11 days with younger donors. Hospital length of stay is similar in older and younger donors (very low quality evidence). ## -key question 3: peri and post-nephrectomy outcomes in living kidney donors with isolated medical abnormalities We identified two systematic reviews that examined peri/post nephrectomy outcomes in donors with IMAs. Both analyzed peri/postoperative outcomes by overweight and obesity status. [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] We did not identify systematic reviews that provided meta-analysis of peri/post-operative outcomes by other IMA groups. ## 3a -overweight/obese donors versus donors with normal bmi Young et al. [fig_ref] Table 7: Key Question 3 Evidence Profile [/fig_ref] included 10 studies examining 484 living donors with a mean BMI of 34.5 kg/m 2 at donation (range: 32-39 kg/m 2 ). Eight studies used an obesity cut-point of 30 kg/m 2 ; the other studies used definitions of BMI ≥31 and 35 kg/m 2 . 14 studies and differentiated between obese and non-obese by defining the former group as those with a body mass index of >30kg/m 2 . [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] Lafranca et al. performed additional analysis to gain better insight into differences within the high BMI group. [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] Three studies of the original analysis could be used as they described multiple cohorts. Kidney donors with a BMI of 30-34.9 kg/m 2 were compared with those with a BMI of 35 kg/m 2 and higher. These two systematic reviews comprised 16 unique studies. Studies were primarily retrospective observational studies. The evidence profile for peri/post nephrectomy outcomes for overweight/obese versus normal BMI donors shows very low quality evidence for several outcomes [fig_ref] Table 7: Key Question 3 Evidence Profile [/fig_ref]. ## Peri/post-operative complications Lafranca et al. pooled results from 7 studies analyzing perioperative complications by BMI status and showed no difference based upon BMI status (RR: 1.01; 95% CI: 0.75 to 1.36). [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] The complication rate was 7% in those with high BMI and 6% in those with low BMI. Complication rates are similar in obese and non-obese donors (very low quality evidence). ## Operative time Lafranca et al. pooled data from 8 studies (n=1105) on operation duration of laparoscopic nephrectomy. The weighted mean difference was 16.9 minutes longer (95% CI: 9.06 to 24.76) for donors with high BMI. [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] ## Length of hospital stay Hospital length of stay was similar across BMI categories (WMD:0.18; 95% CI: -0.02 to 0.39). [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] Length of stay ranged from 1.7 to 7.4 days with high BMI and 1.6 to 5.8 with low BMI. Young et al. pooled similar data and found similar results; however Lafranca et al. is more up to date. Length of stay is similar in obese and non-obese donors (very low quality evidence). [fig_ref] Table 5: Key Question 1 Evidence Profile 1c [/fig_ref] We identified two systematic reviews [bib_ref] Meta-analysis: risk for hypertension in living kidney donors (Structured abstract), Boudville [/bib_ref] and nine observational studies [bib_ref] The long-term quality of life of living kidney donors: A multicenter cohort..., Clemens [/bib_ref] [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] [bib_ref] Acute dialysis risk in living kidney donors, Lam [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] [bib_ref] Risk of serious gastrointestinal bleeding in living kidney donors, Thomas [/bib_ref] [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] that assessed long-term health outcomes after living kidney donation compared to healthy non-donors. Systematic reviews did not include only studies with comparison groups and comparison groups were not always 'healthy' comparisons. Studies reported mortality, cardiovascular events, ESRD, renal function, proteinuria, hypertension, psychosocial outcomes, GI bleeds, fragility fractures, and acute kidney injury requiring dialysis (Appendix D, Tables D5). Studies from which data were extracted reported mean or median lengths of follow-up ranging from 5.5 to 15 years. Several studies used the same group of donors so the number of unique donors analyzed across all outcomes is unclear. The evidence profile for peri/post nephrectomy outcomes for donors versus healthy non-donors shows very low to moderate quality evidence for several outcomes [fig_ref] Table 8: Key Question 4 Evidence Profile [/fig_ref]. ## 19 ## 4a -living kidney donors versus healthy non-donors ## Mortality Three retrospective observational studies compared mortality among living kidney donors to healthy non-donors.(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjøen [/bib_ref] One study [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] compared 1,901 donors to 32,621 healthy non-donor participants of the Nord-Trøndelag Health Study (The HUNT Study). The HUNT study population was drawn from a single county in Norway and enrolled participants without diabetes. Individuals were normotensive and not on blood pressure medications and had a BMI<30. Results revealed increased risk of death in donors (11.7% vs 7.4%, HR: 1.30; 95% CI: 1.11 to1.52) [fig_ref] Table 5: Key Question 1 Evidence Profile 1c [/fig_ref]. Donors were followed for an average of 15 years, while healthy non-donors were followed for 25 years confounding the results. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] In contrast, two studies (one from the United States with a follow-up of up to 12 years and one from Canada with a median follow-up of 6.5 years) revealed lower risk of death in donors compared to healthy non-donors. (A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] The quality of evidence for the outcome was very low. ## Cardiovascular outcomes Cardiovascular events were reported in two studies.(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjøen [/bib_ref] One study revealed greater cardiovascular mortality in donors compared to healthy non-donors (3.6% vs 2.1%, HR: 1.40; 95% CI: 1.03 to1.91), [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] while another study reported no difference in composite death censored cardiovascular outcomes between donors and non-donors (1.3% vs 1.4%, RR: 0.91; 95% CI: 0.61 to1.35).(A. X. Quality of evidence for the outcomes was very low. ## Esrd Two studies compared the rate of ESRD in living kidney donors versus healthy nondonor controls. [bib_ref] Long-term risks for kidney donors, Mjøen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] Both studies showed high relative but low absolute risk increases. The study from Norway reported greater risk of ESRD in donors compared to healthy non-donors (0.5% vs 0.06%, HR: 11.38; 95% CI 4.37 to 29.63). [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] Similarly, the study from the US reported 15-year cumulative incidence rates of ESRD of 30.8 (95% CI: 24.3 to 38.5) per 10,000 patient-years of follow-up in kidney donors compared to 3.9 (95% CI: 0.8-8.9) per 10,000 in healthy non-donors. Quality of evidence for the outcome was moderate. ## Acute dialysis One study reported similar rates of acute dialysis events, as defined by claims in an administrative database, in donors vs non-donors (6.5 versus 9.4/100,000 person-years of follow-up, RR: 0.58 (95% CI 0.08-4.47).(S. O. Lee) Quality of evidence for the outcome was moderate. ## Renal outcomes A systematic review of six studies (189 controls and 239 donors) with a follow-up of 6-13 years, reported 10 (95% CI: 15 to 6) ml/min/1.73m2 lower eGFR in donors compared to nondonors.(A. X. Quality of evidence for the outcome was very low. ## Proteinuria and blood pressure One systematic review of three controlled studies (59 controls and 129 donors) with mean follow-up ranging between 7 and 15 years, reported proteinuria in donors to be 66 (95% CI: 2-108) mg/day greater than non-donors.(A. X. Albuminuria was higher in donors in 2 of 4 studies that compared donors with non-donor controls with the greatest difference of 57 (95% CI 32, 78) mg/day.(A. X. [bib_ref] Proteinuria and reduced kidney function in living kidney donors: A systematic review,..., Garg [/bib_ref] In two studies (67 donors and 51 controls) with follow-up ranging between 2 and 13 years, risk of microalbuminuria was higher in donors compared to controls (20.9% vs 3.9%, RR: 3.9 (95% CI 1.2, 12.6).(A. X. [bib_ref] Proteinuria and reduced kidney function in living kidney donors: A systematic review,..., Garg [/bib_ref] Another systematic review of data from 6 studies with at least 5 years of follow-up after donation reported weighted mean for systolic blood pressure 6 (95% CI 1.6 to 10.5) mmHg ,and diastolic blood pressure 4 (95%CI 0.9-6.7) mmHg higher in donors compared to non-donors. Quality of evidence for the outcomes was very low. ## Psychosocial outcomes One study reported psychosocial outcomes in donors and healthy non-donors: there was no difference in SF-36 components scores, 15D QOL scores, or feeling thermometer scores. Quality of evidence for the outcomes was very low. ## Other outcomes We identified three studies that addressed other outcomes after living kidney donation. All studies were done in the same population in Ontario, Canada. gastrointestinal bleeds in living donors compared to matched non-donors and found similar event rates in donors and non-donor (18.5 versus 14.9 /10,000 person years, (HR: 1.24; 95% CI: 0.87 to 1.81). [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] One study looked at the risk for fragility fractures in living donors in comparison to matched non-donors and found similar event rate/10,000 person years in non-donors vs non-donors (18.7 versus 16.4) (HR: 0.88; 95% CI: 0.58 to1.32).(A. X. One study compared rates of kidney stones with need for surgical interventions (8.3 versus 9.7 per 10,000 person-years, RR: 0.85(95% CI 0.47-1.53) as well as hospitalizations for kidney stones (12.1 versus 16.1 per 10,000 person years, RR: 0.75(95% CI 0.45-1.24)) among kidney donors and healthy non-donors without prior history of kidney stones, respectively, and reported no difference. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Quality of evidence for these outcomes was very low. One retrospective observational study shows no difference in the rate of GI bleeding after a median of 6.5 years follow-up. ## Very low ## -key question 5: long-term health outcomes in living kidney: demographic subgroups 5a -older donors versus older healthy non-donors (table d6) We identified eight studies that compared outcomes in older donors compared to older healthy non-donors. [bib_ref] Living kidney donors ages 70 and older: Recipient and donor outcomes, Berger [/bib_ref] [bib_ref] The long-term quality of life of living kidney donors: A multicenter cohort..., Clemens [/bib_ref] [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Risk of serious gastrointestinal bleeding in living kidney donors, Thomas [/bib_ref] [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Mean (median) follow-up ranged from 5 to 15.1 years. Evidence profile for long term nephrectomy outcomes for donors versus healthy non-donors shows very low to moderate quality evidence for several outcomes [fig_ref] Table 9: Key Question 5 Evidence Profile [/fig_ref]. ## Mortality Three studies from the OPTN registry, [bib_ref] Living kidney donors ages 70 and older: Recipient and donor outcomes, Berger [/bib_ref] compared mortality between older donors and older healthy non-donors. Berger et al. reported survival at 5 and 10 years in donors over age 70 compared to matched non-donors from the NHANES III study. [bib_ref] Living kidney donors ages 70 and older: Recipient and donor outcomes, Berger [/bib_ref] At 10 years of follow-up, 73% of non-donors and 90% of donors were alive (HR for death: 0.37 (95% CI 0.21-0.65) for donors compared to non-donors). donors to a matched cohort of NHANES III. Both studies found mortality higher in older healthy non-donors than in older donors. The most recent study by Reese et al. reported similar risk of death for donors > 55 years old compared to non-donors > 55 years old from the Health and Retirement Study 4.9 versus 5.6 deaths per 1000 person-years, and lower risk of death in donors 60 years or older compared to non-donors 60 years or older (HR: 0.68; 95% CI: 0.49 to 0.95). The quality of evidence for the outcome was very low. ## Cardiovascular outcomes Reese reported similar risk of death or cardiovascular event in older (> 55 and > 60) donors compared to non-donors with Medicare coverage. Garg et al reported no interaction between age and donation for the outcome of death censored cardiovascular events (p=0.48) and similar risk of cardiovascular events for donors and non-donors aged 55 and older (4.4% vs 6.4%, HR: 0.70 (95% CI: (0.3-1.4)).(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] The quality of evidence for the outcome was low. ## Psychosocial One study reported psychosocial outcomes in donors 43 years old and older and healthy non-donors of the same age, there was no difference in SF-36 Mental component summary scores. Quality of evidence for the outcome was very low. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] One study looked at the risk for fragility fractures in living donors in comparison to matched non-donors 55 years and older and found similar event rate/10,000 person years in donors vs non-donors (43.2 versus 39.5) (HR: 1.14; 95% CI: 0.56 to 2.35).(A. X. One study compared rates of kidney stones with need for surgical interventions (9.4 versus 10.4 per 10,000 person-years) as well as hospitalizations for kidney stones (11.1 versus 17.0 per 10,000 person years) among kidney donors and healthy non-donors 40 years or older without prior history of kidney stones, respectively, and reported no difference. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Age did not influence the association between donation and GI bleeding (p for interaction 0.6) , fractures (p for interaction 0.5) , or kidney stones (p for interaction 0.8 .(A. X. [bib_ref] Risk of serious gastrointestinal bleeding in living kidney donors, Thomas [/bib_ref] [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Quality of evidence was rated as low or very low for all of the reported outcomes. [fig_ref] Table 7: Key Question 3 Evidence Profile [/fig_ref] Sixteen included studies analyzed donor outcomes by age at donation They reported the following long-term outcomes: mortality, cardiovascular events, ESRD, renal function, proteinuria, hypertension, GI bleeds, fragility fractures and psychosocial outcomes. Mean lengths of follow-up ranged from 5.5 to 31 years. Quality of evidence was rated low to very low for all of the outcomes [fig_ref] Table 1: PICODD Criteria [/fig_ref]. ## Other outcomes ## 5b -older donors versus younger donors ## Mortality Four studies reported long-term mortality outcomes stratified by pre-donation age. In the three studies comparing mortality in older donors to younger donors (55 years or older in one, 60 years or older in two) as would be expected older donors had greater all-cause mortality than younger donors over an average follow-up time 5.5 to 6.8 years. [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] One small study reported no difference in frequency of deaths in donors who were younger than 18 years of age at donation compared to donors who were 18-30 years at donation over 30 year follow-up (5.1% versus 6.2%, p=0.990).(MacDonald et al.) The quality of evidence for the outcome was low. ## Cardiovascular outcomes One study reported cardiovascular events by donor age.(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] In donors aged 55 and older, the rate for cardiovascular events per 10,000 person years was 4.4, compared to 1.4 in their younger counterparts. Another study reported 9% greater risk of cardiovascular event for each year increase in donor age.(K. L. The quality of evidence for the outcome was low. ## Esrd End-Stage Renal Disease was reported in two studies. The first reported cumulative incidence rates of ESRD at 15 years in donors 18-39 years, 40-49 years, 50-59 years and 60 years and older. ESRD rates were 29.4, 17.4, 54.6 and 70.2 per 10,000 person-years respectively. [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] In one study, white donors who were younger than 35 years of age at the time of donation were more likely to be listed for kidney transplant compared to White donors who were 35 years or older at donation (0.2% vs 0.05%, RR:4.10(95% CI 2.35-7.16); African American donors who were younger than 35 years at the time of donation were also more likely to be listed for kidney transplant compared to African American donors who donated kidney at 35 years of age or later (0.6% vs 0.11%, RR: 7.68( 95% CI 3.25-17.89). The quality of evidence for the outcome was very low. ## Renal function Ten studies reported renal function by age. In the three that looked at those withGFR <60 mL/min, all found older donors at greater risk. [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] [bib_ref] Risk factors for MDRD-GFR of less than 60 mL/min per 1.73 m2..., Lee [/bib_ref] Age at donation was significantly associated with greater odds of CKD (defined as eGFR <60 ml/min/1.73m2) in three studies and not associated in one study. Greater donor age was correlated with lower GFR at follow-up in two studies in Swedish living donors.(Fehrman-Ekholm et al.)-(von Zur-Muhlen, Berglund, Yamamoto, & Wadstrom) Frequency of eGFR < 60 ml/min was greater among donors who were 60 years or older at the time of donation compared to donors who were younger than 60 years of age (80% vs 31%). Older age at donation was associated with increased risk of CKD diagnoses as determined by administrative billing claims over an average 7.7 yrs followup (4% increase per year).(K. L. Mean eGFR was 71ml/min among donors older than 60 at the time of donation compared to 78.5ml/min in younger donors after 6.7 years of follow-up. One study did not find any difference in eGFR, frequency of eGFR <60 ml/min, as well as eGFR < 45 ml/min among donors who donated before they turned 18 compared to donors who donated between the ages of 18 and 30. The one study that looked at serum creatinine found no difference at follow-up for those 21-35 and 36-50, but found a difference in those 51-69 (mean creatinine of 1.0 versus 0.8 mg/dL). The quality of evidence for the outcome was very low. ## Proteinuria Three studies reported proteinuria by age at donation. In one, risk of proteinuria at 5 and 10 years was similar between older and younger donors. [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] In another study mean proteinuria (mg/24h) was also similar. In a study that compared adolescent to adult donors, odds of proteinuria (defined as >1+ on a random dipstick) were not significantly different between adolescent and adult donors at about 30 years of followup. The quality of evidence for the outcome was very low. ## Hypertension Hypertension was reported in six included studies, defined by either blood pressure or treatment by medication. Dols et al. reported risk of HTN in older donors (>60 years old) comparable to that in younger donors (10% versus 6%, p=0.56). [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] In one study older age at follow-up was associated with 5 mmHg higher systolic blood pressure. The quality of evidence for the outcome was very low. ## Psychosocial outcomes Gross et al found that 10 year increase in age at donation was associated with decreased risk of Mental health HRQOL impairment (scoring > 5 points below average) at follow-up (OR (95% CI) 0.74(0.65-0.85). Two studies reported similar SF-36 Mental Component Summary scores in donors of different age at donation. [bib_ref] The long-term quality of life of living kidney donors: A multicenter cohort..., Clemens [/bib_ref] [bib_ref] Longterm follow-up of living kidney donors: quality of life after donation, Johnson [/bib_ref] One study found that older age at donation was associated with increased likelihood of post-donation depression diagnoses.(K. L. Mjoen et al. found that older age at donation was associated with decreased risk of doubt toward donation. [bib_ref] Quality of life in kidney donors, Mjoen [/bib_ref] The quality of evidence for the outcome was very low. ## Diabetes Donors who were younger than 18 years of age at donation had risk of drug treated diabetes similar to that of donors who were 18-30 years of age at donation (RR: 0.61; 95% CI: 0.15 to 2.60).(MacDonald et al.) One study reported that older age at donation was associated with a 5% higher risk of drug-treated diabetes over an average 7.7 yrs of follow-up.(K. L. The quality of evidence for the outcome was low. ## Other outcomes One study looked at the risk for GI bleeds in living donors by age at donation and found a two-fold greater event rate/10,000 person years in donors older than 40 years of age compared to those younger than 40 (23.4 versus 11.9), the difference was not significant. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] One study looked at the risk for fragility fractures in living donors by age at donation and found a greater than three times higher event rate/10,000 person years in donors aged 55 and older compared to those younger than 55 (43.2 versus 12.7 -RR: 2.85; 95% CI: 1.24-6.55).(A. X. One study compared risk of surgical interventions for kidney stones and kidney stones with hospital encounters in donors 40 years or older at the time of donation versus donors younger than 40 years of age and did not find any difference. The quality of evidence for the outcomes was low to very low. [fig_ref] Table 8: Key Question 4 Evidence Profile [/fig_ref] Seven studies compared outcomes between male kidney donors / female kidney donors with male / female healthy non-donors respectively. Follow-up ranged from 5 to 25 years. Two studies evaluated mortality, one study cardiovascular outcomes, one study ESRD, one study depression, and one study each, all from the same donor cohort, evaluated GI bleeding, kidney stones and fragility fractures. Quality of evidenced low to very low for all of the outcomes [fig_ref] Table 1: PICODD Criteria [/fig_ref]. ## 5c -male and female donors vs male and female healthy non-donors ## Mortality One study reported relative risk of death for male donors and non-donors compared to female donors and non-donors. Males (including donors and non-donors) had a greater risk of death (AHR: 1.52; 95% CI: 1.41 to1.65) compared to female donors and non-donors . One study compared mortality of donors and healthy non-donors stratified by sex. Mortality of healthy non-donors was higher than that of donors in males and females. The quality of evidence for the outcome was very low. ## Esrd One study reported relative risk of ESRD for male donors and non-donors compared to female donors and non-donors. Male donors and non-donors had similar risk of ESRD compared to female donors and non-donors (AHR: 0.90; 95% CI: 0.43 to 1.88). The quality of evidence for the outcome was very low. ## Psychosocial outcomes Rates of diagnoses of depression were lower in male donors compared to non-donors (3.1 versus 4.7 per 100 person years), as well as female donors compared to non-donors (6.6 versus 9.2 per 100 person years).(K. L. The quality of evidence for the outcome was very low. ## Other outcomes Three studies addressed other outcomes after living kidney donation; all studies were done in the province of Ontario population.(A. X. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] gastrointestinal bleeds in male and female living donors to matched non-donor controls of the same sex and found similar event rates in donors and non-donors (event rates were 15.7 vs 17.9 /10,000 person years for male donors and nondonors respectively, and 20.1 vs 12.9/10,000 person years for female donors and non-donors respectively, p for interaction 0.2). [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] One study looking at the risk for fragility fractures in male and female living donors in comparison to matched non-donors found similar event rates in donors vs non-donors ( 12.9 vs 13.1/10,000 person years for male donors vs nondonors, and 18.8 vs 22.4/10,000 person years for female donors vs non-donors, p for interaction 0.7).(A. X. One study compared rates of kidney stones with need for surgical interventions (9.1 versus 13.7/ 10,000 person-years for male donors and non-donors and 7.7 vs 7.0 /10,000 person years for female donors and non-donors, p for interaction 0.4) as well as hospitalizations for kidney stones (9.1 versus 14.2/ 10,000 person-years for male donors and non-donors and 7.7 vs 7.0 /10,000 person years for female donors and non-donors, p for interaction 0.03). [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Quality of evidence was low or very low for all of the reported outcomes. [fig_ref] Table 9: Key Question 5 Evidence Profile [/fig_ref] Seventeen studies analyzed donor outcomes by sex. The studies reported mean / median lengths of follow-up ranging from 5.4 to 12.2 years. Quality of evidenced was low to very low for all of the outcomes [fig_ref] Table 1: PICODD Criteria [/fig_ref]. ## 5d -male donors versus female donors ## Mortality Two studies reported mortality. One small study reported two deaths, one among male and one among female donors (2.2% versus 1.7% respectively). In another study, male donors were 70% more likely to die during the 12 year follow-up compared to female donors (2.7% vs 1.9%). The quality of evidence for the outcome was very low. ## Cardiovascular events In one study, male donors were more likely to have cardiovascular events compared to female donors (AHR: 2.11; 95% CI: 1.43 to 3.10).(K. L. In the Ontario study, female donors were less likely to have a death censored cardiovascular event compared to male donors, but the association was not statistically significant (2.4% vs 3.3%, HR (95% CI) : 0.57(0.26-1.23)).(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] The quality of evidence for the outcome was low. ## Esrd Six studies analyzing data from 3 data sources, [bib_ref] Ethnic and gender related differences in the risk of end-stage renal disease..., Cherikh [/bib_ref] [bib_ref] Age, gender, race, and associations with kidney failure following living kidney donation, Gibney [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] all analyzing OPTN data but with different inclusion criteria, reported ESRD events by donor gender. One study reported 1 case of ESRD among male donors (2.2%) and one among female donors (1.7%). In one study, male donors had greater risk of ESRD compared to female donors (RR: 2.24; 95% CI: 1.30 to 3.86). In a study by Muzaale et al., women had a 15 year cumulative incidence of ESRD of 21.1 (14.9 to 29.9) per 10,000 person years compared to 44.1 (32.9 to 59.1) in men. In another study, men had greater risk of ESRD but it was not statistically significant.(Wafa 2011) One study reported greater risk of being waitlisted for a kidney transplant among male donors compared to female donors (0.18% versus 0.04%, RR: 4.83; 95% CI: 2.54 to 9.18). This was true among White and African American donors. The quality of evidence for the outcome was low. ## Renal function Six studies reported renal function by gender. Two studies reported no significant increase in risk of post-donation eGFR <60 ml/min by MDRD in women compared to men.(J. H. One study reported greater odds of iohexol GFR < 60 ml/min/1.73m2 in women compared with men (OR: 3.11; 95% CI:1.11 to 8.67), One study reported greater risk of claims for CKD in male donors compared to female donors (AHR: 1.64; 95% CI: 1.16 to 2.34).(K. L. One study reported similar GFR in male (81.6) and female (79.4) donors at 10 year of follow-up, p-value was not provided, [bib_ref] Long-term follow-up of 102 living kidney donors, Karakayali [/bib_ref] while another study reported higher MDRD eGFR in males (69+13 ml/min/1.73m2) than females (65+12 ml/min/m2), p<0.01.(von Zur-Muhlen et al.) The quality of evidence for the outcome was very low. ## Proteinuria Two studies reported proteinuria by gender. [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] [bib_ref] A higher glomerular filtration rate predicts low risk of developing chronic kidney..., Tsai [/bib_ref] In one study incidence of proteinuria (defined as > 150 mg/day of protein or >1+ dipstick proteinuria on UA) was similar between female and male donors (RR: 1.87; 95% CI: 0.63-5.50). [bib_ref] A higher glomerular filtration rate predicts low risk of developing chronic kidney..., Tsai [/bib_ref] In the second study, albuminuria was less common in women (OR: 0.31, 95% CI: 0.12-0.79). The quality of evidence for the outcome was very low. ## Hypertension Three studies reported HTN by gender.(El-Agroudy et al.; K. L. [bib_ref] A higher glomerular filtration rate predicts low risk of developing chronic kidney..., Tsai [/bib_ref] In one study incidence of HTN was not different between male and female donors at 5.5 years. In another study HTN (>140/90 mmHg) was more common among female donors (24.7 versus 17.8%, p=0.03). A third study revealed a greater risk of drug-treated HTN among male donors (AHR: 1.21; 95% CI: 1.03 to 1.43).(K. L. The quality of evidence for the outcome was very low. ## Psychosocial outcomes Three studies reported psychosocial outcomes by donor gender. K. L. One study reported that women were more likely to find the experience of donation stressful, though the finding was not significant. Another study reported that male donors were not more likely to have doubt toward donation. A study by Lentine et al. revealed a lower rate of depression diagnoses among male (3.1 per 100 person-years) compared to female (6.6 per 100 person-years) donors.(K. L. The quality of evidence for the outcome was very low. ## Diabetes One study reported diabetes diagnosis by gender.(K. L. There was no significant difference in risk of diabetes by claims diagnosis or drug-treated diabetes between male and female donors.(K. L. The quality of evidence for the outcome was very low. ## Other outcomes One study looked at the risk for GI bleeding in living donors by sex and found a small increase in GI bleeding/10,000 person years in male donors compared to female donors (20.1 versus 15.7, not significantly different (RR: 0.78; 95% CI: 0.39 to 1.55)). [bib_ref] Risk of serious gastrointestinal bleeding in living kidney donors, Thomas [/bib_ref] One study looked at the risk for fragility fractures in living donors by sex and found small and non-significant absolute differences in fracture risk in male donors compared to female donors (12.9 versus 18.8 per 10,000 person years) (RR: 0.71; 95% CI: 0.31 to 1.63).(A. X. The quality of evidence for the outcome was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Three studies compared outcomes of African American and/ or Hispanic LKDs to African American and Hispanic healthy non-donors. Follow-up ranged from 6.3 to 7.6 years [fig_ref] Table 1: PICODD Criteria [/fig_ref]. Quality of evidence was rated moderate for ESRD and low to very low for all other outcomes. [fig_ref] Table 1: PICODD Criteria [/fig_ref]. ## 5e -african american / hispanic donors vs african american / hispanic healthy nondonors ## Mortality One study compared mortality between AA donors and AA healthy non-donors, and white donors with white healthy non-donors. Non-donor mortality was slightly higher than donor mortality for both races. The quality of evidence for the outcome was very low. ## Esrd One study compared absolute risk of ESRD in donors and healthy non-donors by race and ethnicity. There was a large and significant increase in relative risk of ESRD for African American, Hispanic, and white donors (compared to non-donors). The 15-year increase in absolute risk was small (< 0.5%). African American donors had the greatest absolute increase in the 15 year incidence of ESRD compared to controls (absolute risk increase 50.8 per 10,000 person years for AA donors (74.7 per 10,000 (95% CI, 47.8-105.8) in AA donors vs 23.9 per 10,000 (95% CI, 1.6-62.4) in AA non-donors) , 29.5 per 10,000 person years for Hispanic donors (32.6 per 10,000 (95% CI, 17.9-59.1) in Hispanic donors vs 6.7 per 10,000 person years (95% CI, 0-15.5) in Hispanic non-donors), and 22 per 10,000 person years for white donors (22.7 per 10,000 (95% CI, 15.6-30.1) in white donors vs 0.0 per 10,000 person years (95% CI, 0.0-0.0) in white non-donors). The quality of evidence for the outcome was moderate for all three racial groups (upgraded for effect size). ## Renal function One study compared eGFR in African American donors compared to African American non-donors. The average serum creatinine was 1.2 +0.3 mg/dL and the average eGFR 77 +19 mL/min/1.73 m 2 in donors and 0.9 +0.2 mg/dL and 109 +17 mL/min/1.73 m 2 , in non-donors, respectively at an average follow-up of 6.8 years. The number (proportion) of donors with an eGFR < 60 and < 45 mL/min/1.73 m 2 was 16 (15.5%) and 6 (6%), respectively, in donors while none of the non-donors had an eGFR<60 mL/min/1.73 m 2 . The quality of evidence for the outcome was low. ## Proteinuria One study compared risk of proteinuria (microalbuminuria) among African American donors and African American healthy non-donors. After an average of 6.8 years from donation, African American donors had greater mean urinary albumin than non-donors, 15 microgram/mg vs 7 microgram/mg, but the difference was not statistically significant. Incidence of microalbuminuria did not differ between African American donors and non-donors (5.8% vs 3.8% [RR: 1.52; 95% CI: 0.55 to 4.16]). The quality of evidence for the outcome was very low. ## Hypertension One study compared risk of hypertension defined as BP> 140/90 mmHg or use of blood pressure medications among African American donors and African American healthy nondonors. After a mean follow-up of 6.8 years, African American donors had greater risk of hypertension compared to African American non-donors (40.8%vs 17.9%, absolute difference of 22.9%, [RR: 2.3; 95% CI: 1.6 to 3.4]). The quality of evidence for the outcome was very low. ## Diabetes One study compared risk of diabetes among African American donors and African American healthy non-donors. After a mean follow-up of 6.8 years, African American donors had a frequency of diabetes similar to that of African American non-donors (1.9% vs 1.7%, absolute risk difference of 0.2%, [RR: 1.14; 95% CI: 0.21 to 6.13]). The quality of evidence for the outcome was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Eight studies reported living donor outcomes by donor race or ethnicity. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Quality of evidenced was low to very low for all of the outcomes. ## 5f -african american / hispanic donors versus white donors ## Mortality Two studies reported on donor mortality by race. Compared to White donors, African American donors had 30 percent greater risk of death after a mean follow-up of 6.3 years (12 year mortality 2.8% vs 1.7%, HR: 1.3; 95% CI: 1.0 to 1.6). Hispanic donors had 40 percent lower mortality compared to White donors (HR: 0.6; 95% CI: 0.4 to 0.9). Aboriginal donors' risk of death was similar to White donors (RR: 1.33; 95% CI: 0.40 to 4.44). The quality of evidence for the outcomes was very low for African American and Aboriginal donors and low for Hispanic donor comparisons. ## Cardiovascular events One study reported cardiovascular event risk (from administrative claims data) by race; African American (RR: 1.15; 95% CI: 0.63 to 2.11) and Hispanic (RR: 0.91; 95% CI: 0.37 to 2.26) donors had similar risk to White donors [fig_ref] Table 1: PICODD Criteria [/fig_ref] ## Renal function Three donor pool studies evaluated renal function in kidney donors by race and insurance status at a median follow-up of 7-14 years. In one study of Medicare-insured donors, African American race and Hispanic ethnicity were associated with a higher risk of postdonation CKD diagnoses compared to White donors.(K. L. Another report by the same group revealed greater risk of claims for CKD diagnoses in African American and Hispanic donors with private insurance compared to White donors with private insurance.(K. [bib_ref] Consistency of racial variationin medical outcomes among publicly and privately insured living..., Lentine [/bib_ref] In this study Hispanic ethnicity was not associated with increased risk of CKD diagnosis among Medicare insured donors.(K. L. In another study, Aboriginal donors had higher eGFR compared to White donors after 14 years of follow-up (adjusted difference 5.9 ml/min). The quality of evidence for the outcome was very low. ## Proteinuria Two studies reported proteinuria by race or ethnicity. Both Medicare insured and privately insured African American donors had a higher risk and Hispanic donors had a similar risk of proteinuria diagnosis compared to similarly insured White donors.(K. L. Aboriginal donors have greater proteinuria compared to White donors (21% vs 4% with > 0.3 gm per 24 hours, RR for (95% CI) 5.89 (1.27 to 27.41)). The quality of evidence for the outcome was very low. ## Hypertension Three studies with two unique cohorts reported hypertension risk by race. ## Psychosocial outcomes One study with a mean follow up of 17 years reported psychosocial functioning by race. Whites reported higher level of social functioning than African Americans (p=0.0007). White donors were more likely to report good health than African Americans (p=0.0034) and other races (p=0.0004). One study found that non-Hispanic white donors had twice the likelihood of depression diagnoses based on billing claims as non-white or Hispanic donors.(K. L. The quality of evidence for the outcome was very low. ## Diabetes ## -key question long term outcomes of donors with isolated medical abnormalities We found no studies that fit our inclusion criteria and compared outcomes of kidney donors with isolated medical abnormities to outcomes of otherwise healthy non-donors matched by the isolated medical abnormality. Following literature compares outcomes of donors with IMA to outcomes of donors without IMA. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Five studies compared long-term outcomes among donors by pre-donation BMI status. [bib_ref] Kidney transplantation with living donors: nine years of follow-up of 628 living..., Gracida [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] Followup ranged from 6.7 to 15.1 years [fig_ref] Table 1: PICODD Criteria [/fig_ref]. The quality of evidence was rated as very low for all outcomes [fig_ref] Table 1: PICODD Criteria [/fig_ref]. ## 6a -obese donors versus non-obese donors ## Mortality One study presented adjusted risk of death per 1 BMI unit increase in a combined cohort of kidney donors and healthy non-donors. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] The study did not find a significant increase in risk of death associated with greater BMI (AHR: 1.01; 95% CI: 0.99 to 1.03 per BMI unit). The quality of evidence for the outcome was very low. ## Cardiovascular mortality One study presented adjusted risk of death from cardiovascular causes per unit BMI increase in a combined cohort of kidney donors and healthy non-donors. Higher BMI was associated with greater risk of cardiovascular mortality (AHR: 1.03; 95% CI: 1.01 to 1.07 per BMI unit). The quality of evidence for the outcome was very low. ## Esrd One study presented adjusted risk of ESRD per unit BMI increase in a combined cohort of kidney donors and healthy non-donors. The study did not find a significant increase in risk of ESRD associated with greater BMI (AHR: 1.13; 95% CI: 0.96 to 1.32 per BMI unit). The quality of evidence for the outcome was very low. ## Renal function Three studies analyzed the association of BMI and renal function. [bib_ref] Kidney transplantation with living donors: nine years of follow-up of 628 living..., Gracida [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] One study at high risk of bias reported follow-up eGFR of 83.9 ml/min in donors with BMI > 30 kg/m2 at baseline compared to eGFR of 78.5 ml/min in donors with normal BMI. [bib_ref] Kidney transplantation with living donors: nine years of follow-up of 628 living..., Gracida [/bib_ref] One study revealed greater odds of iohexol GFR < 60 ml/min/1.73m2 at follow-up per unit increase in BMI at baseline (OR (95% CI): 1.12(1.02-1.23)) . Similarly, another study reported that higher BMI at donation was correlated with lower eGFR at follow-up.(von Zur-Muhlen et al.) The quality of evidence for the outcome was very low. ## Hypertension Two studies reported blood pressure or hypertension by BMI at donation. One study reported MAP of 91.2 in donors with BMI >30 compared to MAP of 88.2 in donors with BMI < 30 at donation. One study reported increased odds of hypertension requiring medication at follow-up associated with greater BMI at donation (OR: 1.12; 95% CI: 1.04 to 1.21 per BMI unit). The quality of evidence for the outcome was very low. ## Psychosocial outcomes One study revealed greater odds of physical component of HRQoL impairment (defined as Physical Component Score >1 SD below sex-by-age norms in donors with higher BMI. Donors with BMI >=35 were more likely to be impaired (OR: 4.32; 95% CI: 2.37 to 7.87) than donors with normal BMI. The same was true with donors whose BMI was 30 -34.9 (OR: 2.85; 95% CI: 2.37 to 7.87) and in donors with BMI 25 -29.9 (OR: 1.84; 95% CI: 1.31 to 2.65). The quality of evidence for the outcome was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Three included studies from three countries analyzed donor outcomes by pre-donation GFR.(J. H. The studies reported mean lengths of follow-up of 5.4 to 11 years. The quality of evidence was very low. ## 6b -donors with lower renal function versus donors with higher renal function ## Renal function Three studies reported kidney function at follow-up by baseline kidney function.(J. H. One study reported no significant association between baseline measured creatinine clearance and odds of MDRD estimated GFR < 60 ml/min/1.73m2: (OR: 1.00; 95% CI: 0.98 to 1.03) per unit change in the measured creatinine clearance.(J. H. Another study revealed an association between greater eGFR at baseline (per 1 ml/min/1.73m2) and lower risk of developing chronic kidney disease defined as eGFR < 60 ml/min/1.73m 2 (OR: 0.95; 95% CI: 0.92 to 0.99). The third study reported a significant correlation between lower eGFR at baseline and lower eGFR at follow-up.(von Zur-Muhlen et al.) Quality of evidence was very low. ## Proteinuria One study reported lack of correlation between lower measured GFR at donation and urine albumin-creatinine ratio at follow-up.(von Zur-Muhlen et al., 2014) Quality of evidence was very low. ## Hypertension One study reported that lower measured GFR at donation was correlated to higher mean arterial blood pressure at follow-up.(von Zur-Muhlen et al.) The quality of evidence for the outcome was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Two studies included 110 donors with impaired glucose metabolism and 775 donors with normal glucose metabolism and followed them for 7-10 years. The quality of evidence was low to very low for all outcomes. (54,55) ## 6c -donors with impaired fasting glucose versus donors with normal glucose tolerance ## Mortality One study reported mortality: 3 of 65 (4.6%) donors with glucose intolerance and 14 of 330 (4.1%) donors with normal glucose tolerance died during an average follow-up of 7.3 years (RR: 1.09; 95% CI: 0.32 to 3.68). Quality of evidence was very low. ## Esrd The same study as noted above for mortality reported no cases of ESRD among 65 donors with impaired glucose tolerance and 2 cases of ESRD among 330 donors with normal glucose tolerance. Quality of evidence was very low. ## Renal function Two studies reported kidney function at follow-up by glucose tolerance or fasting glucose impairment at baseline. One study reported similar MDRD eGFRs at mean follow-up of 10.2 years: donors with impaired fasting glucose at baseline had a mean eGFR of 70.7(16.1) ml/min/1.73m 2 versus donors with normal fasting glucose who had a mean eGFR of 67.3(16.6) ml/min/1.73 m 2 . Another study reported self-reported renal dysfunction in 7.7% of donors with glucose intolerance at baseline and 6.7% of donors with normal glucose tolerance at 7.3 years of followup. [bib_ref] The consequences for live kidney donors with preexisting glucose intolerance without diabetic..., Okamoto [/bib_ref] Quality of evidence was very low. ## Proteinuria One study reported similar albumin/creatinine ratios after 7.3 years of follow-up in donors with and without impaired fasting glucose at baseline (9.8 [23.6] mg/g versus 5.9 [11.0] mg/g, p=0.29). Quality of evidence was very low. ## Hypertension Two studies did not find a difference in incidence of hypertension during the follow-up period between donors with impaired fasting glucose or glucose intolerance and donors with normal glucose metabolism. In one study, 35.6% of donors with impaired fasting glucose and 22.2% of donors with normal fasting glucose developed hypertension after 10.2 years of follow-up. [bib_ref] Prediabetic living kidney donors have preserved kidney function at 10 years after..., Chandran [/bib_ref] In the second study, 29.2% of glucose intolerant donors and 22.1% of donors with normal glucose metabolism developed blood pressure > 140/90 after 7.3 years of follow-up (RR (95% CI): 1.32(0.86-2.03)). [bib_ref] The consequences for live kidney donors with preexisting glucose intolerance without diabetic..., Okamoto [/bib_ref] In the same study, 13.8% of donors with glucose intolerance and 11.2% of donors without glucose intolerance developed drug treated hypertension (RR(95%CI): 1.23(0.63-2.43)). [bib_ref] The consequences for live kidney donors with preexisting glucose intolerance without diabetic..., Okamoto [/bib_ref] Quality of evidence was very low. ## Diabetes Two studies reported greater frequency of diabetes at follow-up between donors with impaired fasting glucose, diabetes, or glucose intolerance and donors with normal glucose metabolism at baseline. In one study, 15.6% of donors with impaired fasting glucose and 2.2% of donors with normal fasting glucose developed diabetes after 10.2 years. [bib_ref] Prediabetic living kidney donors have preserved kidney function at 10 years after..., Chandran [/bib_ref] In the other study, 21.4% of donors with glucose intolerance and 2.4% of donors with normal glucose tolerance developed diabetes by selfreport, and 26.2 and 0% required medications for diabetes respectively after a mean follow-up of 7.3 years. [bib_ref] The consequences for live kidney donors with preexisting glucose intolerance without diabetic..., Okamoto [/bib_ref] Quality of evidence was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] One included study analyzed donor outcomes by pre-donation presence of metabolic syndrome. Metabolic syndrome was defined as meeting three or more of the criteria 1) waist circumference of >88 cm in women or >102 cm in men; 2) hypertriglyceridemia; 3) hyperlipidemia; 4) hyperglycemia; and 5) hypertension (>130/85). This study reported on renal function and proteinuria. The mean length of follow-up was 5 years and data on 140 participants were analyzed. The quality of evidence was very low for all outcomes. ## 6d -donors with metabolic syndrome versus donors without metabolic syndrome ## Renal function One study reported 5-year post-donation MDRD eGFR (mean (SD)) of 66.3(12.7) ml/min/1.73m2 in donors with and 71.8(16.2) ml/min/1.73m2 in donors without metabolic syndrome at baseline. The quality of evidence was very low. ## Proteinuria One study reported 5-year post-donation 24-hour albuminuria (mean (SD)) of 0.5(0.6) mg/day in donors with and 0.2(0.5) mg/day in donors without metabolic syndrome at baseline. The quality of evidence was very low. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Three included studies analyzed donor outcomes by pre-donation hypertension status. [bib_ref] Kidney transplantation with living donors: nine years of follow-up of 628 living..., Gracida [/bib_ref] [bib_ref] Risk factors for MDRD-GFR of less than 60 mL/min per 1.73 m2..., Lee [/bib_ref] One study reported blood pressure as a risk factor for mortality, cardiovascular mortality, and ESRD in a combined cohort of donors and healthy non-donors. Two other studies defined hypertension as BP>140/90 easily controlled with one medication and reported renal function by hypertension status. However, evidence quality was assessed using only was assessed as having a high risk of bias and the comparison groups used in the two studies were not comparable. Quality of evidence was very low for all outcomes [fig_ref] Table 1: PICODD Criteria [/fig_ref]. ## 6e -hypertensive donors versus normotensive donors ## Mortality In one study, a 1 mmHg increase in SBP was not associated with significant increase in risk of death in a mixed cohort of donors and matched non-donors without hypertension (AHR: 1.00: 95% CI: 1.00 to 1.01). The quality of evidence was very low. ## Cardiovascular mortality In one study, a 1 mmHg increase in SBP was associated with a small but significant increase in the risk of cardiovascular death in a mixed cohort of donors and matched nondonors (AHR: 1.01; 95% CI: 1.00 to 1.02). The quality of evidence was very low. ## Esrd In one study, 1 mmHg increase in SBP was associated with a small but significant increase in the risk of ESRD in a mixed cohort of donors and matched non-donors without hypertension (AHR: 1.01; 95% CI: 1.00 to 1.06). The quality of evidence was very low. ## Renal function In one small study more donors with hypertension developed CKD as defined by eGFR < 60 ml/min/1.73m2 compared to donors without hypertension (67% vs 22%, RR: 2.97; 95% CI: 1.51 to 5.83) after 5.4 years of follow-up.(J. H. One study reported similar eGFRs in donors with (78.1 ml/min/1.73m2) and without (78.5 ml/min/1.73m2) hypertension at donation at mean follow-up of 6.7 years. The quality of evidence was very low. ## 6f -donors with proteinuria or hematuria versus donors without None of the included studies analyzed donor outcomes by pre-donation proteinuria or hematuria. [fig_ref] Table 1: PICODD Criteria [/fig_ref] Nine studies evaluated long term donor outcomes by relationship to the recipient. Follow-up ranged from 5 to 17 years. Quality of evidence was rated as moderate to very low for the outcomes [fig_ref] Table 2: Evidence Quality Assessment Criteria [/fig_ref]. ## 6g -long term donor outcomes by relationship to the recipient ## Mortality or cardiovascular outcome Two studies reported cardiovascular outcomes in donors by relationship to the recipient. Both studies used the same cohort of Ontario donors.(A. X. One study reported outcomes of cardiovascular events and mortality by relationship to the recipient. Genetically related living donors had cardiovascular event rate of 1.2 percent while unrelated donors had event rate of 1.6 percent over 6.2 years of follow-up.(A. X. In another study, event rate was similar between donors (1.6 per 1000 person years) and healthy non-donors (1.9 per 1000 person years) and the association was not modified by relationship to the recipient (p for interaction 0.87).(A. X. The quality of evidence for the outcome was very low. ## Esrd One study reported 15 year cumulative incidence of ESRD by relationship to the recipient, cumulative incidence was lower in unrelated donors compared to related donors15.1 (95% CI: 8.7 to 26.3) versus 34.1 (95% CI: 26.9 to 43.3) per 10,000). The quality of evidence for the outcome was moderate. ## Renal function One study did not find an association between relationship to the recipient and CKD (eGFR< 60ml/min/1.73m2).(J. H. Among donors who were a first degree relative of the recipient, 18% had CKD versus 28% among donors who were not first degree relative of the recipient, after 7.4 years of follow-up.(J. H. [bib_ref] Risk factors for MDRD-GFR of less than 60 mL/min per 1.73 m2..., Lee [/bib_ref] The quality of evidence for the outcome was very low. ## Hypertension One study did not find an association between relationship to the recipient and hypertension (15.9% in related and 17.3% in unrelated, RR (95% CI): 1.0(0.7-1.3)).(A. X. The quality of evidence for the outcome was very low. ## Psychosocial outcomes Four studies reported psychosocial outcomes by relationship to the recipient. Related donors had better psychosocial outcomes compared to unrelated donors. Being a first degree relative of a recipient was associated with lower odds of physical HRQOL impairment. Relative other than first degree were 3.5 times more likely to regret donating compared to first degree relatives. Being an unrelated donor was associated with greater risk of having doubts towards donation. Rates of depression diagnoses didn't differ between donors related to recipients, spouses or partners of recipients, and not biologically related or spouse donors (4.9%, 5.0%, and 5.9% respectively) in a privately insured US sample.(K. L. The quality of evidence for the outcome was low. ## 6h -donors with history of kidney stones We identified no studies analyzing long-term donor outcomes by pre-donation kidney stones status. One retrospective study with a moderate risk of bias shows that in living kidney donors higher BMI is associated with a slightly greater risk of developing hypertension over a mean follow-up of 6.7 years. One retrospective observational study shows similar mean albuminuria in donors with metabolic syndrome and those without metabolic syndrome over a mean follow-up time of 5 years. Very Low In one study, a 1 mmHg increase in SBP was associated with an increase in the risk of cardiovascular death in a mixed cohort of donors and matched non-donors without hypertension. Very Low ## Esrd (1 retrospective observational study) ## Moderate-high unknown no serious indirectness Serious Imprecision ## Undetected In one study, a 1 mmHg increase in SBP was associated with an increase in the risk of ESRD in a mixed cohort of donors and matched non-donors without hypertension. ## Very low Renal Function (1 retrospective observational study) ## Moderate-high unknown serious indirectness Serious Imprecision ## Undetected One retrospective observational study with a moderate-high risk of bias shows that CKD was more prevalent among donors with hypertension than donors without hypertension (OR=7.88, 95% CI: 1.14 to 54.45) after median follow-up of 5.4 years. Very Low [fig_ref] Table 1: PICODD Criteria [/fig_ref] We identified two studies addressing pregnancy outcomes by pre-donation or postdonation timings. Both studies compared post-donation pregnancy (n=596) outcomes to pre-donation pregnancy (n=3343) outcomes in 1428 living kidney donors. Outcomes in the Ibrahim et al. study were ascertained by questionnaires using historical recall of events during pregnancy. Outcomes in the Reisaeter study were ascertained from a database. They reported the following outcomes: fetal loss, prematurity, gestational hypertension, gestational diabetes, preeclampsia, proteinuria and low fetal birth weight. Quality of evidence was very low for all of the outcomes. ## Key question 7: female donors of child-bearing age ## Preeclampsia Preeclampsia was reported in both studies. Ibrahim et al. reported greater risk of preeclampsia with post-donation pregnancies (6.6%) compared to pre-donation pregnancies (0.9%), the difference was significant in the analysis that included post-and pre-donation pregnancies of donors with history of either pregnancy, but not significant in the analysis limited to donors with both pre-and post-donation pregnancies. Reisaeter et al. also reported greater frequency of preeclampsia in post-donation pregnancies (5.7%) compared to pre-donation (2.6%) pregnancies. The quality of evidence was very low. ## Fetal loss Fetal loss defined as stillbirth or fetal death was reported in both studies. Both studies compared frequency of stillbirths or fetal deaths between post-donation pregnancies and predonation pregnancies and found they were similar. The quality of evidence was very low. ## Miscarriage Miscarriages were reported in one study. In analysis that included donors with either pre or post-donation pregnancies, frequency of miscarriages was higher in post-donation pregnancies (13.2%) compared to pre-donation pregnancies (8.2%). The difference was not significant in analysis limited to women with both pre-and post-donation pregnancies. The quality of evidence was very low. ## Prematurity Prematurity was reported in both studies. Ibrahim et al. reported greater risk of prematurity with post-donation pregnancies compared to pre-donation pregnancies, the difference was significant in the analysis that included post-and pre-donation pregnancies of donors with history of either pregnancy (6% vs 3.7%, RR(95% CI):1.67(1.05-2.67)), but not significant in the analysis limited to donors with both pre-and postdonation pregnancies (8.7% vs 7.4%, RR(95% CI:1.18(0.59-2.34)). Reisaeter et al. did not find a significant difference in prematurity defined as either < 22 weeks (1% vs0.3%) or < 37 weeks (9.8% vs 7.5%) between post and pre-donation pregnancies. The quality of evidence was very low. ## Gestational hypertension Gestational hypertension was reported in both studies. Ibrahim et al. reported greater risk of gestational hypertension with post-donation pregnancies compared to pre-donation pregnancies, the difference was significant in the analysis that included post-and pre-donation pregnancies of donors with history of either pregnancy (6.9% vs 0.6% (RR(95% CI): 10.9(5.8-20.6))), but not significant in the analysis limited to donors with both pre-and post-donation pregnancies (3.5% vs 0.5%, RR (95% CI): 7.1(0.9-58.2)) . Reisaeter et al. found a similar frequency of gestational hypertension in post and pre-donation pregnancies (2.8% vs 1.8%, RR (95% CI):1.59(0.45-5.62)). The quality of evidence was very low. ## Gestational diabetes Ibrahim et al. reported greater risk of gestational diabetes with post-donation pregnancies compared to pre-donation pregnancies, the difference was significant in the analysis that included post-and pre-donation pregnancies of donors with history of either pregnancy (93.8% vs 0.8%, RR (95% CI): 5.0(2.5-10.2)), but not significant in the analysis limited to donors with both pre-and post-donation pregnancies (0.6% vs 0.5%, RR (95% CI): 1.38(0.65-2.89)). The quality of evidence was very low. ## Proteinuria Ibrahim et al. reported greater risk of proteinuria with post-donation pregnancies compared to pre-donation pregnancies, the difference was significant in the analysis that included post-and pre-donation pregnancies of donors with history of either pregnancy (4.1% vs 1.0%, RR (95% CI): 4.1(2.13-7.99)), but not significant in the analysis limited to donors with both pre-and post-donation pregnancies (4.6% vs 1.5%, RR (95% CI): 2.36(0.72-7.7)). The quality of evidence was very low. ## Low fetal birth weight One study found similar frequency of extremely low birth weight (< 500 gm) (0.9% vs 0.5%) and low birth weight (500-2500gm) (7.5% vs 5.5%, RR (95% CI): 1.38(0.65-2.89)) in post and pre-donation pregnancies. The quality of evidence was very low. Donors with both a pre-and a post-donation pregnancy had similar development of low birth-weight babies after post-donation pregnancy as compared to pre-donation pregnancy. ## Very low # Discussion We conducted a systematic review of evidence related to peri-/post-operative and long term outcomes of living kidney donation and how donor characteristics modify these outcomes. Except for the association of donation with increased risk of ESRD (moderate grade), evidence quality for all other comparisons was low or very low due to limitations with the evidence base. Evidence quality was primarily low or very low when the studies in the evidence base were observational. Limitations such as retrospective designs, selection bias, and confounding were common among observational studies. Confounding or inadequate control of prognostic variables are likely to be the most serious flaws in observational studies. The screening that potential living kidney donors experience is much more comprehensive than the screening of records about individuals' health status collected for other purposes. Matching living kidney donors to records of individuals in these secondary databases on a few variables such as age, sex, race, and BMI status is likely insufficient. An appropriate comparison would involve matching based upon results of health screenings similar to what potential donors experience. However, this represents a less feasible and more expensive study. ## Peri-and post-operative outcomes of living kidney donation Results from previous systematic reviews assessing living kidney donors peri/postoperative outcomes by surgical approach provide evidence about three different comparisons: open versus laparoscopic nephrectomy, standard laparoscopic versus hand-assisted laparoscopic nephrectomy, and left versus right nephrectomy. We identified two systematic reviews that examined peri/post nephrectomy outcomes in donors with isolated medical abnormalities, namely older age and obesity. [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Mixed quality evidence shows laparoscopic living donor nephrectomy results in longer operative times, more reoperations, shorter hospital stays and fewer days to return to work than open donor nephrectomy. Standard laparoscopic nephrectomy had shorter hospital stays than hand-assisted laparoscopic nephrectomy. Very low quality evidence shows similar results with left and right living donor nephrectomy on all outcomes. Apart from operative time, there appears to be no differences in peri and post-operative outcomes for older versus younger donors and donors with higher versus lower BMI. ## Long term outcomes of living kidney donation Moderate quality evidence shows a correlation between living kidney donation and ESRD. Very low quality evidence shows a correlation between kidney donation and mortality, cardiovascular events, low kidney function, proteinuria, hypertension, and psychosocial outcomes. Very low quality evidence shows that age does not modify the associations. In living kidney donors, older age is a risk factor for all cause and CV mortality, ESRD, CKD, HTN, fractures. There is very low grade evidence that female donors have lower reported death rates, CV events, and ESRD events but higher prevalence of lower eGFR compared to male donors. It is unknown whether gender modifies outcomes of living kidney donation. African American race appears to be a risk factor for ESRD, hypertension, CKD, proteinuria, and diabetes. Aboriginal ethnicity appears to be a risk factor for diabetes, HTN, and proteinuria. Association of Hispanic ethnicity with poor outcomes is inconsistent. We found moderate grade evidence that African American, Hispanic and White donors appear to have greater absolute risk of ESRD compared to non-donors, with African American donors sustaining the greatest increase in absolute risk. We found very low grade evidence from small retrospective observational studies with nonuniform exposure, outcome definitions and ascertainment and high attrition rate that some isolated medical abnormalities are associated with risk of worse kidney function, proteinuria, hypertension or diabetes but it remains unclear whether donation modifies association between isolated medical abnormalities and clinical outcomes. From evidence of very low grade from two studies with serious design limitations preeclampsia, gestational hypertension, and preterm delivery complicated post-donation pregnancies more frequently than pre-donation pregnancies. Interpretation of the evidence is limited by the retrospective observational nature of the studies, risk of bias introduced by unobserved differences between donors and controls, high attrition in some studies, small sample sizes to ascertain clinical outcomes, short duration follow-up to see rare events such as ESRD and non-uniform outcome definitions and ascertainment. As all evidence in the field is of an observational nature, no causality can be inferred. In addition, our report does not address the impact of these donor characteristics on recipient outcomes which are also an important component in donation decision making. ## Outcomes of living kidney donors compared to healthy non-donors Living kidney donation is an intervention for which it may not be possible to conduct a randomized controlled trial to evaluate the short-term and long-term outcomes compared to not donating a kidney. Kidney donors are carefully selected for donation and are healthier than general population. In order to minimize bias, our review included only studies that compared long term outcomes in living kidney donors to outcomes of matched healthy controls. However, there is strong potential for findings to be biased by selection and/or residual confounding between donors and controls. Furthermore, some findings (such as increased mortality in older vs. younger donors or those with comorbidities) may be due to underlying demographics or comorbidities rather than kidney donation itself. We included four studies that compared clinical outcomes such as mortality, cardiovascular events, and ESRD during long-term follow-up of on average 5 years to 15 years.(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] The data were obtained from administrative donor registries of three countries: the United States, the Canadian province of Ontario, and Norway. Non-donor comparisons were obtained from an administrative database in one study(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] and from population based cohorts in the other studies. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] Two studies showed lower mortality in living kidney donors(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] while another study [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] found higher all-cause mortality and cardiovascular mortality in kidney donors compared to controls. The discrepancy in the findings is puzzling. It is difficult to find biological plausibility of nephrectomy extending life span. It is likely that the lower mortality in donors can be explained by residual confounding. Mjoen et al. demonstrated greater mortality in living kidney donors compared with matched non-donor controls. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] However, these results might have been confounded by several issues -donors were almost 10 years older than non-donors (mean age of 46.0 versus 37.6), time of cohort entry differed between donors and non-donors, and donors were followed for up to 43.9 years compared to non-donors who were followed for a maximum of 24.9 years allowing for more events to occur. These differences could have biased the study towards finding greater mortality among donors compared to non-donors. Alternatively, it is possible that mortality differences were due to lower kidney function and greater incidence of ESRD in donors compared to non-donors. Therefore, it is difficult to draw conclusions on long-term mortality due to living kidney donation. Two studies compared ESRD in living kidney donors compared with healthy non-donor controls. [bib_ref] Long-term risks for kidney donors, Mjøen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] Both showed rates of ESRD almost 10 times higher among donors compared to non-donors, though absolute risk increases were small. For example, in Norway, incidence of ESRD in donors was 302 per million person years compared to the overall incidence of ESRD of 100 per million person-years. In the US study, estimated lifetime risk of ESRD was 90 per 10,000 donors. Although higher than the rate of 14 per 10,000 in healthy non-donors it was still lower than the rate of 326 per 10,000 representatives of the general population [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] These estimates are limited by the relatively short follow-up duration making lifetime ESRD risk estimates imprecise. Additionally, neither data source had longitudinal measurements of kidney function among kidney donors and comparator population. Despite these limitations, the evidence raises concern about of the effect of kidney donation on ESRD risk, especially in those with very long life expectancy. Two systematic reviews reported lower eGFR, slightly higher proteinuria, and greater incidence of hypertension among kidney donors compared with healthy non-donors Although quality of evidence for these outcomes is very low, it is possible that these early changes mediate the association between kidney donation and greater rate of ESRD in kidney donors. In addition, related donors have a family history of ESRD and therefore are inherently at increased risk. For example, in the Mjoen study all nine donors who developed ESRD were related to graft recipients and had immunologic causes of ESRD [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] However, family history of ESRD does not fully explain the increase in ESRD rates among kidney donors: in the Muzaale et al. study, donors with biological relationship to the recipient had only about twice the 15 year cumulative incidence of ESRD (34.1) compared to non-related donors (15.1 per 10,000). [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] As 15 year incidence of ESRD is 8 times higher in donors compared to healthy non-donors, some of the increased risk is likely attributable to donation itself rather than donor characteristics. However, because of study design limitations, we graded the evidence as moderate. Life time risk of ESRD associated with donation, especially for young donors remains unclear. Prospective cohort studies with contemporaneous recruitment of kidney donors and matched healthy non-donors with long term follow-up and longitudinal measurements of kidney function, urinary protein and blood pressure as well as ascertainment of clinical outcomes such as cardiovascular events, ESRD and death are needed to fill in the information gap. Meanwhile, current evidence provides important information for informed consent of potential donors. Evidence of greater risk of ESRD among kidney donors might impact criteria for donor selection, especially among young donors who have long projected life spans and are at risk for health event outcomes. Evidence of risk associated with kidney donation should also promote careful follow-up among kidney donors and promotion of good access to care for donors as well as healthy lifestyle choices in order to mitigate the risks associated with kidney donation. ## Long term outcomes in living kidney donors within demographic subgroups (age, sex, race) age Eight studies compared long-term outcomes in older donors and older healthy nondonors. In all three studies that compared mortality in older donors to older healthy nondonors, [bib_ref] Living kidney donors ages 70 and older: Recipient and donor outcomes, Berger [/bib_ref] mortality was higher among older healthy non-donors than in older donors. This finding likely reflects residual selection bias, as older individuals who are approved for donation are likely healthier than their older non-donor counterparts selected from population cohort studies based on available data. Older age did not modify the association between donation and CV events,(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] clinically significant nephrolithiasis, [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] gastrointestinal bleeding, [bib_ref] Risk of serious gastrointestinal bleeding in living kidney donors, Thomas [/bib_ref] or fractures.(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] Over a limited follow-up duration, greater donor age increased risk for death, [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] cardiovascular events,(A. X. [bib_ref] Cardiovascular disease in kidney donors: matched cohort study, Garg [/bib_ref] ESRD, [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] lower kidney function [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] [bib_ref] Risk factors for MDRD-GFR of less than 60 mL/min per 1.73 m2..., Lee [/bib_ref] hypertension [bib_ref] Living kidney donors: Impact of age on long-term safety, Dols [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] and diabetes.(K. L. However, this is not surprising as age is significant risk factor for all these outcomes regardless of kidney donation status. Thus the greater outcomes noted in older versus younger donors may not be due to kidney donation per se. Psychosocial outcomes were similar to younger donors. Older donors were less likely to regret donating. [bib_ref] Quality of life in kidney donors, Mjoen [/bib_ref] As few studies checked for interaction between age and donation for outcomes of interest, it remains unknown whether age modifies long term risks inherent in donation. year cumulative incidence of ESRD in donors 60 years or older, 50-59 years and 18-39 years with the lowest cumulative incidence among donors who were 40 to 49 years of age at donation. [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] Greater cumulative incidence in very young donors is concerning. Life time risk of ESRD is higher for young donors compared to older donors. A single center study evaluated long term outcomes among donors who donated their kidney before 18 years of age. [bib_ref] Medical outcomes of adolescent live kidney donors, Macdonald [/bib_ref] The study found that donating a kidney prior to the age of 18 did not increase the risk of hypertension, proteinuria, eGFR<60 ml/min/1.73m2 and diabetes over an average of 31 years of follow-up compared to donating between 18 and 30, though for those who developed these conditions time to diagnosis was similar between the age groups. [bib_ref] Medical outcomes of adolescent live kidney donors, Macdonald [/bib_ref] In conclusion, older donors had similar to better outcomes compared to older healthy non-donors though these findings are likely due, at least in part, to selection biases between groups. Age is a risk factor for poor outcomes after donation, though it is unknown whether donation modifies the risk associated with age. Most available studies have limited follow-up making estimation of life time risk of uncommon events difficult. Life-time risk of long term harms associated with donation (e.g. ESRD) is greater in young donors with long life expectancy. However, because the life-time risk of ESRD is greater in those with long-life expectancy regardless of kidney donation status it is not clear whether donation alters that risk. Long cohort studies that include donors and matched non-donors of all age groups are needed to better delineate the risks. ## Sex Mortality of healthy non-donors was higher than that of donors in both sex strata. Male sex was a risk factor for death [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] and cardiovascular events.(K. L. Male donors had greater risk of ESRD compared to female donors in one study and a greater risk of being placed on a kidney transplant waiting list, but male sex was not a risk factor for ESRD in a mixed cohort of donors and healthy non-donors. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] Association between sex and lower GFR and hypertension in kidney donors was inconsistent. [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] ; K. L. Psychosocial outcomes were largely similar between genders [bib_ref] Longterm follow-up of living kidney donors: quality of life after donation, Johnson [/bib_ref] [bib_ref] Quality of life in kidney donors, Mjoen [/bib_ref] , though one study found that, among privately insured U.S. donors, women had twice the rate of post-donation depression diagnoses compared to men.(K. L. For all of these outcomes it is not clear if kidney donation alters the risk association with an individual's sex. ## Race When compared with healthy African American non-donors, African American donors have slightly lower mortality but greater rate of ESRD. [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] While the evidence for mortality is likely explained by residual confounding, evidence for ESRD is concerning. Although overall rate of ESRD is low, there is a significant increase in the rate of ESRD in donors compared with healthy non-donors across all races, with African American donors acquiring the greatest risk (absolute risk increase 50.8 / 10,000 person years for African American donors, 29.5 for Hispanic donors, and 22 for White donors, compared to nondonors). [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] In addition, African American donors have higher risk of hypertension but not of albuminuria or diabetes compared with African American nondonors. [bib_ref] Medical outcomes in African American live kidney donors: a matched cohort study, Doshi [/bib_ref] When compared to White donors, African American donors had a greater risk of death, hypertension, diabetes mellitus, chronic kidney disease, proteinuria.. [bib_ref] Living kidney donors requiring transplantation: focus on African Americans, Gibney [/bib_ref] [bib_ref] Risk of End-Stage Renal Disease Following Live Kidney Donation, Muzaale [/bib_ref] However, White donors more commonly developed depression diagnoses compared with non-White donors.(K. L. While African American donors incur the highest ESRD risk attributable to donation on top of already higher risk of ESRD associated with African American race, there is greater organ shortage in African American population with ESRD. Incident rate of ESRD in African Americans is more than 3 times that of Caucasians and African American patients have decreased access to transplantation, that manifests in lower rates of placement on the waiting list and longer waiting times while waitlisted.(K. L. [bib_ref] Health outcomes among non-Caucasian living kidney donors: Knowns and unknowns, Lentine [/bib_ref] Despite the need for African American living kidney donors it is essential to select donor candidates who are less likely to incur harms of donation and to develop ESRD. Further research is needed to establish risks attributable to donation in African American donors compared to healthy African American non-donors and to determine how isolated medical abnormalities such as obesity, metabolic syndrome, glucose intolerance and mild hypertension modify the risk. Testing for apolipoprotein L1 (APOL1) alleles associated with poor renal prognosis might help risk stratification of African American living donors. Aboriginal donors had higher eGFR, but had greater frequency of hypertension, diabetes, and proteinuria compared to White donors. [bib_ref] Long-term medical outcomes among Aboriginal living kidney donors, Storsley [/bib_ref] ## Long term outcomes in living kidney donors with isolated medical abnormalities We identified studies that provided long term follow-up of living kidney donors by kidney function at donation, presence of proteinuria, hematuria, history of nephrolithiasis, obesity, impaired glucose tolerance or fasting glucose, and presence of metabolic syndrome. ## Body mass index Our systematic review includes five studies that compared long-term outcomes of kidney donors by pre-donation BMI, [bib_ref] Kidney transplantation with living donors: nine years of follow-up of 628 living..., Gracida [/bib_ref] [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] [bib_ref] Single-centre long-term followup of live kidney donors demonstrates preserved kidney function but..., Von Zur-Muhlen [/bib_ref] BMI was not associated with all-cause mortality or ESRD in a cohort of donors and matched healthy non-donors. [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] Higher BMI was associated with lower GFR at follow-up, greater risk of hypertension [bib_ref] Long-term consequences of kidney donation, Ibrahim [/bib_ref] [bib_ref] Single-centre long-term followup of live kidney donors demonstrates preserved kidney function but..., Von Zur-Muhlen [/bib_ref] and greater odds of physical component of health related quality of life impairment. The quality of evidence was very low for all outcomes. High BMI is generally considered a contraindication for donation: four existing guidelines considered BMI > 35 a contraindication (ERBP, BTS, SEN ONT, AF). A study by no difference in short term (3 months and 12 months) mortality after kidney transplantation by donors' BMI. A systematic review that addressed a question of the relation between BMI and short-term outcomes of laparoscopic donor nephrectomy did not find any difference between high and low BMI for short term outcomes such as warm ischemia time, estimated blood loss, length of stay, perioperative complications, or decrease in GFR, but did find longer operation duration, greater risk for conversion to open nephrectomy, and greater rise in serum creatinine in donors with higher BMI. [bib_ref] Systematic review and meta-analysis of the relation between body mass index and..., Lafranca [/bib_ref] Only one study had follow-up that exceeded one year; this did not find any difference in serum creatinine between donors with BMI >30 compared to donors with lower BMI, but found greater risk of developing hypertension in obese donors over 11 years of follow-up. [bib_ref] Long-term renal function and cardiovascular disease risk in obese kidney donors, Tavakol [/bib_ref] Two other systematic reviews found greater incidence of hypertension among overweight and obese donors compared to non-obese donors. [bib_ref] Shifting paradigms in eligibility criteria for live kidney donation: a systematic review, Ahmadi [/bib_ref] [bib_ref] Health outcomes for living kidney donors with isolated medical abnormalities: a systematic..., Young [/bib_ref] Our systematic review confirms their finding that obesity is a risk factor for hypertension and cardiovascular disease in kidney donors. These findings are consistent with obesity as a risk factor in a non-donor population.(P. [bib_ref] Overweight and obesity as determinants of cardiovascular risk: the Framingham experience, Wilson [/bib_ref] It remains unknown if donation modifies long term risk of obesity and how obesity interacts with other donor characteristics. From the current literature it is unclear if there is a threshold BMI above which donor prognosis worsens. Future large prospective cohort studies that compare donors from various BMI categories to healthy non-donors from the same BMI category are needed to determine whether overweight and obese donors can be safely accepted for live kidney donation. ## Impaired glucose metabolism, diabetes or metabolic syndrome We identified two studies that reported long term outcomes of donors with impaired glucose metabolism and one study that reported long term outcomes of donors with metabolic syndrome compared to donors without these abnormalities. Non-surprisingly, donors with impaired glucose metabolism were more likely to be diagnosed with diabetes during the followup compared with donors with normal glucose metabolism. Other outcomes did not differ between the groups. Donors with metabolic syndrome had lower eGFR and higher proteinuria that was small in magnitude and of uncertain clinical significance, compared to donors without metabolic syndrome. This evidence is of very low quality. ## Baseline renal function Three studies reported long term outcomes by baseline renal function with very low grade of evidence for all outcomes. These data are limited by variable definition of kidney function at baseline and follow-up, retrospective nature and high attrition. None reported clinical outcomes. Although, in one study donors with baseline eGFR > 90 ml/min took a longer time to develop CKD compared to donors with baseline eGFR< 90 ml/min (median time to CKD > 7 years compared to 3.55 years respectively), [bib_ref] A higher glomerular filtration rate predicts low risk of developing chronic kidney..., Tsai [/bib_ref] evidence was insufficient to recommend a kidney function threshold for kidney donation. In addition, it is unknown whether other donor characteristics such as age, race, or presence of other medical abnormalities should modify the threshold GFR. Further studies are needed to inform clinical practice. ## Blood pressure Only three studies reported long-term donor outcomes by baseline blood pressure. Quality of evidence was low to very low for all outcomes. Higher baseline blood pressure in a mixed cohort of donors and healthy non-donors was associated with cardiovascular mortality and ESRD [bib_ref] Long-term risks for kidney donors, Mjoen [/bib_ref] mirroring findings in the general population. Donors with baseline hypertension were more likely to develop CKD at follow-up.(J. H. [bib_ref] Risk factors for MDRD-GFR of less than 60 mL/min per 1.73 m2..., Lee [/bib_ref] Again, it is unknown whether donation modifies the risk associated with hypertension or how other donor characteristics interact with hypertension influencing the risk of donation. ## Proteinuria, hematuria, nephrolithiasis We found no studies with >100 participants with > 5 years of follow-up that reported outcomes of living kidney donors by proteinuria, hematuria, or history of nephrolithiasis. Donors without a history of nephrolithiasis have a risk of nephrolithiasis comparable to that of matched non-donors. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Male donors had lower rate of surgical procedures for nephrolithiasis compared to male non-donors over 8.4 years of follow-up. [bib_ref] Risk of Kidney Stones With Surgical Intervention in Living Kidney Donors, Thomas [/bib_ref] Few studies of long term outcomes for donors with isolated medical abnormalities were available. Most were retrospective with incomplete follow-up and outcome ascertainment. Studies were too small to document clinical and patient centered health outcomes. Definitions of isolated medical abnormalities and outcomes differed between the studies. Further research should determine life-time risk of ESRD and cardiovascular events associated with the isolated medical abnormalities of interest in the general population and how kidney donation alters the risk associated with medical abnormalities. Pooled data from the currently available well characterized population based cohorts with measurement of proteinuria, kidney function, blood pressure, lipid and glucose metabolism, etc. as well as careful ascertainment of renal and cardiovascular outcomes can be used to define life time risk in the general population. Well-designed prospective cohort studies that include both kidney donors and matched healthy non-donors with standardized definitions and measures of participant characteristics and outcomes are needed to establish risks attributable to kidney donation. Knowledge of these baseline risks and more importantly the risks attributable to kidney donation would greatly facilitate the donor selection process and informed consent. ## Female donors of child-bearing age -pregnancy outcomes Our report includes two studies of pregnancy outcomes in kidney donors. [bib_ref] Pregnancy and birth after kidney donation: the Norwegian experience, Reisaeter [/bib_ref] Both studies compared outcomes of post-donation pregnancies to outcomes of pre-donation pregnancies and found a greater rate of preeclampsia in post-donation pregnancies (6.6% in post-and 0.9% in pre-donation pregnancies in the Ibrahim et al study and 5.7% in post-compared to 2.6% in pre-donation pregnancies in the Reisaeter study). [bib_ref] Pregnancy and birth after kidney donation: the Norwegian experience, Reisaeter [/bib_ref] In addition, Ibrahim but not Reisaeter reported greater rates of prematurity and gestational hypertension in postdonation pregnancies. [bib_ref] Pregnancy and birth after kidney donation: the Norwegian experience, Reisaeter [/bib_ref] Both studies had design features limiting validity and generalizability. One was done in a single center in Norway and pregnancy outcomes were obtained from a centralized birth registry. [bib_ref] Pregnancy and birth after kidney donation: the Norwegian experience, Reisaeter [/bib_ref] Another study was done in Minnesota. Pregnancy outcomes were self-reported by women years after their pregnancies and had a substantial number of donors lost to follow-up. Neither study had matched healthy comparison groups. Neither study reported blood pressure values, kidney function or proteinuria during pregnancy. Bias due to recall in the Ibrahim study as well as bias due to ageing of women between pregnancies could have confounded the results. After the conclusion of our literature search we became aware of an additional study that would have met eligibility criteria. [bib_ref] Gestational Hypertension and Preeclampsia in Living Kidney Donors, Garg [/bib_ref] used an administrative provincial healthcare database from Ontario to match 85 kidney donors without prior history of pregnancy complications in 1:6 ratio with 510 healthy non-donors and followed them prospectively for a median of 10.9 years for the primary outcome of gestational hypertension or preeclampsia. Donors had 131 pregnancy and non-donors had 788 pregnancies during the follow-up. Overall donors and non-donors were matched well with respect to their known characteristics. Outcomes were obtained from diagnostic claims codes. Similarly to the above studies, they found that the combined outcome of gestational hypertension or preeclampsia was more common in donors compared to non-donors (11% vs 5%). There were no differences between donor and non-donor pregnancies for outcomes of Cesarean section, preterm birth at < 37 weeks of gestation, or low birth weight.(A. [bib_ref] Gestational Hypertension and Preeclampsia in Living Kidney Donors, Garg [/bib_ref] Study limitations included that this was a retrospective cohort, used claims based outcome definitions, lacked biochemical parameter measures during pregnancy, controlled for a limited number of variables and thus had potential for unmeasured differences between donors and non-donors, was relatively small in sample size, was conducted in a predominately white population in a single province in Canada and may have had differential outcome ascertainment.(A. [bib_ref] Gestational Hypertension and Preeclampsia in Living Kidney Donors, Garg [/bib_ref] Despite these limitations, this study addressed some sources of bias that affected prior evidence. While supporting prior findings of greater rate of pre-eclampsia and gestational hypertension in kidney donors the overall grade of evidence for these outcomes would not change significantly with inclusion of this study to our report. Other maternal and fetal outcomes were similar in donors and matched non-donors, although the study was not powered to detect rare outcomes. # Limitations We focused our inclusion criteria to studies with at least 100 participants, adequate controls, and follow-up of at least 5 years. In the absence of randomized controlled trials, the best available evidence comes from observational studies. Unfortunately, few prospective cohort studies have been conducted and the bulk of the evidence on this topic comes from retrospective studies. These studies rarely have sufficient data to adequately match donors to non-donor comparison groups or statistically control for all potential confounders. The risk that selection bias between donor and non-donors results in differences in outcomes observed is large. Thus the quality of evidence for each outcome was rated as low to very low. Outcomes are often varied in how they are reported and may not be validated, or do not allow pooling or have small absolute differences of unknown clinical importance. Psychosocial outcomes are defined by a variety of instruments, rarely validated and quite heterogeneous with few clinical differences. This significantly limits our confidence in study results. It is unclear whether the differences in long-term outcomes are due to donation or to inherent differences between the groups. Data for long term outcomes are particularly scarce for donors with isolated medical abnormalities. While clinicians, policy makers, patients and donors must act the strength and quality of data currently available limits accurate information. Further research in the area is needed to inform clinicians, policy makers, donors and recipients alike. # Future research needs In theory, randomized trials could generate estimates of donor risk that are less prone to bias; however, randomized trials of donation are not ethically feasible. Large prospective cohort studies with contemporaneously identified kidney donors and matched healthy non-donors with careful cohort characterization, uniform variable definition and outcome ascertainment are needed. If included, donors with isolated medical abnormalities can be matched to non-donors with similar conditions and condition severity. In particular it would be helpful to know how healthy non-donors differ from healthy donors. Studies that conduct further "donor screening" of healthy non-donors may yield such information. Further research that determines lifetime risk associated with living kidney donation is necessary to fully understand the effect of living kidney donation on donors and their families. This is particularly important because much of the association of outcomes with demographics and comorbidities observed in donors is not unique and may not be due to donation (e.g. increase mortality, cardiovascular events etc. with age, hypertension, obesity etc.). In addition, the field would benefit from determining life-time risk of ESRD and cardiovascular events associated with the isolated medical abnormalities of interest in the general population and how this risk is modified by kidney donation. This information can be used to determine donor acceptance criteria, to provide informed consent of prospective living donors, and to structure long term donor follow-up and support programs. [table] Table 1: PICODD Criteria [/table] [table] Table 2: Evidence Quality Assessment Criteria [/table] [table] Table 3: Key Question 1 Evidence Profile 1a: Peri/Post Nephrectomy Outcomes -Open versus Laparoscopic Nephrectomy [/table] [table] Table 4: Key Question 1 Evidence Profile 1b: Peri/Post Nephrectomy Outcomes -Standard Laparoscopic versus Handassisted Laparoscopic Nephrectomy [/table] [table] Table 5: Key Question 1 Evidence Profile 1c: Peri/Post Nephrectomy Outcomes -Left versus right laparoscopic live donor nephrectomy [/table] [table] Table 6: Key Question 2 Evidence Profile 2a: Peri/Post Nephrectomy Outcomes -Older versus younger donors [/table] [table] Table 7: Key Question 3 Evidence Profile: Peri/Post Nephrectomy Outcomes -Obese versus non-obese donors [/table] [table] Table 8: Key Question 4 Evidence Profile: Long Term Living Kidney Donation Outcomes -Living Kidney Donors compared to Healthy Non-donors [/table] [table] Table 9: Key Question 5 Evidence Profile: Long Term Living Kidney Donation Outcomes -Older donors versus Older Healthy Non-donor Controls [/table]	None	https://europepmc.org/articles/pmc5540357?pdf=render	Abstract The 2017 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors is intended to assist medical professionals who evaluate living kidney donor candidates and provide care before, during and after donation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach and guideline recommendations are based on systematic reviews of relevant studies that included critical appraisal of the quality of the evidence and the strength of recommendations. However, many recommendations, for which there was no evidence or no systematic search for evidence was undertaken by the Evidence Review Team, were issued as ungraded expert opinion recommendations. The guideline work group concluded that a comprehensive approach to risk assessment should replace decisions based on assessments of single risk factors in isolation. Original data analyses were undertaken to produce a “proof-in-concept” risk-prediction model for kidney failure to support a framework for quantitative risk assessment in the donor candidate evaluation and defensible shared decision making. This framework is grounded in the simultaneous consideration of each candidate's profile of demographic and health characteristics. The processes and framework for the donor candidate evaluation are presented, along with recommendations for optimal care before, during, and after donation. Limitations of the evidence are discussed, especially regarding the lack of definitive prospective studies and clinical outcome trials. Suggestions for future research, including the need for continued refinement of long-term risk prediction and novel approaches to estimating donation-attributable risks, are also provided. In citing this document, the following format should be used: Kidney Disease: Improving Global Outcomes (KDIGO) Living Kidney Donor Work Group. KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors. Transplantation. 2017;101(Suppl 8S):S1–S109.
71877bfd6ab98354f6db91f938a07ccb3f30d1b4	pubmed	Epidermoid cancers of the oropharnyx	Epidermoid cancers of the oropharnyx ## Classification The TNM classification of the International Union Against Cancer (UICC) is the one most commonly used. ## Prognostic factors Prognosis is related to: q the degree of locoregional extent as assessed clinically (the size and mobility of the primary tumour, extension to muscle or bone, the presence of lymph nodes and whether they are fixed) q histological factors linked to the tumour (tumour grade, thickness, quality of the surgical margins) q histological factors linked to lymph nodes (invasion, capsular rupture, nodal site and a number of involved nodes). The role of tumour markers as prognostic factors is currently being evaluated. Stage at diagnosis is the factor most predictive of survival. In general, the survival rate of patients with locally advanced disease (stage III or IV) is less than half that of patients with early stage disease (stage I or II). Distant metastases are uncommon at presentation. ## Treatment modalities The therapeutic techniques include surgery, radiotherapy, brachytherapy and combined radiotherapy and chemotherapy. As there are no randomized trials to guide management in oropharyngeal cancer, all therapeutic decisions should be made by a multidisciplinary team, in order to define the treatment best suited to each individual case. ## Tumours of the base of the tongue There is no difference between external radiotherapy, radiotherapy plus brachytherapy or surgery with or without radiotherapy for local control of T1-T3 disease that is in the order of 70-90% (level of evidence C). For T4 tumours, the rate of local control is considerably lower. There may be an advantage in favour of combination surgery and radiotherapy. ## Tumours of the tonsillar fossae and anterior pillars For limited stage disease (T1-T2), external radiotherapy, radiotherapy plus brachytherapy and surgery followed by postoperative radiotherapy give equivalent results in terms of local control (90% for T1 and 75-80% for T2 tumours) (level of evidence C). For T3 tumours, the combination of radiotherapy and brachytherapy is better (65-72%) than radiotherapy alone (37-67%) (level of evidence C). Surgical series do not detail results in terms of T stage. The results of surgery alone are not directly comparable to those of radiotherapy/brachytherapy but are similar. For T4 tumours, no comparison between different treatments is possible. The failure rate is greater than that for T3 tumours (level of evidence C). ## Tumours of the soft palate and uvula The three treatment modalities (surgery, radiotherapy, radiotherapy and brachytherapy) give equivalent rates of local control for limited stage disease (70-100% for T1 and 60% for T2 tumours) (level of evidence C). There is no consensus as to the best modality for stage T3/T4 disease. ## Lymph node areas The results of treatment of cervical lymph node areas with surgery or radiotherapy are equivalent for N0 and N1 disease with a high rates of control (96-100% for N0, 90-93% for N1 disease). If nodes are involved, postoperative radiotherapy seems to reduce the frequency of recurrence (level of evidence C). There is no consensus as to the relative efficacy of radiotherapy and surgery for T3 disease, but as the rate of local recurrence tumours is high (in the order of 30%), if either method is used alone. They are usually combined. This applies to the treatment of lymph node areas for all the cancers of the upper aerodigestive tract. ## Chemotherapy Neoadjuvant and adjuvant chemotherapy do not improve locoregional control or survival in oropharyngeal cancer (level of evidence A). Combined radiochemotherapy, either alone or in addition to surgery, can improve both local control and survival in extensive but potentially curable lesions of the oropharnynx (T3, T4a, N0 to N3) when compared to surgery and radiotherapy (level of evidence A). The role of radiochemotherapy as compared to radiotherapy alone (particularly with hyperfractionation), remains to be confirmed in clinical trials. Neoadjuvant or adjuvant chemotherapy should not be offered to patients with cancer of the oropharynx who are potentially treatable by locoregional methods (level of evidence A). Combination radiochemotherapy given postoperatively for cancers at risk of local recurrence, or given as sole treatment for extensive cancers, are options. If possible, these patients should be included in clinical trials. ## Treatment strategy ## T1, n0, m0 tumours of the oropharnyx There is no standard. Surgery and radiotherapy have equivalent efficacy (level of evidence B). Simple surgical excision by the oral route, brachytherapy or external radiotherapy are therapeutic options . The choice of treatment depends on the likelihood of functional and cosmetic sequelae, on social considerations and the views of the patient. Surgery is preferable for lateral lesions if it can be done via the oral route, as this will result in very few functional sequelae and in young patients lessens the risk of second malignancies. When the margins of surgical excision are narrow (less than 5 mm) or invaded, additional radiotherapy is recommended (level of evidence B). Elective treatment of lymph node areas is optional. If the primary tumour is treated surgically, this should consist of an exploration of the supra-omohyoid area, followed by a selective neck dissection if one or more nodes are positive, preserving the sternocleidomastoid muscle, jugular vein and spinal accessory nerve. For lateral tumours, cervical irradiation can be limited to the ipsilateral cervical zones without compromising local control (level of evidence B). Treatment of local recurrence gives the same results in terms of cervical control and survival (level of evidence B). The choice of treatment of lymph node areas should be made according to the preference of the patient and the multidisciplinary team. ## T1, n1, m0/t2, n0-n1, m0 tumours There is no standard. Surgical excision plus exploration of the supra-omohyoid nodes (with clearance if the nodes are positive), external radiotherapy to the tumour and the cervical nodes or conventional radiotherapy plus brachytherapy are the therapeutic options. The choice of treatment is individualized and dependent on performance status, age and patient preference. The therapeutic options for the primary tumour include surgery and external radiotherapy or brachytherapy plus external radiotherapy, the efficacy of which are equivalent for this type of lesion with a local control rate in the order of 90% (level of evidence B). Surgery is preferable for lateral tumours and infiltrating or ulcerative tumours which are likely to respond less favourably to radiotherapy. Additional radiotherapy is necessary when the surgical margins are narrow (less than 5 mm), or involved, to reduce the risk of local recurrence (level of evidence B). Radiotherapy alone, or radiotherapy plus brachytherapy, is preferable for those in whom surgery is likely to produce a considerable functional deficit. Elective treatment of uninvolved lymph node areas (N0) can be considered for larger tumours (T2) in order to reduce the risk of cervical relapse (level of evidence B). For lateral tumours, cervical irradiation can be limited to ipsilateral cervical nodes (level of evidence B). In patients who have had surgery, the presence of unequivocal nodal disease, histological involvement of several nodes or capsular rupture, are indications for postoperative irradiation to reduce the risk of cervical recurrence (level of evidence B). ## T3, n0-n2 m0/t1-t2, n2, tumours There is no standard. The options are: surgical excision plus neck dissection, radical resection followed by postoperative radiotherapy, postoperative radiochemotherapy, external radiotherapy plus brachytherapy, hyperfractionated radiotherapy or combined radiochemotherapy. External radiotherapy should be considered if the tumour is totally exophytic. All patients should be considered for entry into controlled trials. The macroscopic appearance of the tumour (exophytic or ulcero-infiltrating) can dictate the choice of treatment. Surgery is preferable for infiltrating lesions (level of evidence C). Radiotherapy associated with brachytherapy gives equivalent results to surgery. This is preferable to combination surgery/radiotherapy in exophytic disease or in those cases with minimal infiltration when the predicted functional outcome following surgery is important (level of evidence B). The combination of surgery and postoperative radiotherapy is more effective than radiotherapy alone, or radiotherapy associated with brachytherapy for extensive ulceroinfiltrative tumours (level of evidence B). The addition of chemotherapy either combined with radiotherapy or given postoperatively, significantly increases local control and survival (level of evidence A), but also increases morbidity. At present, there is no consensus as to the role of hyperfractionated radiotherapy. The are various surgical methods (e.g. differences in route of approach, techniques of reconstruction, etc), but there is little difference with respect to functional result. There is no justification for the routine resection of the mandible, except when there is obvious invasion of bone. Postoperative specialist rehabilitation that includes functional aids for every-day living must be offered to patients. In view of the frequency of microscopic nodal involvement, cervical lymph node areas should be treated routinely. Cervical clearance is always preferable to radical clearance because of the difference in functional outcome and because the rate of local control is the same (level of evidence B). For patients with N1 disease, neck dissection or adenectomy is indicated if nodes persist following potentially curable external radiotherapy. This additional surgery is generally recommended if the nodes were originally larger than 3 cm. There is no standard. Treatment and prognosis depends on the operability of the primary tumour and/or lymph nodes. For stage T4, N0-N2, M0/all N3 disease with resectable tumour and nodes the options are: q surgery plus postoperative radiotherapy q surgery plus concomitant radiochemotherapy q concomitant radiochemotherapy alone. Patients should be included in therapeutic trials whenever possible. For resectable tumours, the combination of surgery and radiotherapy is the most efficacious treatment with a control rate in the order of 60-70% (level of evidence B). Postoperative radiochemotherapy or radiochemotherapy alone are options, if possible within controlled trials. The surgical methods utilised (i.e. the route of approach and methods of reconstruction) will depend on the expertise and experience of the surgeon, who must be familiar with the diverse techniques used in these complex situations. In those patients refusing surgery, radiochemotherapy and hyperfractionated radiotherapy given within a study can be considered. For non-resectable T4, N0-N2, M0/all N3 tumours, external radiotherapy and experimental treatment within controlled trials are therapeutic options. Combined radiochemotherapy, with radiotherapy protocols evaluating different schema of hyperfractionation, brachytherapy, new types of ionizing radiation and hyperthermia are being evaluated. The primary aim of treatment is palliation. External radiotherapy will occasionally allow subsequent surgery of curative intent. Patients should be included in controlled trials whenever possible. ## Follow-up Clinical examination, naso-fibroscopy of the upper aerodigestive tract, and clinical assessment of nodal areas are routine investigations. An annual chest X-ray is justified in those patients at risk of a bronchial cancer. Additional investigations are undertaken according to symptomatology. In the case of suspicion of locoregional recurrence or distant spread, the evaluation should be the same as the initial assessment. The recommended frequency of follow-up is: clinical examination every 3 months for the first 2 years, then every 6 months for the following 3 years, then annually. ## Internal reviewers JP Armand (Institut Gustave Roussy, Villejuif), A Banal (Centre René Huguenin, Saint-Cloud), C. Borel (Centre Paul Strauss, Strasbourg), S Bourdin (Centre René Gauducheau, Nantes), B [fig] Figure 1, Figure 2: Treatment of limited-stage carcinoma of the oropharynx Standard there is no standard Options • postoperative radiotherapy • combination radiochemotherapy • inclusion in controlled trials Margins involved or Capsular rupture or Involvement of multiple nodes Evaluation of histological factors and risk of recurrence • excision margins • nodal involvement • capsular rupture Limited disease post surgery Postoperative treatment of limited-stage disease T4, N0-N2, M0/all N3 tumours [/fig] [fig] Figure 5: Treatment of advanced-stage disease [/fig] [table] 40: JL Renaud-Salis et al British Journal of Cancer (2001) 84 (Supplement 2), 37-41 © 2001 FNCLCC Standard • there is no standard • multidisciplinary assessment Options • external radiotherapy • radiotherapy + brachytherapy • combined radiochemotherapy • inclusion in trialsFigure 3 Treatment of extensive disease Epidermoid cancers of the oropharnyx 41 Treatment of T1 − T2, N2 or T3, N0 − N2 disease Figure 4 Assessment of advanced-stage diseaseExtensive disease: T4 and/or all N3 Standards • there is no standard • multidisciplinary assessment Options • external radiotherapy • combination radiochemotherapy • hyperfractionated radiotherapy • new types of ionizing irradiation • radiotherapy combined with hyperthermia • inclusion in controlled trials Standards • there is no standard • multidisciplinary assessment Options • surgery plus postoperative radiotherapy • surgery plus combined radiochemotherapy • combined radiochemotherapy • hyperfractionated radiotherapy • inclusion in controlled trials [/table]	None	https://europepmc.org/articles/pmc2408845?pdf=render	There are about 7000 new cases of epidermoid carcinoma of the oropharynx per year making up 95% of malignant oropharyngeal tumours. The incidence has been steadily rising and France has the highest incidence of this cancer in the world. The vast majority of oropharyngeal cancers are squamous cell carcinomas. This document does not consider other rare neoplasms (e.g. mucosal melanoma, plasmacytoma, soft-tissue sarcoma or minor salivary gland tumours) occasionally found in the head and neck. The management of patients with oropharyngeal cancer requires a multidisciplinary team of individuals with expertise in all aspects of the special care needs of these patients. These guidelines were validated in June 1999 by the working group. An update is planned for 2001/2
5f61b04119e1bbeab3f2b42c53d9c3f9240bca00	pubmed	Guideline for Posterior Atlantoaxial Internal Fixation Assisted by Orthopaedic Surgical Robot	Guideline for Posterior Atlantoaxial Internal Fixation Assisted by Orthopaedic Surgical Robot Atlantoaxial transarticular facet screw fixation (Magerl technique) and C 1 lateral mass screws combined with C 2 pedicle screws fixation (Harms technique) are the most commonly used techniques for posterior internal fixation in the upper cervical spine. Upper cervical spinal surgery is a technically demanding and challenging procedure because of complicated anatomical structures and frequent occurrence of anomalies. Accurate insertion of screws allows for stable and secure internal fixation, which is necessary for both techniques. Traditional methods under fluoroscopic assistance in this region cannot meet the requirements of high levels of accuracy and security during the procedure. Robot-assisted spinal surgery can provide accurate and reliable guidance during the screw insertion, which is evidenced in the literature. As a recently developed technique, robot-assisted surgery is supposed to be performed by skilled surgeons who have received standard training for robotic surgery. The standardized upper cervical spinal surgery assisted by the robot system needs to be introduced to these surgeons. Based on the consensus of consultant specialists, the literature review, and our local experience, this guideline included the introduction of the robotic system, the workflow of robot-assisted procedures, and the precautions to take during procedures. This guideline aims to provide a standardization of the robotic surgery for posterior atlantoaxial internal fixation. # Introduction T he atlantoaxial joint acts as a highly mobile hinge joint at the craniocervical junction. Atlantoaxial deformity usually causes serious bulbomedullary compressive lesions, which mainly results from upper cervical spinal instability and manifests as spinal cord dysfunction. Internal fixation is the mainstay treatment for atlantoaxial instability [bib_ref] Analysis of the treatment of 576 patients with congenital craniovertebral junction malformations, Li [/bib_ref] [bib_ref] Basilar invagination: a study based on 190 surgically treated patients, Goel [/bib_ref]. The initial method for atlantoaxial fixation was using steel wire and laminar clamps; however, it cannot provide enough strength; even with external fixation, the atlantoaxial fixation failure rate was still high [bib_ref] Skeletal traction in the treatment of fractures and dislocations of the cervical..., Gallie [/bib_ref] [bib_ref] Atlanto-axial arthrodesis by the wedge compression method, Brooks [/bib_ref] [bib_ref] The interspinous method of posterior atlantoaxial arthrodesis, Dickman [/bib_ref]. As the fixation technique has developed over the past few decades, the instrumentation for atlantoaxial fixation has been greatly updated, and several types of fixation methods have been reported and applied in surgery [bib_ref] Posterior atlantoaxial fixation: a review of all techniques, Huang [/bib_ref] [bib_ref] Atlantoaxial fixation: overview of all techniques, Mummaneni [/bib_ref]. The most commonly used methods for atlantoaxial fixation were atlantoaxial transarticular facet screws (Magerl technique) [bib_ref] Atlantoaxial transarticular screw fixation: update on technique and outcomes in 269 patients, Finn [/bib_ref] [bib_ref] Surgical stabilization of C1 and C2 fractures, Grob [/bib_ref] or atlantal lateral mass screws combined with axial pedicle screws (Harms technique) [bib_ref] Biomechanical evaluations of various c1-c2 posterior fixation techniques, Sim [/bib_ref]. Both methods can provide rigid fixation and have a high fusion rate. The craniocervical junction comprises complicated anatomical structures, including the atlantoaxial joint, adjacent ligaments, vertebral arteries, and the spinal cord [bib_ref] The effect of variations in the expression of pili on the interaction..., Rayner [/bib_ref]. To make it worse, deformities over the upper cervical spine have aberrant anatomy of both the cervical vertebra structure and the vertebral artery route in individuals [bib_ref] Symptomatic vertebral artery compression by the rod of a C1-C2 posterior fusion..., Terterov [/bib_ref] [bib_ref] The anatomical suitability of the C1-2 complex for transarticular screw fixation, Paramore [/bib_ref] [bib_ref] Anatomic study of the axis for surgical planning of transarticular screw fixation, Igarashi [/bib_ref] [bib_ref] Vertebral artery variations at the C1-2 level diagnosed by magnetic resonance angiography, Uchino [/bib_ref]. As a result, the screw placement is a highly risky procedure, which may result in screw perforations and high vertebral artery injury rate [bib_ref] Analysis of anatomical variations of bone and vascular structures around the posterior..., Hong [/bib_ref] [bib_ref] The ponticulus posticus: implications for screw insertion into the first cervical lateral..., Young [/bib_ref]. The internal fixation in the settings of atlantoaxial instability is regarded as challenging, especially in patients with craniocervical anomalies [bib_ref] A review of complications associated with craniocervical fusion surgery, Lall [/bib_ref]. Traditional posterior screw insertion for atlantoaxial fixation requires extensive exposure during surgery to distinguish the anatomical marks, and the C-arm X-ray machine is repeatedly used to confirm the position of screws. Nowadays, with the development of the concept of "precision medicine", computer-assisted navigation systems and surgical robotics have been developed and widely applied in clinical practice. Many studies have demonstrated that application of a real-time 3D navigation system in surgery will significantly improve the accuracy of screw placement, and reduce intraoperative blood loss and the intraoperative radiation dose compared with the traditional freehand surgical method, especially in atlantoaxial fixation surgery [bib_ref] Surgical management of symptomatic os odontoideum with posterior screw fixation performed using..., Weng [/bib_ref] [bib_ref] Isocentric C-arm three-dimensional navigation versus conventional C-arm assisted C1-C2 transarticular screw fixation..., Yang [/bib_ref] [bib_ref] Comparison of isocentric C-arm 3-dimensional navigation and conventional fluoroscopy for C1 lateral..., Yang [/bib_ref]. With intelligent operation planning, virtual simulation, real-time 3D image guidance, and accurate and stable robot arm operation, the orthopaedic robot system can also achieve precise screw insertion in minimally invasive surgery. Compared with other surgical assistive technology, robot-assisted spinal surgery is reported to have better results in terms of improving the precision of screw placement, reducing intraoperative radiation, and reducing surgical bleeding [bib_ref] Comparison of accuracy of pedicle screw insertion among 4 guided technologies in..., Fan [/bib_ref] [bib_ref] Comparison of the accuracy between robot-assisted and conventional freehand pedicle screw placement:..., Liu [/bib_ref]. Based on review of the literature on orthopaedic robot systems that are used in spinal surgery, the TianJi Robot (developed by Beijing Jishuitan Hospital and Beijing Tinavi Technology) is the only robot that can be used for posterior screw insertion in the craniocervical area [bib_ref] Spinal robotics: current applications and future perspectives, Roser [/bib_ref] [bib_ref] A review of surgical robots for spinal interventions, Bertelsen [/bib_ref] [bib_ref] Robot-assisted posterior C1-2 transarticular screw fixation for atlantoaxial instability: a case report, Tian [/bib_ref]. Specific robot-assisted surgical procedures and operative precautions for posterior atlantoaxial transarticular screw fixation (Magerl technique) and C 1 lateral screw together with C 2 pedicle screw fixation (Harms technique) are described below. ## Orthopaedic surgical robot A n orthopaedic surgical robotic system mainly uses preoperative or intraoperative images for surgical planning, providing accurate positioning of surgical tools or implants through robotic arm movement and rigid guidance, assisting the surgeon to complete surgical operations. The work process mainly includes four steps: (i) surgical planning, where the surgeon carries out the surgical planning and selects suitable implants on the patient images using the device software; (ii) spatial registration, involving obtaining the spatial coordinates of the surgical trajectories via patent algorithm and tools; (iii) trajectory positioning, where the robotic arm automates movement by holding the surgical instruments to the desire position according to the spatial coordinates of the surgical trajectory; and (iv) assisted surgery, where the surgeon performs the surgical operation under the guidance of the robotic arm. The orthopaedic surgical robotic system is composed of multiple sets of equipment, and its work steps involve images and optical data acquisition, spatial registration and image fusion, surgical planning, and mechanical positioning. To avoid ambiguity and standardize the work steps, this study will define the hardware equipment, the operation steps, and the concepts related to the orthopaedic surgical robotic system. The principles and equipment are illustrated below [fig_ref] C 1: Lateral Mass Screw and C 2 Pedicle Screw Internal Fixation [/fig_ref]. ## Computer-assisted navigation technique A surgical assisted technique that combines modern computer, stereotactic, and medical imaging, to guide the surgeons for precise surgical planning and operation. ## Orthopaedic surgical robotic technique A surgical assisted technique that combines computerassisted navigation and surgical robotics, to guide the surgeons for precise surgical planning and operation. ## Patient tracker A tracker connected to the patient's anatomy during surgery to reflect or emit infrared light to the optical tracking camera. ## Robotic arm A mechanism having two or more degrees of freedom, a certain degree of autonomy, and that is capable of automatically performing a predetermined task according to human instructions. ## Robotic arm tracker A tracker connected to the robotic arm during surgery to reflect or emit infrared light to the optical tracking camera. ## Camera The main component of the optical tracking system, a mechanical device for spatial positioning and tracking. The working principles of the TianJi Robot system. ## Guider A navigation surgical tool that is attached to the end of the robot arm for positioning the surgical trajectory and has a quick connection interface to the base. ## Registration A mechanical device for spatial coordinate mapping and calibration. ## Robotic workstation The robotic workstation holds the navigation computer system, the surgical planning software, and the robot operation software. ## Positioning The process of moving the robotic arm and guider to the planned trajectory position. ## Target audience All personnel who participate in orthopaedic robot-assisted spinal surgery, which includes spine surgeons, nurses and engineers, are the target audience of this operative guideline. Manipulation of the surgical procedure and relative machine or mechanical devices should follow the standardized operative process recommended by the guideline. Proceed with precaution and consider the factors that could influence robotic navigation accuracy and endanger the patient's safety. ## Indications and contraindications Indications Indications for treatment include: instability of the atlantoaxial joint caused by various pathogenesis with or without bulbomedullary compression; spinal anomalies atlas dysplasia (e.g. occipitalization of the atlas), axis dysplasia (e.g. os odontoid), basilar invagination, and Klippel Feil syndrome; spinal trauma, including odontoid fracture and transverse ligament injury; and autoimmune disease and tumors (rheumatoid arthritis and tumors compromising the atlantoaxial joint stability). ## Contraindications Contraindications include: systematic diseases, such as severe hemorrhagic disease, respiratory function failure, and other diseases that contraindicate general anesthesia or a major surgery; patient position requirement cannot be satisfied; patient cannot tolerate radiation exposure; tracker position cannot meet the needs of accurate navigation; and a qualified navigation image cannot be obtained. ## Robot-assisted procedures ## Patient preparation After general anesthesia, patient positioning is the same as the requirements for traditional procedures: place the patient in a prone position and fix the head onto the operating table using the Mayfield frame. If Magerl's procedure is performed and preoperative C 1,2 dislocation exists, C 1,2 reduction should be attempted by adjusting the position of the frame, which is monitored under fluoroscopy. If the C 1,2 fusion is performed with autogenous iliac bone grafting, bone grafting is suggested to be performed prior to the C 1,2 procedure. During prepping and draping, an anchoring site for the patient tracker should be prepped and exposed. In open surgery, exposure is extended for anchoring the patient tracker. In percutaneous minimally invasive surgery, the patient tracker should be anchored at first and subsequently the stab wounds are created under robotic guidance. ## Robotic equipment preparation The TianJi Robot system consists of a robotic arm, an optical tracking system, a robotic workstation, and a navigation toolkit. The TianJi Robot system and the components around the robotic arm are shown in Figs. 2 and 3. All the relevant equipment is recommended to be arranged as follows in the operating room [fig_ref] Figure 4: Schematic diagram of operation room [/fig_ref]. Posterior Atlantoaxial Transarticular Screw Internal Fixation (Magerl Technique) 1. The patient tracker is commonly anchored onto the adjacent vertebral spinous process. The clamp connecting the patient tracker to the spinous process should be tightened and then the patient tracker is switched on (during open surgery: anchor the patient tracker onto the C 3 or C 4 spinous process; during percutaneous surgery: anchor the patient tracer onto the Mayfield frame). If posterior sublaminar wire fixation (Brooks technique) is performed at the same setting, the titanium cable is passed beneath the C 1 and C 2 lamina. Tighten the titanium cable, and the temporary clamp is used to fasten the titanium cable. 2. Adjust the position of the camera towards the operation space and the patient tracker. 3. Install the registration and place it into the operating area so that the registration is within the fluoroscopy field. 4. Image acquisition: Perform 3D image scanning and complete the registration and spatial registration. 5. Designing and planning: Plan bilateral Magerl screws' parameters (diameter, length) in the robotic workstation. The screw entry point and the direction are designed based on the 3D images. 6. After the screw guider is installed, move the guider to the surgical field. The positioning accuracy will be displayed in the software interface in real time during the movement of the robot arm. Note: (i) If you find that the robot arm may touch the patient or surrounding obstacles, immediately press the emergency stop button; and (ii) the guider should be as close as possible to the operating area. 7. Sleeve installation: Place the sleeve into the screw guider. For percutaneous minimally invasive surgery, stab wounds can be made according to the position of the sleeve in contact with the skin. For open surgery, the sleeve is brought to the cortical bone surface after the bony surface is exposed. 8. Screw placement: The K-wire was drilled into the vertebrae, and then the optimal position is verified by fluoroscopy. If it is a cannulated screw, it can be instrumented directly along the K-wire; if it is a conventional screw, use the cannulated tap to prepare the trajectory first, and then insert the screw. 9. Remaining procedures: After the instrumentation is completed, verify the screw position by fluoroscopy. If the bone graft fusion is planned, complete corresponding operations. (7) of Magerl technique. 8. Screw placement: The K-wire is drilled into the vertebrae, and then the optimal position is verified by fluoroscopy. If it is a cannulated screw, it can be instrumented directly along the K-wire; if it is a conventional screw, use the cannulated tap to prepare the trajectory first, and then insert the screw. 9. Remaining procedures: after the instrumentation is completed, verify the screw position by fluoroscopy. If the reduction is satisfactory, install the connecting rod and pre-tighten the screw heads; if the repositioning is unsatisfactory, then further adjustment is needed for atlantoaxial alignment or the curvature of the connecting rod until the reduction is satisfactory. If the bone graft fusion is planned, complete the corresponding operation [fig_ref] Figure 5: Workflow of robot-assisted procedures [/fig_ref]. Precautions R obot-assisted orthopaedic technology is a complex system based on advanced technologies such as image registration and fusion, robotics and automation technology, and precise equipment manufacturing. Its accuracy depends on these components of systems working properly; thus, it is affected by many factors. Common factors causing errors and strategies dealing with common errors are listed below. ## Personnel requirements Doctors should have conventional surgical experience, relevant anatomical knowledge to determine whether the navigation system is accurate or not, and the ability to switch to conventional surgery when the robotic system fails to operate. ## Environmental and equipment requirements The operating room should have an appropriate area, with a good grounding system and power supply. The operating table should be radiolucent, avoiding metal artifacts that may affect the fluoroscopic process. The operating table base should not obstruct the intraoperative fluoroscopic machine obtaining intraoperative images. The operating environment should meet the normal working requirements according to the robot manual (including ambient temperature, humidity, air pressure, and voltage). The preoperative navigation kit should be sterilized and placed on the operating table. The camera is placed on one side of the operating bed, above and facing towards the field, and cannot be blocked by the tray or the head frame. The C-arm machine is moved from one side of the operating bed when it is used and is suggested to have a ground mark to guide the position properly. The main control trolley and the C-arm should be far from the operating area to facilitate the technician's operation. ## Image acquisition requirements The fluoroscopic images should demonstrate all the bony structures of key anatomical regions. The registration is clearly shown in the fluoroscopic field and the camera could simultaneously recognize and capture the spatial position information of the patient tracker and the robot arm tracker. ## Tracker placement requirements The tracker should be placed according to the operation and the patient's condition. When placing an external tracker, it should be firmly anchoring on the free arm, and the free arm should be firmly anchored onto the Mayfield head frame to avoid errors. ## Navigational deviation: image drift The spatial position of the anatomy at the surgical site is required to be relatively fixed after the images are acquired. Any factors causing the image deviations between the guided position and the real position are regarded as image drift. The doctor should have the ability to determine if the navigation image is drifting. When image drift is suspected, select obvious anatomical landmarks, such as apex of spinous process, facet joints or transverse roots for verification. If the positioning is accurate, continue the surgery; however, if it is uncorrectable drift, rescanning is necessary. Common reasons for image drift include the following items, which need to be noted. Relative Displacement of the Anatomical Structures and the Patient Tracker 1. Due to the large degree of motion of the upper cervical vertebrae, if the surgeon is excessively pulling the soft tissue, it will cause a large relative displacement between the bony structures. Therefore, the intraoperative manipulation needs to be gentle, and the positioning accuracy should be noted during the manipulation. 2. Decompression or osteotomy will destroy the stability of the spine, resulting in relative displacement between the anatomical structures. If intraoperative conditions permit, the procedure of fixation is advised to be perform at first and followed by the remaining procedures to avoid image drift. If the accuracy is still uncertain, the doctor should select the anatomical landmark for verification. 3. If the patient's position changes, it may cause the changing of the spatial position of the patient's anatomical structures, and image acquisition and surgical planning should be re-executed. ## Patient tracker loosening The patient tracker needs to be firmly anchored to the patient's anatomy. If the intraoperative tool or the surgeon accidentally moves or touches the tracker, or the tracker is pulled by the skin during minimally invasive surgery, the position of the tracker would be changed. That will lead to a decrease in positioning accuracy or a failure in positioning. In this situation, image acquisition and surgical planning should be repeated. ## Misalignment caused by lighting problems The robot system must maintain good reflection and reception of infrared light. If the angle or distance exceeds the receiving range, or other light interference, it may cause misalignment. The camera should be adjusted so that the surgical field is in the center of its detection range. Since the tracker reflects the light to the camera, strong direct light and blood staining on the refection ball of the tracker may interfere the refection and reception process of infrared light. Thus, strong direct light or blood staining on the tracker should be avoided. Regular Maintenance of Robot Equipment 1. Data cable: Check whether the transmission data line interface is loosening or disconnected. If the data cable is aging, it needs to be replaced. 2. Robotic tools: Before the operation, the robot tool should be carefully checked for metal fatigue to prevent the tool from breaking during the operation. 3. System accuracy: Accuracy calibration should be performed periodically. ## Others The upper cervical vertebra has a high degree of movement, which requires a careful and experienced surgeon. If the robotic arm is found to be unable to reach the designated position due to the surrounding environment during the operation, the surgical path should be adjusted. If there is a sudden power failure of the robot system, the system should be restarted: If only the mechanical system of the mechanical arm is powered off, it is generally unnecessary to reacquire images and redo the surgical planning, but if the overall system of the robot is powered off, the image acquisition and surgical planning should be repeated. [fig] Figure 2: TianJi Robot system. [/fig] [fig] C 1: Lateral Mass Screw and C 2 Pedicle Screw Internal Fixation (Harms Technique) 1. The patient tracker is commonly anchored onto the adjacent vertebral spinous process. The clamp connecting the patient tracker to the spinous process should be tightened and then the patient tracker is switched on (during open surgery: anchor the patient tracker onto the C 3 or C 4 spinous process; during percutaneous surgery: anchor the patient tracer onto the Mayfield frame). 2. Same as step (2) of Magerl technique. 3. Same as step (3) of Magerl technique. 4. Same as step (4) of Magerl technique. 5. Designing and planning: plan bilateral lateral mass screw and C 2 pedicle screw parameters (diameter, length) in the robotic workstation. The screw entry point and the direction are designed based on the 3D images. 6. Same as step (6) of Magerl technique. 7. Same as step [/fig] [fig] Figure 3: TianJi Robot navigation and positioning tools installation, including fixed ring, tracker, tool guider, lock screw, and holder base. [/fig] [fig] Figure 4: Schematic diagram of operation room. When performing robotic surgery, it is recommended that the operation room be arranged as shown. [/fig] [fig] Figure 5: Workflow of robot-assisted procedures. [/fig]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/os.12454	Atlantoaxial transarticular facet screw fixation (Magerl technique) and C1 lateral mass screws combined with C2 pedicle screws fixation (Harms technique) are the most commonly used techniques for posterior internal fixation in the upper cervical spine. Upper cervical spinal surgery is a technically demanding and challenging procedure because of complicated anatomical structures and frequent occurrence of anomalies. Accurate insertion of screws allows for stable and secure internal fixation, which is necessary for both techniques. Traditional methods under fluoroscopic assistance in this region cannot meet the requirements of high levels of accuracy and security during the procedure. Robot‐assisted spinal surgery can provide accurate and reliable guidance during the screw insertion, which is evidenced in the literature. As a recently developed technique, robot‐assisted surgery is supposed to be performed by skilled surgeons who have received standard training for robotic surgery. The standardized upper cervical spinal surgery assisted by the robot system needs to be introduced to these surgeons. Based on the consensus of consultant specialists, the literature review, and our local experience, this guideline included the introduction of the robotic system, the workflow of robot‐assisted procedures, and the precautions to take during procedures. This guideline aims to provide a standardization of the robotic surgery for posterior atlantoaxial internal fixation.
d799643bbfb5c49d560a6b4951e6b2230a64bb5d	pubmed	Considerations for Pediatric Heart Programs During COVID-19: Recommendations From the Congenital Cardiac Anesthesia Society	Considerations for Pediatric Heart Programs During COVID-19: Recommendations From the Congenital Cardiac Anesthesia Society GLOSSARY AAOCA = anomalous aortic origin of a coronary artery; ACS = American College of Surgeons; AGMP = aerosol-generating medical procedures; ASE = American Society of Echocardiography; CCAS = Congenital Cardiac Anesthesia Society; CHD = congenital heart disease; CICU = cardiac intensive care unit; CMS = Center for Medicare and Medicaid Services; COVID-19 = coronavirus disease 2019; CPB = cardiopulmonary bypass; CT = clotting time; EACA = epsilon amino caproic acid; ECMO = extracorporeal membrane oxygenation; EXTEM = extrinsic test from thromboelastometry; FC = fibrinogen concentrate; FEIBA = factor eight inhibitor bypassing activity; FFP = fresh frozen plasma; FIBTEM = fibrinogen test from thromboelastometry; HEPA = high-efficiency particulate air; IDA = iron-deficiency anemia; MUF = modified ultrafiltration; PCC = prothrombin complex concentrate; PDA = patent ductus arteriosus; PLT = platelets; PPE = personal protective equipment; RBC = red blood cell; RT-PCR = reverse transcription-polymerase chain reaction; RV-PA = right ventricle to pulmonary artery; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TEE = transesophageal echocardiography; TXA = tranexamic acid; VAD = ventricular assist device T he coronavirus disease 2019 (COVID-19) pandemic has impacted congenital cardiac surgical programs with significant reduction in case load, implementation of patient triage strategies, and development of personal protective equipment (PPE) guidelines. This document summarizes current status and implications of COVID-19 in congenital cardiac surgery outlining recommendations from the Congenital Cardiac Anesthesia Society (CCAS; [fig_ref] Figure 1: Considerations for Pediatric Heart Programs during COVID-19 pandemic, postpandemic, and the future [/fig_ref]. ## Reorganization of heart program decrease in case load and prioritization In response to the rapid recognition of challenges faced by health care infrastructures related to the COVID-19 outbreak, a broad call to restrain "elective" surgical procedures was announced by the Center for Medicare and Medicaid Services (CMS) and the American College of Surgeons (ACS) in March 2020.Multidisciplinary committees should discuss cases prioritization based on ACS definition of emergent and urgent procedures, taking into consideration hospital capacity and local resources available during the COVID-19 pandemic . [bib_ref] COVID-19: crisis management in congenital heart surgery, Stephens [/bib_ref] ## Heart transplantation To date, most pediatric heart transplant programs in the United States continue to deem heart transplant as an urgent/emergent surgical procedure. The recommendation from the International Society of Heart and Lung Transplantation states that the patient should report no new-onset clinical symptoms consistent with COVID-19, no close contact with a confirmed case, and no travel within 14 days (https://ishlt.org/ishlt/media/documents/SARS-CoV-2_-Guidance-for-Cardiothoracic-Transplant-and-VAD-centers.pdf). In addition, the document recommends COVID-19 testing before transplant, assuming a rapid turn-around assay is available. Patients with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection should not undergo transplantation. In regard to the processes that surround donor offers and procurement, the surgical recovery of organs by the local teams should be promoted whenever possible to minimize potential exposure and traveling across the country. ## Monitoring the wait list Most congenital cardiac programs ceased scheduling elective procedures in anticipation of the surge in COVID-19-positive patients requiring hospitalization. This has resulted in a dynamic expanding procedural wait list which will have to be managed with consideration of the following: 1. Continuously reassessing and reprioritizing of all patients on list a. Implementing telehealth, virtual check-in, and/or remote monitoring 2. Recognition that every patient's clinical status and pending procedure is unique and a decision to further postpone must be multidisciplinary based on: a. Potential for significant deterioration which could result in harm such as therapy otherwise not indicated, prolonged hospital stay, or mortality b. Institutional abilities to schedule cases (physical plant, human resources) c. Time course of COVID-19 crisis 3. Ongoing effective, timely communication with patients/families, referring physicians, and proceduralists As restrictions lessen, a plan needs to be in place not only for caring for the remaining patients on the wait list but also for addition of new patients. ## Resumption of activity In the COVID-19 outbreak, defining the transition of pandemic to postpandemic remains unclear. The stringency and duration of strategies such as physical distancing and PPE use will impact the timing and magnitude of a potential "second wave" of infections which may prolong the pandemic phase. Formal documentation of herd immunity by testing individuals' immune status may help define a stable SARS-CoV-2 resilient health care workforce, allowing faster return to higher surgical volumes. Prioritization based on medical needs across surgical specialties is important as many pediatric cardiac centers will share resources (eg, personnel) with other surgical specialties. Monitoring for clinical deterioration during recommended wait times mitigates harm, affords opportunities to inform future care plans, and provides a structured and just approach to return of surgical services. ## Resuming activity in practice In the recovery phase following the COVID-19 pandemic, delayed surgeries will need to be rescheduled. This will likely require overtime shifts and expanded utilization of currently available operating rooms and catheterization laboratories. In some institutions, additional operating rooms may be allocated to meet this demand, but that approach assumes that perioperative personnel can be mobilized. In many institutions, cardiac intensive care unit (CICU) and step-down cardiac floor capacities are a limiting factor in the number of cases that can be performed. Programs that have well-established "fast-track" protocols will be able to leverage that expertise to help relieve potential congestion in the CICU and stepdown floor. In each program, serious consideration will have to be given to further delaying procedures associated with long CICU and hospital stays in favor of performing procedures with short stays. To put a finer point on it, a program may not be able to justify performing a procedure with an average CICU stay of 6-7 days in place of performing multiple cases with an average CICU stay of 1-2 days. "Fast-track" surgical procedures and diagnostic catheterizations could be performed on the weekend to reduce the inpatient volume during the week. Alternatively, these patients could be recovered in an extended recovery room environment allowing the CICU and step-down units to handle a larger caseload. ## Diagnostic testing for sars-cov-2 The purpose of testing is to facilitate diagnosis to guide supportive patient management and to implement measures to limit the spread of the virus. There are 2 broad categories of SARS-CoV-2 tests: those that detect the virus itself and those that test for the immune response of the host to the virus. Tests for Viral RNA The preferred testing method is the real-time reverse transcription-polymerase chain reaction (RT-PCR). Within 5 days of the onset of symptoms of COVID-19, patients have high viral loads in their upper and lower respiratory tracts. [bib_ref] Viral load of SARS-CoV-2 in clinical samples, Pan [/bib_ref] A nasopharyngeal or oropharyngeal swab may be used to collect a specimen. For patients with pneumonia, lower respiratory tract secretions may be collected from bronchoalveolar lavage fluid. Detection rates in each sample vary between patients and may change over the course of their illness. [bib_ref] The laboratory diagnosis of COVID-19 infection: current issues and challenges, Tang [/bib_ref] Testing patients for SARS-CoV-2 helps identify those who are infected, which is useful for individual patient management, as well as for implementing mitigation strategies to prevent spread in health care facilities and the community. It may also help with the appropriate choice of PPE for health care providers. Although these tests have become more widely available, the huge demand for them has created supply chain challenges. One of the current limitations regarding preoperative testing for SARS-CoV-2 comes from the variability in sensitivity and specificity of the different tests available. [bib_ref] Laboratory diagnosis of emerging human coronavirus infections -the state of the art, Loeffelholz [/bib_ref] The rate of false negative for some of those tests can be as high as 30%. It is therefore extremely important to consider the sensitivity and positive predictive value of the test used in each institution before a decision to deescalade the level of PPE can be made. The vast majority of heart programs have started testing inpatients and outpatients scheduled for cardiac surgery and cardiac catheterization. ## Antibody tests Antibody tests can identify individuals who have been exposed to SARS-CoV-2 and have developed immunity, which could protect them from future infections. Development of immunity may enable previously infected health care workers to return to work with relative safety. [bib_ref] Protective immunity after COVID-19 has been questioned: what can we do without..., Melgaço [/bib_ref] Congenital heart programs could consider deployment of these individuals to environments where the risk of infection is highest thereby protecting nonimmune members of the workforce from infection. ## Minimizing the impact of exposure to covid-positive individuals on small dedicated teams Cardiac anesthesia teams are composed of a small number of dedicated attendings and extended care providers. If a substantial number of cardiac anesthesia team members become ill or need to self-isolate due to exposure to a COVID-19-positive patient, colleague or family member, normal care delivery cannot be sustained. Segregating anesthesia providers and other cardiac specialty members into teams that are kept isolated from each other minimizes the risk of virus transmission. Attempting to operationalize team separation is challenging when faced with 24/7/365 coverage, simultaneous emergencies and illness (COVID-19 or otherwise), or exposure of one or more team members to a positive patient. ## Airway manipulation Aerosol-generating medical procedures (AGMP), such as endotracheal intubation and extubation, mask ventilation, tracheal suctioning, and inadvertent lung injury during positive pressure ventilation produce significant amounts of aerosolization and may be a significant source for the spread of SARS-CoV-2. [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref] Careful airway management of suspected or infected patients is therefore crucial. Adequate muscle relaxation and rapid sequence induction are recommended to avoid mask ventilation. [bib_ref] Pediatric airway management in COVID-19 patients -consensus guidelines from the Society for..., Matava [/bib_ref] Cuffed tubes should be utilized to minimize gas leaks. Selection of the nasal or oral route for intubation should be based on institutional experience and preference with consideration given to the priority of rapidly securing the airway. Once the trachea is intubated and the endotracheal tube secured, an inline suction device should be placed to avoid inadvertent contamination of the environment during tracheal suctioning. A high-efficiency particulate air (HEPA) filter should routinely be placed distal to the Y-connector of the circle system in addition to the filters normally placed on the inspiratory and expiratory limbs. Regardless of the site of extubation, appropriate PPE and room decontamination is essential. ## Ppe in the operative room or the cardiac catheterization suite In COVID-19-positive patients or suspected patients, PPE must be worn at all times. In asymptomatic patients who have not undergone COVID-19 testing, PPE is recommended during AGMP. Some institutions with well-established COVID-19 testing are relaxing the requirement for PPE during AGMP for patients who have tested negative in the preceding 24 hours. PPE should, at a minimum, include properly fitted N95 masks, eye and face shields, fluid impervious gowns, and gloves. When available, additional equipment such as positive airway purifying respirators should be considered to further reduce the risk of exposure. In all patients, except those tested to be negative for COVID-19, all nonessential personnel should be a minimum of 6 feet from the patient or ideally outside the room during AGMP. Only the minimum number of properly trained personnel should be in attendance during any AGMP. The use of video laryngoscopes is highly recommended both to assist in airway visualization and to maximize the distance from the patient to the caregiver's face during the procedure. It is recommended that a "COVID" cart with all of the appropriate equipment be placed immediately outside the patient's room to minimize time acquiring the necessary items. Finally, it is the responsibility of the provider to properly dispose of all contaminated materials into a double-sealed bag at the conclusion of the procedure while gowned in PPE to avoid accidental contamination of environmental staff. To prevent contamination of anesthesia and perioperative personnel and workspace equipment, perioperative simulation should be promoted. Checklists should be created in collaboration with Surgical Quality and Safety teams. ## Caring of newborn with congenital heart disease born of a covid-19-positive mother In retrospective analyses of neonates born to mothers with suspected or confirmed COVID-19, many newborns remained COVID-19 negative, but several exhibited respiratory distress and death have XXX XXX - Volume XXX - Number XXX www.anesthesia-analgesia.org 5 been reported. 9,10 In 1 cohort, 3 newborns who were infected with SARS-CoV-2 had positive nasal and anal swabs at days 2 and 4 of life. All 3 experienced fever, lethargy, and pneumonia and were nasal swab negative by day 6 or 7 of life.The most likely route of transmission of SARS-CoV-2 from mother to newborn is via respiratory droplets during close contact. In the setting of acute maternal COVID-19 shortly before birth, maternal antibody production and fetal passive immunity may not have had time to develop, leaving the neonate relatively defenseless. [bib_ref] Expert consensus for managing pregnant women and neonates born to mothers with..., Chen [/bib_ref] There is currently no evidence of vertical transmission of SARS-CoV-2 from mother to fetus. Multidisciplinary planning must occur ideally before and certainly after the birth of a child with CHD who is born of a suspected or confirmed COVID-19 mother. Severe COVID-19 symptoms in the mother may lead to fetal distress and preterm labor and delivery, which may gravely impact the newborn cardiopulmonary physiology. [bib_ref] Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia, Zhu [/bib_ref] After delivery, the cord should be immediately clamped and the neonate isolated from the mother. If transport is required to the pediatric hospital after birth, full PPE is required throughout all phases. The newborn should be isolated and closely monitored for symptoms for 14 days. If emergent surgery is required, the operating room team must treat the newborn as SARS-CoV-2 infected and observe strict isolation procedures. In the middle ground are the neonates with lesions typically treated nonemergently within the first few days of life, such as the Norwood or arterial switch operations. The risks and benefits of proceeding with surgery versus waiting must be carefully weighed by a multidisciplinary team on a case by case basis. ## Cardiovascular imaging Echocardiography represents the primary imaging modality for diagnosis, management, and longterm surveillance of these patients. In response to the spread of COVID-19, the American Society of Echocardiography (ASE) has recently published a statement addressing protection of patients and echocardiography service providers to prevent viral transmission. Based on the recognition that children and those affected by CHD represent potential confounding elements in this pandemic, recommendations specific to the pediatric, fetal, and CHD populations have also been outlined in a supplement statement. [bib_ref] Specific considerations for pediatric, fetal, and congenital heart disease patients and echocardiography..., Barker [/bib_ref] These are based on acknowledging known differences between the pediatric and adult populations in terms of COVID-19 prevalence, symptomatology, and disease severity and other factors that impact imaging. [bib_ref] Epidemiology of COVID-19 among children in China, Dong [/bib_ref] Most echocardiography laboratories have adopted these ASE recommendations which CCAS supports. Key points of these continually updated guidelines suggest that echocardiographic studies be performed when they are expected to provide clinical patient benefit based on established appropriate use criteria with other examinations to be deferred/rescheduled. 14 It is desirable to determine patient COVID-19 status whenever possible, to limit provider exposure during the examination, and to prevent equipment/ reading room transmission. Performance of transesophageal echocardiography (TEE) imaging is considered to increase the risk of SARS-CoV-2 spread secondary to both droplet and aerosol transmission. Currently, nonessential TEE examinations and those unlikely to impact clinical care have been or are being postponed or canceled. In many adults with CHD, these studies take place in sedated, nonintubated patients, a circumstance that could provoke aerosolization of a significant number of viral particles in infected patients. Consequently, alternative imaging modalities should be considered outside clinical settings that strongly merit the use of TEE such as during urgent or emergent cardiac surgery in neonates, children, and adults with CHD, and selected nonelective catheter-based interventions. Other situations require careful assessment of the benefit of the TEE study versus risks related to potential COVID-19 exposure and should also consider available PPE resources. Although epicardial echocardiography is considered a valuable adjunct to intraoperative imaging, TEE is known to overcome many of its limitations. Accordingly, during the COVID-19 pandemic, standardized TEE algorithms should be developed in conjunction with all stakeholders and influenced by local institutional policies, that consider study indications and COVID-19 status to guide procedural precautions and the use of PPE, as well as protocols for equipment handling, allowing for ongoing patient benefits and the safest application of the imaging modality. [bib_ref] Specific considerations for pediatric, fetal, and congenital heart disease patients and echocardiography..., Barker [/bib_ref] [bib_ref] ASE statement on protection of patients and echocardiography service providers during the..., Kirkpatrick [/bib_ref] CARDIOPULMONARY BYPASS AND ANTICOAGULATION FOR COVID-19 PATIENTS There are currently no reported cases of children with known COVID-19 undergoing cardiac surgery with cardiopulmonary bypass (CPB). There is no evidence that the anticoagulation strategy for a patient undergoing a procedure on CPB should be altered due to COVID-19, but the cardiac care team should be aware that the thrombosis risk is increased in this population. [bib_ref] High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter..., Helms [/bib_ref] In the event CPB is utilized in a patient with COVID-19, scavenging of exhaust gas from the CPB machine is recommended. Currently, there are publications from China showing the COVID-19 virus in the blood. [bib_ref] Detection of SARS-CoV-2 in different types of clinical specimens, Wang [/bib_ref] This would indicate it may be possible to transmit the virus to the exhaust ports of an oxygenator and out into the environment. However, plasma leakage into the hollow fiber oxygenator is the most likely way for the virus to be aerosolized from the CPB circuit. Fortunately, when oxygenators are www.anesthesia-analgesia.org ANeSTheSiA & ANALGeSiA COVID-19 and Pediatric Heart Programs used as recommended, plasma leakage is extremely uncommon. Scavenging systems are easy to apply and already utilized in many centers that routinely deliver inhaled anesthetic gases during CPB. ## Blood shortage and conservation Although the reduction in elective cases has decreased blood product utilization, social isolation measures have resulted in a rapid decrease in overall blood donations. Daily communication with the blood center and key clinical teams is necessary to predict whether inventory is available to cover daily needs. As cardiac anesthesiologists, it is our duty to implement perioperative blood conservation strategies. Blood conservation guidelines for neonates and children undergoing cardiac surgery have been published and provide a resource to help develop institutional protocols. [bib_ref] Patient blood management for neonates and children undergoing cardiac surgery: 2019 NATA..., Faraoni [/bib_ref] Although not well studied in children with CHD, preoperative treatment of anemia and iron deficiency should be considered with either oral or intravenous iron. An erythropoietin stimulating agent may be considered in specific cases. Prophylactic administration of an antifibrinolytic should be used when appropriate. Efforts should also be made to minimize the resultant hemodilution of CPB, including reduction of the prime volume and the use of a nonblood prime in infants weighing >5 to 7 kg. [bib_ref] Fresh frozen plasma versus crystalloid priming of cardiopulmonary bypass circuit in pediatric..., Dieu [/bib_ref] Because units of red blood cells are aging, blood banks may not be able to provide fresh blood for neonatal cardiac patients. Due to the risk of hyperkalemia associated with older and large volume transfusions, physicians should be vigilant regarding the age of blood products received, the need for irradiation, and the use of washing techniques before transfusion. Nonallogeneic coagulation agents, like desmopressin, fibrinogen concentrate, 20 or prothrombin thrombin complex concentrate, may be considered based on underlying coagulopathy. Multimodal center-specific transfusion algorithms using a restrictive approach and coagulation assessment based on either standard coagulation tests or viscoelastic tests have been shown to be effective in reducing transfusion requirements. ## Summary The COVID-19 pandemic has impacted congenital cardiac surgical programs with significant reduction in case load, implementation of patient triage strategies, and development of PPE guidelines. Our opinion piece is based on current knowledge and experience. Due to the lack of robust evidence, strategies will be evolving, and recommendations will certainly change over the next months. It is important that congenital cardiac surgical programs collect data to understand the impact of the COVID-19 pandemic on the incidence of adverse events and resource utilization. E . Toolbox for blood conservation that can be used as an example to design institutional toolbox. CT indicates clotting time; EACA, epsilon amino caproic acid; EXTEM, extrinsic test from thromboelastometry; FC, fibrinogen concentrate; FEIBA, factor eight inhibitor bypassing activity; FFP , fresh frozen plasma; FIBTEM, fibrinogen test from thromboelastometry; IDA, iron-deficiency anemia; MUF, modified ultrafiltration; PCC, prothrombin complex concentrate; PLT, platelets; RBC, red blood cell; TXA, tranexamic acid. [fig] Figure 1: Considerations for Pediatric Heart Programs during COVID-19 pandemic, postpandemic, and the future. COVID-19 indicates coronavirus disease 2019; PPE, personal protective equipment. [/fig] [table] Table: Cardiac Lesions and Surgical Prioritization Obstructed total anomalous pulmonary venous return. Heart transplant. ECMO or VAD placement in hemodynamically unstable patient. PDA stents in an unstable patient on prostaglandin. AAOCA with recent hemodynamic instability. Stenotic RV-PA conduit with severe ventricular dysfunction. Thrombosed shunt. Tamponade. Balloon atrial septostomy. Abbreviations: AAOCA, anomalous aortic origin of a coronary artery; ECMO, extracorporeal membrane oxygenation; PDA, patent ductus arteriosus; RV-PA, right ventricle to pulmonary artery; VAD, ventricular assist device. www.anesthesia-analgesia.org ANeSTheSiA & ANALGeSiA COVID-19 and Pediatric Heart Programs [/table]	None	None	During COVID-19: Recommendations From the Congenital Cardiac Anesthesia Society David Faraoni, University of Toronto Lisa A. Caplan, Texas Childrens Hospital James A. DiNardo, Harvard Medical School Nina Guzzetta, Emory University Wanda C. Miller-Hance, Texas Childrens Hospital Gregory Latham, University of Washington Mona Momeni, Catholic University Louvain Susan C. Nicolson, University of Pennsylvania James P. Spaeth, University of Cincinnati Katherine Taylor, University of Toronto Only first 10 authors above; see publication for full author list.
a7725e3c430581e0a106d95b9f71cf00f76546b8	pubmed	Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID‐19	Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID‐19 ## \| introduc ti on The novel coronavirus disease of 2019 (COVID- [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] (SARS) and Middle East respiratory syndrome (MERS-CoV). [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] [bib_ref] Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill..., Obi [/bib_ref] [bib_ref] Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from..., Giannis [/bib_ref] COVID-19 is associated with marked abnormalities in markers of hypercoagulability, including elevated levels of D-dimer, fibrinogen, and factor VIII; a shortened activated partial thromboplastin time (aPTT); and an elevated sepsis induced coagulopathy (SIC) score. [bib_ref] Cardiovascular considerations for patients, health care workers, and health systems during the..., Driggin [/bib_ref] Investigational therapies for the management of severely ill COVID-19 patients may carry an increased risk for VTE or have implications for drug-drug interactions with established agents used for the acute and chronic management of VTE, such as the direct oral anticoagulants (DOACs) and vitamin K antagonists such as warfarin. ## \| me thods This guidance statement is a collaborative effort of the Perioperative and Critical Care Thrombosis and Haemostasis Subcommittee, along with members of the Control of ## Anticoagulation and disseminated intravascular coagulation Subcommittee of the SCC. The guidance provided is anchored on a narrative review of pertinent literature, with a search occurring until April 18, 2020, coupled with responses to a standardized and independently administered survey of preferred practices related to the diagnosis, prevention, and treatment of VTE in COVID-19 patients (Appendix S1) and conducted by the McMaster Centre for Transfusion Medicine using an independent, multi-institutional, and multidisciplinary panel of experts in the field of thrombosis and hemostasis. The survey of experts was done using a single cross-sectional assessment approach with an expectation that all (100%) panelists would select a pre-specified management option or to indicate, through the "other option" category, that alternative management was preferred. This one-time approach, rather than a multi-step, iterative approach (eg, Delphi method), was deemed appropriate in the context of the topic (COVID-19 and thrombosis) where requisite evidence, typically used in an iterative approach, is not available. Our aim was to identify where consensus existed and, of equal importance, to identify where there was a lack of consensus on clinical management. ## \| the d iag nos is of v te in hos pitalized covid -19 patients The diagnostic assessment of suspected VTE in hospitalized COVID-19 patients is challenging, especially for critically ill patients in whom, typically, it is important to reliably confirm or exclude VTE. Imaging studies for deep vein thrombosis (DVT) or pulmonary embolism (PE) may be avoided due to concerns of transmitting infection in non-COVID-19 hospital wards or to health-care workers. The frequent finding of an elevated D-dimer in very ill hospitalized COVID-19 patients may prompt an aggressive diagnostic approach for VTE, despite the controversy that a very elevated D-dimer (>4.0 mg/L) may not be a reliable predictor of VTE in this population but rather a marker of poor overall outcome. [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] [bib_ref] ISTH interim guidance on recognition and management of coagulopathy in COVID-19, Thachil [/bib_ref] One recent study found a sensitivity of 85.0% and specificity of 88.5% for diagnosing VTE in patients with D-dimer levels >1.5 mg/L, but the study was based on a small sample size. [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] Bedside imaging studies such as point-of-care compression ultrasonography to assess for lower and upper extremity DVT or bedside echocardiography to assess for right ventricular strain associated with PE may be difficult to obtain due to patient instability or the requirement of prone positioning in patients with acute respiratory distress syndrome (ARDS), and may lack sufficient specificity and sensitivity to diagnose VTE as patients with pneumonia may have right ventricular strain without PE. [bib_ref] Early use of echocardiography in patients with acute pulmonary embolism: findings from..., Bikdeli [/bib_ref] However, in the clinical context of unexplained sudden deterioration of pulmonary status or acute lower extremity erythema or swelling, these tests may be useful in aiding the clinical suspicion for VTE. These concerns should be balanced by emerging data that the incidence of VTE in hospitalized COVID-19 patients with severe pneumonia or in ICU settings is higher than that reported by historical data in similar patients, with an incidence of VTE of 27% (95% confidence interval [CI]: 17-37) in one study using standard thromboprophylaxis and an incidence of 25% in another study without prophylaxis. [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] ## \| v te prophyl a xis in non -i cu hos pitalized covid -19 patients Hospitalized acutely ill medical patients, including those with infections such as viral pneumonia, are at increased risk for VTE, and antithrombotic practice guidelines recommend thromboprophylaxis with twice-or thrice-daily subcutaneous unfractionated heparin (UFH), once-daily subcutaneous low-molecular-weight heparin (LMWH), or fondaparinux to reduce this risk, although fondaparinux is infrequently used due to its long half-life and reversibility concerns. [bib_ref] Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, Kahn [/bib_ref] [bib_ref] American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis..., Schünemann [/bib_ref] Patients hospitalized with severe COVID-associated pneumonia may have a further heightened risk of VTE, but this issue remains unresolved. Preliminary reports in patients with severe pneumonia due to COVID-19 as well as previous reports of severe pneumonias/severe acute respiratory syndromes from other viruses such as influenza H1N1 or MERS-CoV suggest a multi-fold higher risk for VTE and, in particular, an increased risk for PE. [bib_ref] Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill..., Obi [/bib_ref] In addition, patient-specific VTE risk factors such as advanced age, a prior history of VTE, a history of or active cancer, immobility, and thrombophilia, had been incorporated prior to the COVID-19 era to assess overall VTE risk using standardized VTE risk assessment scores such as Padua VTE or IMPROVE VTE risk scores, [bib_ref] New paradigms in venous thromboprophylaxis of medically ill patients, Spyropoulos [/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] which had been externally validated. [bib_ref] Validation of risk assessment models of venous thromboembolism in hospitalized medical patients, Greene [/bib_ref] [bib_ref] External validation of a risk assessment model for venous thromboembolism in the..., Mahan [/bib_ref] [bib_ref] External validation of the risk assessment model of the international medical prevention..., Rosenberg [/bib_ref] A recent study from China in hospitalized patients with COVID-19 reported that 40% of patients had a high risk of VTE using the Padua VTE model, although the use of thromboprophylaxis was not reported. [bib_ref] Attention should be paid to venous thromboembolism prophylaxis in the management of..., Wang [/bib_ref] The optimal VTE risk stratification scheme for hospitalized COVID-19 patients requires further study, including the use of very elevated D-dimer levels (>6 times the upper limit of normal that appear to be a consistent predictor of thrombotic events and poor overall prognosis in this population. [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] However, given the relatively high rates of VTE found in early reports, the use of a "universal" thromboprophylactic strategy for all hospitalized patients with COVID-19 appears more appropriate than an individualized VTE risk assessment approach at present. ## \| v te prophyl a xis in i cu hos pitalized covid -19 patients Hospitalized COVID-19 patients who are managed in an ICU or CCU setting have an overall poor prognosis, with the proportion of severe cases approaching 26% (95% CI: 17.4-34.9) and reported case-fatality rates of 42%. [bib_ref] Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review..., Fu [/bib_ref] The presence of co-morbid conditions (eg, cardiovascular disease, obesity); a SIC score ≥ 4 and elevated levels of D-dimer (>6 times ULN), C-reactive protein, and troponins; and other markers of disseminated intravascular coagulopathy (DIC) as assessed by the ISTH scoring system are associated with a worse prognosis. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] It is uncertain whether changes in hemostasis parameters are a direct consequence of the SARS-CoV2 virus or a result of a systemic inflammatory response syndrome (SIRS) that is produced by a cytokine storm after viral infection. [bib_ref] COVID-19: consider cytokine storm syndromes and immunosuppression, Mehta [/bib_ref] In addition, the heightened prothrombotic tendency in the critically ill hospitalized patients with COVID-19 pneumonia, leading to VTE and especially, in situ pulmonary artery microthrombi, is evident in case series and pathologic studies as an endpoint of pulmonary inflammation. [bib_ref] Acute pulmonary embolism and COVID-19 pneumonia: a random association?, Danzi [/bib_ref] One study reported an incidence of VTE of 25% (20/81) and a mortality of 40% (8/20) among patients hospitalized with severe COVID-19 pneumonia who had VTE; another study found an incidence of VTE and arterial thromboembolism of 27% and 3.7%, respectively, in 184 COVID-19 patients who were in an ICU setting and were receiving standard-dose thromboprophylaxis. [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] Last, the use of tissue plasminogen activator in the treatment of COVID-19-associated ARDS was associated with only transient improvement of pulmonary function. [bib_ref] Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome..., Wang [/bib_ref] The optimal thromboprophylaxis strategy in the critically ill hospitalized COVID-19 patient population is uncertain. Emerging clinical data suggest that the use of either prophylactic to intermediate doses of LMWH (eg, enoxaparin, 40-60 mg daily) in very sick COVID-19 patients (D-dimer > 6 times ULN; SIC score ≥ 4) is associated with improved outcomes and a better prognosis. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] A previous report that assessed treatment-dose UFH in patients with ARDS who were afflicted with influenza H1N1, found that patients with H1N1-associated ARDS who received therapeutic anticoagulation had 33-fold fewer VTE events than those treated given prophylactic-dose UFH or LMWH. The use of empiric therapeutic-dose anticoagulation has been advocated by some for the critically ill hospitalized COVID-19 patients, especially in ICU settings; however, data on the efficacy and safety of this approach is limited. [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] There are ongoing randomized trials that aim to assess the efficacy and safety of ## \| guidance statement 3 VTE prophylaxis in sick ICU hospitalized COVID-19 patients: 1. Routine thromboprophylaxis with prophylactic-dose UFH or LMWH should be used after careful assessment of bleed risk. Intermediate-dose LMWH (50% of respondents) can also be considered in high risk patients. Patients with obesity as defined by actual body weight or BMI should be considered for a 50% increase in the dose of thromboprophylaxis. Treatment-dose heparin should not be considered for primary prevention until the results of randomized controlled trials are available. ## Multi-modal thromboprophylaxis with mechanical methods (ie, intermittent pneumonic compression devices) should be considered (60% of respondents). ## \| dur ati on of thromboprophyl a xis in hos pitalized covid -19 patients The risk of hospital-associated VTE extends for up to 6 weeks post-hospital discharge in high VTE risk medically ill patients, including those with pneumonia, sepsis, and any condition requiring management in an ICU setting. [bib_ref] New paradigms of extended thromboprophylaxis in medically ill patients, Macdougall [/bib_ref] At least 60% of all VTE events in medically ill patients occur in the post-hospital discharge period, with the first 3 weeks being associated with a >five-fold increased risk in fatal PE. 14 Earlier studies of extended thromboprophylaxis with DOACs revealed either limited efficacy or an increase in major bleed risk, and particularly due to these safety concerns, the most recent antithrombotic guidelines recommended against routine post-discharge thromboprophylaxis in medically ill patients, including those with pneumonia. [bib_ref] American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis..., Schünemann [/bib_ref] However, more recent data reveal that in selected populations at high VTE risk and low bleed risk, based on key risk factors or risk models for thrombosis and bleeding, extended-duration thromboprophylaxis for approximately 4 weeks with prophylactic-dose LMWH (eg, enoxaparin, dalteparin, tinzaparin) or a DOAC (eg rivaroxaban, betrixaban) provides a net clinic benefit by reducing VTE risk without incurring a significant increase in the risk of major bleeding. [bib_ref] Rivaroxaban for thromboprophylaxis in acutely ill medical patients, Cohen [/bib_ref] [bib_ref] Improved Benefit Risk Profile of Rivaroxaban in a Subpopulation of the MAGELLAN..., Spyropoulos [/bib_ref] [bib_ref] Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced..., Hull [/bib_ref] This benefit appears more pronounced in patients whose index hospitalization was due to infectious disease, particularly pneumonia. [bib_ref] Rivaroxaban for thromboprophylaxis among patients recently hospitalized for acute infectious diseases: a..., Cohoon [/bib_ref] Recent data also support that a modified IMPROVE VTE score using established cut-offs plus elevated D-dimer (>2 times ULN) identifies patients at an almost three-fold higher risk for VTE in whom there is a significant benefit for extended-duration thromboprophylaxis. [bib_ref] Modified IMPROVE VTE risk score and elevated d-dimer identify a high venous..., Spyropoulos [/bib_ref] This finding may be especially relevant for post-discharge VTE risk mitigation in COVID-19 patients. In the absence of COVID-19-specific data, it is reasonable to consider extended-duration thromboprophylaxis with LMWH or a DOAC for at least 2 weeks and up to 6 weeks post-hospital discharge in selected COVID-19 patients who are at low risk for bleeding and with key VTE risk factors such as advanced age, stay in the ICU, cancer, a prior history of VTE, thrombophilia, severe immobility, an elevated D-dimer (>2 times ULN), and an IMPROVE VTE score of 4 or more. ## \| guidance statement 4 Duration of VTE prophylaxis for hospitalized COVID-19 patients: 1. Either LMWH (30%) or a DOAC (ie, rivaroxaban or betrixaban; 30% of respondents) can be used for extended-duration thromboprophylaxis. 2. Extended post-discharge thromboprophylaxis should be considered for all hospitalized patients with COVID-19 that meet high VTE risk criteria. The duration of post-discharge thromboprophylaxis can be approximately 14 days at least (50% of respondents), and up to 30 days (20% of respondents). ## \| v te tre atment in hos pitalized covid -19 patients There are multiple validated and approved strategies to treat hospitalized patients with a new VTE including the use of UFH/ LMWH bridging therapy to dose-adjusted warfarin, the use of UFH/LMWH lead-in therapy with a switch to dabigatran/edoxaban, or a monotherapy approach with rivaroxaban/apixaban. [bib_ref] Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report, Kearon [/bib_ref] In hospitalized COVID-19 patients, parenteral anticoagulation with UFH or LMWH may have advantages over other strategies due to the absence of known drug-drug interactions with antiviral agents or investigational therapies used to treat COVID-19. Moreover, the use of LMWH may have further advantages in this setting due to lack of routine monitoring and decrease of health-care worker exposure to infection due to frequent blood draws necessary with intravenous UFH, which may require higher-than-usual doses from possible heparin resistance due to acute phase reactants. DOACs may also have further disadvantages in this setting due to potential drug-drug interactions via CYP3A4 mechanisms with certain antivirals (ie, lopinavir/ritonavir) and immunomodulatory investigational COVID-19 therapies, as well as potential for lack of reversal agents or specific antidotes in some hospitals. [bib_ref] Cardiovascular considerations for patients, health care workers, and health systems during the..., Driggin [/bib_ref] However, in the post-hospital discharge setting, DOACs provide advantages over vitamin K antagonists such as warfarin due to the lack of need for routine monitoring and subsequent minimization of patient contact with the health-care environment. ## \| guidance statement 5 VTE treatment in hospitalized COVID-19 patients: 3. The duration of treatment should be at least 3 months (50% of respondents). ## \| d iscuss i on COVID-19 is emerging as a highly contagious disease with coagulopathic manifestations that appear to have unique characteristics. Initial data support a high incidence of thromboembolic disease, and especially VTE, in hospitalized COVID-19 patients, as well as poorer outcomes for COVID-19 patients with pre-existing cardiovascular disease. [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] [bib_ref] Cardiovascular considerations for patients, health care workers, and health systems during the..., Driggin [/bib_ref] Due to the risk of infectivity with a need to minimize contact with health-care workers and the health system; the diagnosis of VTE in critically ill, unstable hospitalized COVID-19 patients (especially in the ICU) that may need prone positioning and may not be able to undergo standard objective testing; the potential for new VTE risk stratification strategies using novel dosing intensities of established thromboprophylaxis regimens; new paradigms of post-hospital discharge and extended thromboprophylaxis; and careful considerations of antithrombotic management due to the potential for drug-drug interactions with investigational or immunomodulatory therapies, health-care workers will need to understand special considerations for the management of VTE in hospitalized COVID-19 patients. There is an urgent need for high quality data, especially from randomized controlled trials, using a coordinated effort by health-care What is the optimal agent/duration of extended thromboprophylaxis? ## Treatment of vte What is the optimal agent and duration for VTE treatment? Inhospital? In the outpatient setting? [fig] 5: Expert clinical guidance statements and clinical pathways from large academic health-care systems favor the use of standard-dose regimens with LMWH or UFH (especially for patients with a creatinine clearance < 30 mL/min); mechanical thromboprophylaxis (intermittent pneumatic compression) when anticoagulants were contraindicated; use of multimodal (anticoagulant and mechanical) prophylaxis strategies in the critically ill and completely immobile COVID-19 population; 7,28 and the use of VTE risk stratification using either clinical criteria (body mass index [BMI] >30 kg/m 2 ), VTE risk scores, and/or biomarkers (eg, very elevated D-dimer levels) to suggest intermediate-or higher-dose LMWH or UFH regimens (eg enoxaparin 0. mg/kg twice-daily; enoxaparin 40 mg twice-daily, intravenous UFH targeted to an anti-factor Xa level of 0.30-0.70 IU/mL). Many institutional protocols of hospitalized COVID-19 patients now incorporate obesity (BMI > 30 kg/m 2 ) or morbid obesity (BMI > 40 kg/m 2 ) to administer intermediate-dose LMWH for thromboprophylaxis. 29 [/fig] [fig] 1: Established guidelines should be used to treat patients with confirmed VTE, with advantages of LMWH in the inpatient setting and DOACs in the post-hospital discharge setting. A change from treatment-dose DOAC or vitamin K antagonists (VKA) to in-hospital LMWH should be considered especially for patients in critical care settings or with relevant concomitant medications, and dependent on renal function and platelet counts. Anticoagulant regimens should not change based solely on D-dimer levels. 2. A change of anticoagulant regimen (ie, from prophylactic or intermediate-dose to treatment-dose regimen) can be considered in patients without established VTE but deteriorating pulmonary status or ARDS (50% of respondents). [/fig]	None	http://www.jthjournal.org/article/S1538783622016257/pdf	The novel coronavirus disease of 2019 (COVID-19) pandemic, as declared by the World Health Organization, is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Cardiovascular disease and, in particular, venous thromboembolism (VTE) has emerged as an important consideration in the management of hospitalized patients with COVID-19. The diagnosis of VTE using standardized objective testing is problematic in these patients, given the risk of infecting non-COVID-19 hospitalized patients and hospital personnel, coupled with the usual challenges of performing diagnostic testing in critically-ill patients. Early reports suggest a high incidence of VTE in hospitalized COVID-19 patients, particularly those with severe illness, that is similar to the high VTE rates observed in patients with other viral pneumonias, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS-CoV).
d40c5669cc94fe7798efa96e53ec7f8ee6ab1642	pubmed	Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation	Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized. In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of Inter-Introduction Background Autoimmune diseases (ADs) are heterogeneous both in manifestation and severity. Immunosuppressive therapy, including novel biological therapies, enables short-term disease control and minimization of organ damage in most cases, but long-term treatment-free remission and/or definitive cure remain elusive. Major organ involvement, rapidly progressing disease and persistent disease activity result in significant disability, reduction in quality of life (QoL) and life expectancy. Toxicities of chronic treatment and the personal and societal costs are considerable. In this context, haematopoietic SCT (HSCT) has been used in severe AD for the past 15 years to control otherwise resistant disease activity, or even cure, by inducing fundamental immunological changes never previously seen with other forms of therapy. The concept of HSCT in severe ADs initially evolved in animal models, [bib_ref] Rationale for bone marrow transplantation in the treatment of autoimmune diseases, Ikehara [/bib_ref] [bib_ref] Stem cell transplantation for severe autoimmune diseases: new proposals but still unanswered..., Marmont [/bib_ref] [bib_ref] Immunomodulation of autoimmunity in MRL/lpr mice with syngeneic bone marrow transplantation (SBMT), Karussis [/bib_ref] [bib_ref] Syngeneic bone marrow transplantation eliminates V beta 8.2 T lymphocytes from the..., Burt [/bib_ref] [bib_ref] Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation..., Burt [/bib_ref] [bib_ref] Stem cell transplantation in experimental models of autoimmune disease, Van Bekkum [/bib_ref] [bib_ref] Stem cell transplantation for autoimmune disorders. Preclinical experiments, Van Bekkum [/bib_ref] with the potential benefits in humans supported by reports of profound clinical response of ADs to HSCT performed for other conventional indications. [bib_ref] Prolonged remission of longstanding systemic lupus erythematosus after autologous bone marrow transplant..., Snowden [/bib_ref] [bib_ref] Immunoablation followed or not by hematopoietic stem cells as an intense therapy..., Marmont [/bib_ref] From 1995, the first HSCT procedures specifically for ADs were performed, and, in 1996, the European Group for Blood and Marrow Transplantation (EBMT) AD Working Party (ADWP) was launched. [bib_ref] Haematopoietic precursor-cell transplants for autoimmune diseases, Marmont [/bib_ref] [bib_ref] Blood and marrow stem cell transplants in auto-immune disease: a consensus report..., Tyndall [/bib_ref] The collaboration was progressively built on by active involvement with specialist European societies working together with the EBMT, specifically the European League against Rheumatism and its working groups in Systemic Sclerosis (EUSTAR) and Lupus Erythematosus (Eurolupus), the European Crohn's and Colitis Organization, and the European Committee for Treatment and Research in Multiple Sclerosis. Further interactions outside of Europe involved the Center for International Bone Marrow Transplant Registry 12 and the National Institutes of Health, [bib_ref] Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and..., Pasquini [/bib_ref] [bib_ref] Haematopoietic stem cell transplantation for severe AD, Saccardi [/bib_ref] along with large HSCT programmes in the field, such as Northwestern University, Chicago, and active groups in Australia, Brazil and China. A database dedicated to adult and paediatric patients with AD treated with high-dose chemotherapy and autologous, syngeneic or allogeneic HSCT was created and EBMT centres were requested to report all procedures with annual updates. Thereafter, specific data forms were introduced into the Central EBMT database (http:// www.ebmt.org/4Registry/registry3.html). It is currently estimated that around 3000 AD patients have now been treated worldwide by HSCT. [fig_ref] Table 1: EBMT database of autoimmune diseases, June 2011 Abbreviation [/fig_ref] summarizes the current EBMT AD Registry as of June 2011 in terms of AD indications in the adult (X18 years) and paediatric (o18 years) age groups. The majority of adult patients have been treated with autologous HSCT (n ¼ 1090), with donor HSCT (n ¼ 25) comprised of related donor HSCT (n ¼ 20, including two syngeneic HSCT) and unrelated donor HSCT (n ¼ 5). Likewise most paediatric patients also underwent autologous HSCT (n ¼ 119), although donor HSCT was proportionally more frequent (n ¼ 40), with related donor HSCT (n ¼ 24, including two syngeneic HSCT) and unrelated donor HSCT (n ¼ 16). The remainder of worldwide cases have been reported to the United Statesbased CIBMTR, or have been performed in Asia or the Eastern Mediterranean regions, or are present in other individual centre registries outside of Europe, such as Northwestern University, Chicago. [bib_ref] Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and..., Pasquini [/bib_ref] [bib_ref] Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases:..., Burt [/bib_ref] [bib_ref] Stem cell transplantation: progress in Asia, Sun [/bib_ref] [bib_ref] Hematopoietic stem cell transplantation: a global perspective, Gratwohl [/bib_ref] Successive analyses of the EBMT database provided evidence for the feasibility and the toxicity of the HSCT procedures across a large number of ADs. [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases, Gratwohl [/bib_ref] [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on..., Farge [/bib_ref] Prospective phase I/II studies were progressively reported across a wide range of AD, including multiple sclerosis (MS), [bib_ref] Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis:..., Fassas [/bib_ref] [bib_ref] Autologous stem cell transplantation in progressive multiple sclerosis-an interim analysis of efficacy, Fassas [/bib_ref] [bib_ref] High-dose immunosuppressive therapy with PBPC support in the treatment of poor risk..., Koza´k [/bib_ref] [bib_ref] Hematopoietic stem cell transplantation for systemic sclerosis with rapid improvement in skin..., Burt [/bib_ref] [bib_ref] High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe..., Nash [/bib_ref] [bib_ref] CD34+ selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report..., Carreras [/bib_ref] [bib_ref] Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact..., Saccardi [/bib_ref] [bib_ref] Intense T cell depletion followed by autologous bone marrow transplantation for severe..., Samijn [/bib_ref] [bib_ref] Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase..., Burt [/bib_ref] systemic sclerosis (SSc), [bib_ref] High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes, Mcsweeney [/bib_ref] [bib_ref] High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis:..., Nash [/bib_ref] [bib_ref] Autologous non-myeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis, Oyama [/bib_ref] [bib_ref] Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic..., Vonk [/bib_ref] systemic lupus erythematosus (SLE), [bib_ref] Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases:..., Burt [/bib_ref] rheumatoid arthritis (RA), [bib_ref] A phase I/II dose escalation study of intensified cyclophosphamide and autologous blood..., Snowden [/bib_ref] [bib_ref] High dose chemotherapy and hematopoietic stem cell transplantation: a study of treatment..., Verburg [/bib_ref] [bib_ref] A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation..., Moore [/bib_ref] juvenile chronic arthritis (JIA), [bib_ref] Autologous haemopoietic stem-cell transplantation in four patients with refractory juvenile chronic arthritis, Wulffraat [/bib_ref] [bib_ref] Autologous stem cell transplantation in children with severe progressive systemic or polyarticular..., Brinkman [/bib_ref] [bib_ref] Autologous T cell depleted haematopoietic stem cell transplantation in children with severe..., Abinun [/bib_ref] Crohn's disease (CD) [bib_ref] Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease, Oyama [/bib_ref] [bib_ref] Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn's..., Cassinotti [/bib_ref] [bib_ref] Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory..., Burt [/bib_ref] and type 1 diabetes (T1D). [bib_ref] Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes..., Voltarelli [/bib_ref] [bib_ref] C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation..., Couri [/bib_ref] [bib_ref] Potential role of immunoablation and hematopoietic cell transplantation in the treatment of..., Snarski [/bib_ref] In the most recent general retrospective analysis, among 900 patients undergoing first autologous HSCT, the overall 5-year survival was 85%, with 43% PFS. Outcomes varied with diagnosis, age and centre activity. [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on..., Farge [/bib_ref] Retrospective analysis of limited numbers of allogeneic HSCT, including the use of donor T-cell infusions, confirmed the ability to achieve very prolonged remission, but with significantly more toxicity and TRM than with autologous HSCT. [bib_ref] Allogeneic hematopoietic SCT for patients with autoimmune diseases, Daikeler [/bib_ref] Other retrospective analyses were used to support the feasibility, safety and efficacy in specific ADs, including MS, SSc, SLE, RA, JIA, autoimmune cytopenias, vasculitis and paediatric diseases. [bib_ref] Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure..., Binks [/bib_ref] [bib_ref] Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study, Fassas [/bib_ref] [bib_ref] Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical..., De Kleer [/bib_ref] [bib_ref] Autologous stem cell transplantation in the treatment of systemic sclerosis: report from..., Farge [/bib_ref] [bib_ref] Autologous stem cell transplantation for systemic lupus erythematosus, Jayne [/bib_ref] [bib_ref] Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis: a report from..., Snowden [/bib_ref] [bib_ref] Haematopoetic stem cell transplantation for refractory autoimmune cytopenia, Passweg [/bib_ref] [bib_ref] Autologous stem cell transplantation for progressive multiple sclerosis: update of the European..., Saccardi [/bib_ref] [bib_ref] Haematopoietic stem cell transplantation for vasculitis including Behcet's disease and polychondritis: a..., Daikeler [/bib_ref] [bib_ref] Haematpoietic stem cell transplantation in severe autoimmune diseases in children. Results and..., Rabusin [/bib_ref] The results of retrospective and prospective studies were the basis for randomized phase II/III studies in the major disease indications: in SSc (ASTIS, http://www.astistrial. com; ASSIST, http://www.clinicaltrials.gov; SCOT, http:// www.clinicaltrials.gov); in MS (ASTIMS, http://www. astims.org; MIST (Multiple Sclerosis International Stem cell Trial), http://www.clinicaltrials.gov); and in CD (ASTIC, http://www.nottingham.ac.uk/icr/astic/). ## Mechanism of action For many years, the use of HSCT to induce tolerance by replacing (allogeneic) or resetting (autologous) immune responses in patients with ADs by HSCT remained an attractive prospect, [bib_ref] Cell therapy for autoimmune diseases: does it have a future?, Radbruch [/bib_ref] arising from genetically prone and immunized animal models of AD treated with allogeneic, syngeneic, autologous and pseudo-autologous HSCT. [bib_ref] Rationale for bone marrow transplantation in the treatment of autoimmune diseases, Ikehara [/bib_ref] [bib_ref] Stem cell transplantation for severe autoimmune diseases: new proposals but still unanswered..., Marmont [/bib_ref] [bib_ref] Immunomodulation of autoimmunity in MRL/lpr mice with syngeneic bone marrow transplantation (SBMT), Karussis [/bib_ref] [bib_ref] Syngeneic bone marrow transplantation eliminates V beta 8.2 T lymphocytes from the..., Burt [/bib_ref] [bib_ref] Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation..., Burt [/bib_ref] [bib_ref] Stem cell transplantation in experimental models of autoimmune disease, Van Bekkum [/bib_ref] [bib_ref] Stem cell transplantation for autoimmune disorders. Preclinical experiments, Van Bekkum [/bib_ref] The preclinical evidence for a graft-vs-autoimmune effect important in the replacement of a dysfunctional immune system by allogeneic HSCT has been subsequently supported by clinical evidence. [bib_ref] Allogeneic hematopoietic SCT for patients with autoimmune diseases, Daikeler [/bib_ref] [bib_ref] Clinically demonstrable anti-autoimmunity mediated by allogeneic immune cells favorably affects outcome after..., Hinterberger [/bib_ref] [bib_ref] Refractory Evans' syndrome treated with allogeneic SCT followed by DLI. Demonstration of..., Marmont [/bib_ref] [bib_ref] Haemopoietic stem cell transplantation in autoimmune diseases: a European perspective, Hough [/bib_ref] [bib_ref] Feasibility of allogeneic hematopoietic stem cell transplantation for autoimmune disease: position statement..., Griffith [/bib_ref] [bib_ref] Pure white cell aplasia (PWCA) relapsing after allogeneic BMT and successfully treated..., Marmont [/bib_ref] In autologous HSCT, analysis of the regenerating adaptive immune system showed normalization of the restricted T-cell repertoire, with sustained shifts in T-and B-cell subpopulations from memory to naı¨ve cell dominance, supportive of thymic reprocessing and re-education of the reconstituting immune system. [bib_ref] Thymic output generates a new and diverse TCR repertoire after autologous stem..., Muraro [/bib_ref] [bib_ref] Analysis of immune reconstitution after autologous bone marrow transplantation in systemic sclerosis, Farge [/bib_ref] In addition, restoration of normal or raised levels of CD4 þ regulatory T cells with the disappearance of circulating plasmablasts is reported in JIA, [bib_ref] Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive..., De Kleer [/bib_ref] [bib_ref] Autologous bone marrow transplantation in autoimmune arthritis restores immune homeostasis through CD4+CD25+Foxp3+..., Roord [/bib_ref] [bib_ref] Regulatory T cells in autologous stem cell transplantation for autoimmune disease, Van Wijk [/bib_ref] and unusual CD8 þ FoxP3 þ regulatory T-cell subsets, capable of inhibiting the pathogenic Tcell response to autoepitopes in nucleosomes, are seen in SLE following autologous HSCT, but not after conventional immunosuppressive therapies. [bib_ref] Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation..., Alexander [/bib_ref] [bib_ref] Regulatory T cell (Treg) subsets return in patients with refractory lupus following..., Zhang [/bib_ref] These results separated the nonspecific immunosuppressive changes, observed in both blood and tissue after cytotoxic therapy, 62,68 from immune re-educative changes supporting immune tolerance. [bib_ref] Restoring self-tolerance: lessons from the clinic, Muraro [/bib_ref] Other downstream changes, such as reduction in dermal fibrosis, [bib_ref] High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis:..., Nash [/bib_ref] [bib_ref] Skin involvement in scleroderma-where histological and clinical scores meet, Verrecchia [/bib_ref] [bib_ref] Autologous stem cell transplantation for systemic sclerosis, Farge [/bib_ref] with increased dermal microcirculation [bib_ref] Capillary regeneration in scleroderma: stem cell therapy reverses phenotype?, Fleming [/bib_ref] [bib_ref] Autologous stem cell transplantation improves microcirculation in systemic sclerosis, Miniati [/bib_ref] and early regression of the extent of CT scan fibrosis [bib_ref] Autologous hematopoietic stem cell transplant in systemic sclerosis: quantitative high resolution computed..., Launay [/bib_ref] in systemic sclerosis were reported. ## Advances in biological therapies and other non-hsct treatments The advent of many novel biological therapies improved outcomes in many ADs in recent years. Nonetheless, significant numbers of patients fail to respond or develop resistance to modern biological-based therapies or develop unacceptable side effects and severe infectious complications, long-term malignancies or secondary ADs. [bib_ref] Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for..., Loh [/bib_ref] [bib_ref] Secondary autoimmune diseases occuring after stem cell transplantation for an autoimmune disease:..., Daikeler [/bib_ref] [bib_ref] Reconstitution Graves' disease following autologous haematopoietic stem cell transplantation (HSCT) for severe..., Tailor [/bib_ref] In addition, chronic administration of novel treatments is also a major socioeconomic challenge. There remains a need for highly active, but deliverable treatment regimens for patients with a poor prognosis due to rapidly progressive and treatment-resistant ADs. Guidelines' process and aims The first guidelines published in 1997 represented a relatively uniform approach toward developing the field both within and outside clinical trials, with an emphasis on registry reporting. [bib_ref] Blood and marrow stem cell transplants in auto-immune disease: a consensus report..., Tyndall [/bib_ref] Further brief, revised recommendations are included in various iterations of the general EBMT indications for HSCT. [bib_ref] Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders:..., Ljungman [/bib_ref] The aims of these current updated guidelines are to support HSCT centres running a local trial, or dealing with a complex AD patient, and also to guide health-care administrative bodies and insurance companies. There is an emphasis on patient safety, with criteria for selection and HSCT procedural aspects, underpinned by a requirement for accreditation of HSCT programmes by JACIE (Joint Accreditation Committee of International Society for Cellular Therapy and EBMT) or equivalent quality management systems, which improve clinical outcomes in HSCT. [bib_ref] Introduction of a quality management system and outcome after hematopoietic stemcell transplantation, Gratwohl [/bib_ref] [bib_ref] Ten years after the first inspection of a candidate European centre, an..., Chabannon [/bib_ref] Where possible, inclusion of patients on prospective clinical studies, ideally randomized controlled trials, and also prospective noninterventional studies (in accordance with current EBMT registry guidelines) is also essential for development of the field. Levels of evidence have been inserted according to the currently accepted EBMT grading system. Each disease-specific panel session workshop reported at the EBMT-and National Institutes of Health-supported meeting in Florence, November 2009, [bib_ref] Haematopoietic stem cell transplantation for severe AD, Saccardi [/bib_ref] was used as a source of consensus. Subsequently, the guidelines were formally discussed at two successive EBMT ADWP meetings in March and October 2010 and proposed recommendations circulated among active members before finalization in close interaction with the EBMT Paediatric Diseases Working Party and the Australasian Society for BMT. [fig_ref] Table 1: EBMT database of autoimmune diseases, June 2011 Abbreviation [/fig_ref] ## General recommendations Clinical practice Evidence for the feasibility, efficacy and toxicity of HSCT in various adult and paediatric ADs has been summarized in a large number of detailed reviews and registry analyses. [bib_ref] Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases:..., Burt [/bib_ref] [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases, Gratwohl [/bib_ref] [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on..., Farge [/bib_ref] [bib_ref] Haematopoietic stem cell transplantation for autoimmune disorders: the American perspective, Popat [/bib_ref] [bib_ref] Hematopoietic stem cell transplantation in autoimmune diseases: is the glass half full..., Illei [/bib_ref] [bib_ref] Haemopoietic stem cell transplantation-an evolving treatment for severe autoimmune and inflammatory diseases..., Kapoor [/bib_ref] [bib_ref] Haematopoietic SCT in autoimmune diseases in children: rationale and new perspectives, Rabusin [/bib_ref] [bib_ref] Hematopoietic stem cell transplantation for pediatric autoimmune disease: where we stand and..., Krauss [/bib_ref] [bib_ref] Clinical applications of blood-derived and marrowderived stem cells for nonmalignant diseases, Burt [/bib_ref] [bib_ref] Hematopoietic cell transplantation for autoimmune disease: updates from Europe and the United..., Sullivan [/bib_ref] The risks of toxicity and TRM vary between donor source, intensity of conditioning regimens and AD category, and the potential for safer yet equally effective non-HSCT treatments should be actively pursued in all cases, including modern biological therapies, where deliverable. ## Recommendations HSCT should be considered as a therapeutic option at second line or beyond for patients with severe ADs progressing despite standard established and/or approved therapy (level II). In patients for whom HSCT represents a treatment option, referral should be made to a centre with appropriate inter-disciplinary interaction using combined haematological and AD specialist experience to select and manage AD patients. Such centres should have JACIE accreditation or equivalent (level II). Whenever possible, HSCT in AD should be performed in the context of a phase II or III clinical trial with welldefined end points and eligibility criteria in accordance with good clinical practice and appropriate regulatory requirements (level III). Approved prospective non-interventional studies may provide meaningful clinical data where full phase III randomized controlled trials are not feasible, and are the preferred option over 'ad hoc' procedures (level III). If no study or clinical trial is available, the patient should be considered under the EBMT category 'Clinical Option' (CO) after documented multidisciplinary meetings, clinical/research ethics committee review and/or external expert second opinions from both HSCT and relevant AD specialists. The alternative non-HSCT treatment options, including potential participation in other clinical trials, should be central to this assessment (level III). In addition to JACIE accreditation (or equivalent), centres should specifically train staff (physicians, nurses, data managers) in specific ADs (level III). ## Data reporting and biobanking The international HSCT registries are central to the development of HSCT to ADs. The EBMT database is the largest worldwide and unique MED-A and specific MED-B forms for MS, SSc, SLE, RA and CD can be downloaded at http://www.ebmt.org/4Registry/registry3. html. Complete data registration has proven more challenging than 'routine', predominantly haematological, indications for HSCT since follow-up lies predominantly outside the specialty of haematology, data managers are generally less familiar with AD, and, in the long term, many patients are seen in departments outside the transplant centre. HSCT provides a unique opportunity to collect adequate serum, plasma and cell samples in addition to biological samples according to each AD category and organ involvement at baseline, during the immunosuppressionfree remission, and at potential relapse for both and pathogenetic and mechanistic studies. Local or central biobanking, within regulatory requirements, is essential. ## Recommendations Long-term formalized follow-up and data reporting of all AD patients after HSCT to registries are a minimum recommendation. EBMT MED A (or equivalent) and disease-specific MED B (or equivalent) data reporting are available for these purposes. Annual review and data reporting is recommended to capture all outcomes, including late effects of HSCT (level III). Centres performing HSCT for ADs should provide systems for long-term follow-up. Annual simultaneous follow-up consultation of the AD specialist and the HSCT specialist is recommended. If patients are discharged from the transplant centre for mid/long-term follow-up under the referring specialist, the contact details should be available to the registry (level III). Data managers should be adequately trained and supervised by relevant BMT and AD specialists (level III). Biobanking within current regulatory frameworks allowing to maximise the utility of stored biological samples should be actively sought (level III) ## Statistical aspects The number and heterogeneity of parameters used to measure various ADs, [bib_ref] Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS), Kurtzke [/bib_ref] [bib_ref] From BILAG to BLIPS-disease activity assessment in lupus past, present and future, Isenberg [/bib_ref] [bib_ref] Derivation of the SLEDAI. A disease activity index for lupus patients. The..., Bombardier [/bib_ref] their rarity, the lack of standard first-line therapy, long-term outcome data of new biological therapies and unified definitions for remission or cure all present challenges in the statistical evaluation of HSCT in AD. Concepts familiar to HSCT practice, such as early TRM, PFS and OS, are unusual to AD specialists, and 'classical' statistical approaches used in HSCT are less easily applied. Several considerations are important to designing studies of HSCT in AD. Firstly, the definitions of the end point of interest, especially of relapse and progression, need validation. The usual definition of PFS used to evaluate HSCT in oncology includes both relapse and disease progression. In ADs, these two events may be biologically and clinically distinct, and AD-specific metrics require individual consideration, with, for example, relapse in ADs not necessarily resulting in progression to increased disability or death. Secondly, in most chronic AD patients, QoL is frequently the most important parameter and may be assessed using a variety of generic or disease-specific instruments. Although validated, QoL end points may be associated with a high co-efficient of variation, even in the normal population, and the required numbers to achieve statistical power may be significantly increased compared with end points conventionally used in oncology, such as PFS, OS, relapse or death. Randomized clinical trials (RCTs) are the best method to reveal the effects of a therapeutic intervention and many systematic 'evidence-based medicine' reviews only accept this level of evidence. However, in HSCT in ADs, challenges may arise in unbalanced randomization between treatment intensity and TRM risk, the rarity of disease or indication, the assessment of the outcome through an activity score, the definition of drug-free remission and the required duration of follow-up to assess a real benefit. In view of such ethical and practical issues, some important clinical questions are unlikely to be adequately answered by RCTs, and other clinical trial designs may be more appropriate to reassure AD specialists with a view to ultimately establishing large international trials with adequate statistical power. Therefore, in the context of HSCT in AD, the following alternatives to RCTs may be considered: Prospective cohort studies, which follow a group of patients to assess whether events differ according to prognostic factors and therapeutic options, are the best observational approach and are more reliable than retrospective cohort studies. Casecontrol studies compare a group of patients who experience an event with another not experiencing the same event, and examine how exposure to a suspected agent (for example, therapeutic intervention) differs between groups. This type of study design is useful to ascertain the cause of rare events, although provides weaker evidence than cohort studies. In non-randomized studies, the major challenge is the avoidance of bias caused by confounding factors linked both to studied factors and to the outcome. For example, observed differences between treatments may be linked to the reason for choosing either treatment may result in selection bias. The statistical method used should adjust the comparisons for all potential prognostic factors, and the causality between treatment and observed difference should be discussed. ## Recommendations Well-defined and validated parameters for each type of AD should be used to define response progression and remission (level III). In principle, randomized controlled trials are preferred, but significant challenges should be recognized in their application to HSCT in ADs (level III). Prospective non-interventional studies provide an alternative and pragmatic means of increasing clinical knowledge, while eliminating bias associated with retrospective studies (level III). ## Health economics Despite international variation in health-care provision, all systems have finite and constrained resources and delivery of 'high-cost, low-volume' procedures, such as HSCT, is a public health challenge. Progress in the field of HSCT in ADs has been limited by funding not only of clinical trials, but also of individual HSCT procedures irrespective of the health-care provider. Previously, standard treatments in many ADs were relatively inexpensive. However, chronic administration of modern biological therapies, potentially for many years, now accumulates substantial costs. Although preliminary health economic and QoL studies have been undertaken, further work is necessary, particularly in conjunction with clinical trials, to determine whether single 'one-hit' intensive HSCT-based treatments may prove cost-effective by preventing, delaying or otherwise limiting the need for biological and other treatments. [bib_ref] High dose chemotherapy followed by autologous peripheral blood stem cell transplantation or..., Verburg [/bib_ref] [bib_ref] Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory..., Tappenden [/bib_ref] [bib_ref] Hematopoietic SCT for the treatment of multiple sclerosis, Atkins [/bib_ref] Recommendations Economic considerations should feature early and prospectively in the planning of clinical trials (level III). Studies using other sources of data (registry and established clinical trials) should be used in evaluating the potential cost-effectiveness of HSCT compared with modern non-HSCT treatment options (level III). ## Autologous hsct Mobilization of PBSCs for autologous HSCT Autologous HSCT can be performed with either PBSC or BM, although use of BM has been rare, and largely restricted to the paediatric setting. In most ADs, mobilization is safe, but G-CSF alone may induce disease flare. Combining G-CSF with chemotherapy helps prevent flare and improve yields of PBSC with significant decrease of T cells in the PBSC harvest. [bib_ref] A randomised, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy..., Snowden [/bib_ref] [bib_ref] Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor, Openshaw [/bib_ref] [bib_ref] Collection of hematopoietic stem cells from patients with autoimmune diseases, Burt [/bib_ref] [bib_ref] Mobilization, harvesting and selection of peripheral blood stem cells in patients with..., Statkute [/bib_ref] [bib_ref] Peripheral blood CD34+ cell mobilization in 42 patients with severe autoimmune disease, Zhang [/bib_ref] No systematic studies analyse the different types of mobilization chemotherapy, but the majority of patients received priming doses of CY of 2-4 g/m 2 . [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on..., Farge [/bib_ref] PBSCs are more easily mobilized in some AD than others, due to previous treatments or the intrinsic nature of some ADs. Apart from steroids, immunosuppressive, antimitotic or immunomodulatory drugs should be discontinued as early as clinically feasible before mobilization. Careful cardiac evaluation is important before use of mobilizing CY, especially in SSc and SLE, or in MS after use of mitoxantrone: electrocardiogram, cardiac ultrasound and, for SSc, pulmonary artery pressure, 24 h electrocardiogram, gating and magnetic resonance imaging (MRI) evaluation should be evaluated in view of early reports of potentially fatal cardiac toxicity, which decreased since the consensus statement concerning cardiotoxicity occurring during HSCT for ADs. [bib_ref] Consensus statement concerning cardiotoxicity occurring during haematopoietic stem cell transplantation in the..., Saccardi [/bib_ref] In patients with JIA, life-threatening and fatal macrophage activation syndrome was reported both during mobilization of PBSC and following engraftment of PBSC. [bib_ref] Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical..., De Kleer [/bib_ref] [bib_ref] Autologous stem cell transplantation in children with severe progressive systemic or polyarticular..., Brinkman [/bib_ref] [bib_ref] Current perspectives of autologous stem cell transplantation for severe juvenile idiopathic arthritis, Wulffraat [/bib_ref] Extreme care should be exercised giving any form of mobilization chemotherapy to severe immune thrombocytopenia (ITP) or Evans' syndrome patients as these states are refractory to platelet transfusion and fatal bleeding reported. [bib_ref] Peripheral blood stem cell mobilization in refractory autoimmune Evans syndrome: a cautionary..., Martino [/bib_ref] In Crohn's disease, reported episodes of potentially life-threatening sepsis during neutropenia after mobilization, [bib_ref] Complete remission of Crohn's disease after high-dose cyclophosphamide and autologous stem cell..., Kreisel [/bib_ref] [bib_ref] Infectious complications during the mobilization phase in patients with refractory Crohn's disease..., Rovira [/bib_ref] and consideration should be made to antibiotic prophylaxis and close monitoring, with a low threshold for in-patient admission. ## Recommendations Autologous HSC may be derived from peripheral blood or BM. Mobilized PBSCs are preferred based on ease of procurement and better engraftment characteristics (level II). Mobilization procedures and stem cell processing should be performed in JACIE (or equivalent) accredited collection centres (level III). Priming chemotherapy is recommended to enhance mobilization while maintaining disease control and to prevent potential flare, which may be a consequence of G-CSF alone (level I). The recommended mobilization regimen is CY at 2-4 g/ m 2 with uromixetan (Mesna) and cautious hyperhydration followed by G-CSF 5-10 mg/kg (level II). A minimum dose of 2 Â 10 6 /kg CD34 þ cells should be reinfused, irrespective of any graft manipulation (level II). Back-up harvest is recommended, especially when graft manipulation has been undertaken (level III). When CY-primed mobilization fails, a second attempt at PBSC mobilization or BM harvest should be considered following avoidance of immunosuppressive drugs, where possible. Despite the lack of evidence in patients with AD, the use of plerixafor and G-CSF may be reasonable in poor mobilizers after weighing up the benefits and risks. Steroid cover should be considered to reduce risk of disease flare related to G-CSF. Cases of failure from mobilization should be reported to the EBMT or other registry (level III). Mobilization may be associated with increased risk of mortality and morbidity in ADs: * Caution should be exercised in SSc and SLE, where CY priming may be associated with potentially fatal cardiac complications (level II). * Caution should be exercised in any patient with ITP (primary or secondary), in whom mobilization with CY may be associated with potentially life-threatening bleeding events (level II). * Caution should be exercised in patients with CD undergoing mobilization who appear to be at increased risk of severe infection. Consideration should be made for antibiotic prophylaxis and increased monitoring or in-patient admission (level III). ## Conditioning regimens for autologous hsct The original guidelines proposed that centres restricted their initial studies to one of four 'standard' HSCT regimens used in haemato-oncology and aplastic anaemia: Although TBI had been the focus of many animal studies and had potential advantages, excess toxicity was acknowledged to be an issue. [bib_ref] Blood and marrow stem cell transplants in autoimmune disease. A consensus report..., Tyndall [/bib_ref] In the EBMT registry analyses, most patients had received high-dose CY-based regimens, mainly directed against rheumatological conditions (SSc, RA, SLE). The most commonly used regimen was the 'BEAM' regimen (BCNU 300 mg/m 2 on day À6, Ara-C 200 mg/m 2 and etoposide 200 mg/m 2 on day À5 to À2, melphalan 140 mg/m 2 day À1), principally for MS, where it was frequently combined with anti-T globulin (ATG). Use of TBI was relatively rare (6%), but featured significantly in the treatment of JIA (45%). Conditioning regimens were divided retrospectively into (a) 'high intensity', including TBI or high-dose busulphancontaining regimens, (b) 'low intensity', referring to CY alone, melphalan alone and fludarabine-based regimens, or (c) 'intermediate intensity', including other combinations, such as BEAM, and, in most patients, the combined use of ATG with high-dose CY or other chemotherapy. There was a significant relationship between efficacy and intensity, balanced by the inverse relationship with toxicity as reflected by TRM. Overall, 'intermediate intensity' conditioning regimens were associated with significantly improved outcomes compared with 'low-' and 'high-' intensity regimens. [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases, Gratwohl [/bib_ref] [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on..., Farge [/bib_ref] Although more profound responses are possible with high-intensity regimens, caution should be exercised given the substantial short-and long-term toxicity. A further analysis of the MS data supports the significantly higher TRM with oral high-dose busulphan. [bib_ref] Autologous stem cell transplantation for progressive multiple sclerosis: update of the European..., Saccardi [/bib_ref] The use of irradiation-containing protocols outside of clinical trials has been questioned owing to the long-term adverse effects, including malignancies, even after low-dose irradiation. [bib_ref] Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases:..., Burt [/bib_ref] [bib_ref] Hematopoietic stem cell transplantation in autoimmune diseases: is the glass half full..., Illei [/bib_ref] [bib_ref] Pubertal development and growth after total-body irradiation and bone marrow transplantation for..., Bakker [/bib_ref] [bib_ref] Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total..., Burt [/bib_ref] [bib_ref] The rationale behind autologous autoimmune hematopoietic stem cell transplant conditioning regimens: concerns..., Burt [/bib_ref] [bib_ref] Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies, Ferry [/bib_ref] [bib_ref] Follow-up care for young adult survivors of cancer: lessons from pediatrics, Eiser [/bib_ref] [bib_ref] Risks of immune system treatments, Burt [/bib_ref] Allergic reactions to ATG and other serotherapy may be prevented with intermediate-dose corticosteroids. This may be especially important in patients with MS where fever can worsen neurological symptoms. [bib_ref] Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact..., Saccardi [/bib_ref] [bib_ref] The Uhthoff phenomenon: a potential post transplant complication in advanced progressive multiple..., Morris [/bib_ref] Recommendations Given the relatively high risk of TRM and late effects of 'high-intensity' conditioning regimens (including irradiation at any dose), their use should be restricted to clinical trial setting (level III). If a patient is being treated under the EBMT CO category, the following intermediate intensity conditioning regimens provide a balance between safety and efficacy, while facilitating data analysis and clinical trial planning (level II): * CY 200 mg/kg with polyclonal or monoclonal anti-Tcell serotherapy is recommended generally; with CY 120 mg/kg, fludarabine 150 mg/kg and ATG (or other anti-T-cell serotherapy) as an alternative in paediatrics. * For MS specifically BEAM þ ATG (or other anti-Tcell serotherapy) is recommended. * Choice of anti-T-cell serotherapy will depend on availability, but may include polyclonal ATG (for example, thymoglobulin, Fresenius and lymphoglobulin type) and MoAbs (for example, alemtuzumab). Consideration should be given to the short-and longterm toxicities of the various types of serotherapy (level II). ## Graft manipulation in autologous hsct Lymphocyte depletion of autologous PBSC was originally recommended and its use has been widespread, particularly in the form of CD34 þ selection. [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on..., Farge [/bib_ref] Despite the availability of various clinical grade separation devices for graft manipulation, and theoretical concepts supporting the use of T-or B-cell depletion, none of the EBMT registry outcome analyses to date support ex vivo depletion strategies. A randomized controlled pilot trial in 30 severe RA using 'low-intensity' conditioning with CY 200 mg/kg showed no benefit for CD34 þ selection. [bib_ref] A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation..., Moore [/bib_ref] In addition, the selection procedure adds significantly to the cost of an autologous procedure and potentially requires additional numbers of CD34 þ cells to be harvested. Given that pathogenetic mechanisms vary between ADs, a tailored approach to graft manipulation within clinical trials may ultimately be appropriate, but for the present there is little to support the routine use of graft manipulation. ## Recommendations There is no evidence to support ex-vivo graft manipulation, although decisions can be made on an individual patient basis (level II). Ex-vivo graft manipulation should be the focus of clinical trials (level III). General status for autologous HSCT, infection prophylaxis and supportive care Patients with ADs often have significantly reduced immunity related to chronic immunosuppressive treatments and intrinsic immune suppression in some diseases, such as SLE and T1D. The profoundly immunosuppressive nature of the conditioning regimens (use of ATG or other anti-Tcell serotherapy), and ex-vivo graft manipulation of the autologous harvest, are associated with increased risk of acquired and re-activated infections. Instances of infections more commonly associated with allogeneic HSCT, including EBV post transplant lymphoproliferative disorder and CMV disease, have been reported. [bib_ref] Autologous stem cell transplantation for progressive multiple sclerosis: update of the European..., Saccardi [/bib_ref] [bib_ref] Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected..., Nash [/bib_ref] [bib_ref] A pilot trial for severe, refractory systemic autoimmune disease with stem cell..., Leng [/bib_ref] In addition, there are also reports of fever being associated with neurological deterioration in patients with MS, [bib_ref] Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact..., Saccardi [/bib_ref] [bib_ref] The Uhthoff phenomenon: a potential post transplant complication in advanced progressive multiple..., Morris [/bib_ref] and engraftment syndrome has been recognized as an potential issue in patients with ADs. [bib_ref] Engraftment syndrome: a common cause for rash and fever following autologous hematopoietic..., Oyama [/bib_ref] [bib_ref] Engraftment syndrome after auto-SCT: analysis of diagnostic criteria and risk factors in..., Carreras [/bib_ref] The risks of TRM and other serious complications should be minimized by patient selection and by minimizing infective and other risks with prophylactic, pre-emptive and other supportive care strategies. Facilities for treating patients with AD with autologous HSCT should be broadly similar to those available for allogeneic HSCT practice. Although induction of infertility is not universal, 32,116 the effect of HSCT on gonadal function is also an important aspect of the pre-HSCT counselling. Although EBMT registry analyses [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases, Gratwohl [/bib_ref] [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on..., Farge [/bib_ref] have shown that PFS improves in younger age groups (o35 years), there is no evidence upon which to base an upper age limit. ## Recommendations ## (ii) uncontrolled infection Any uncontrolled acute or chronic infection, including HIV, human T-lymphotropic virus type 1 and 2, hepatitis B surface antigen positivity and hepatitis C PCR positivity, should be considered as a contraindication (level II). ## (iii) pregnancy Pregnancy should always be excluded within 7 days of administering mobilization chemotherapy or HSCT with a blood based b-human chorionic gonadotrophin assay (level III). (ii) Infection prophylaxis In-patient accommodation for HSCT period All patients should be accommodated in isolation facilities, with appropriate clean air facilities (for example, laminar flow or HEPA) in accordance with JACIE accreditation standards during BM aplasia/ severe neutropenia (level II). ## Bacterial, fungal and viral prophylaxis All patients should receive broad-spectrum antibacterial prophylaxis during aplasia (for example, quinolones), anti-fungal prophylaxis (for example, azoles) and herpes prophylaxis (aciclovir) during and for at least 100 days post transplant (level II). All patients who are negative for anti-CMV antibodies should receive CMV-negative blood products (level II). All patients should receive prophylaxis against Pneumocystis jiroveci (for example, oral co-trimoxazole (TMP/SMX) 3 times weekly as tolerated or, if not tolerated, alternatives, such as nebulized pentamidine, dapsone or atovaquone) for at least 100 days post transplant (level III). All patients positive for anti-toxoplasma antibodies should receive oral co-trimoxazole (TMP/SMX) daily until day -1, then after reconstitution of blood counts 3 times weekly for at least 100 days post transplant, as tolerated, as per Pneumocystis jiroveci (level II). Consideration should be made to risk of reactivation of tuberculosis, with prophylaxis through the period of immune suppression where appropriate (level II). I.v. Ig replacement may be considered in carefully selected cases after weighing up the benefits, risks and costs of administration (level III). (iii) Pre-emptive therapy CMV reactivation (diagnosed by PCR or Ag) should be treated with ganciclovir, valganciclovir or foscarnet according to centre policy and protocols (level II). (iv) Therapy of fever and proven infections ## (ii) transfusion Platelet and erythrocyte transfusions should be administered according to centre policy and protocols. Blood products should be irradiated. ## (iii) fertility, pregnancy and menopause Before mobilization and HSCT, consideration should be given to chemotherapy-induced infertility (semen, oocyte or embryo cryopreservation as appropriate) risk of induction of premature menopause, and ultimate need for hormone replacement therapy, where appropriate. Pregnancy should be excluded within 7 days of administering mobilization or conditioning chemotherapy (level III). ## (d) follow-up after hsct and ongoing responsibility for the patient All patients should remain under the direct routine care of the transplant specialist for at least 100 days post transplant, or longer, if necessary until clinically stable. Thereafter, combined care between transplant specialist and referring organ/AD specialist with joint annual review as a minimum is recommended (level III). where large-scale multicentre clinical studies are active or are potentially feasible for a proportion of patients. Patients who are unfit for HSCT should be excluded. ## Principal indications for autologous hsct Multiple sclerosis. MS is the most frequent chronic inflammatory demyelinating disease, with a prevalence of 1 in 700 adults, believed to be mediated by autoreactive lymphocytes that invade the central nervous system causing damage to oligodendrocytes and axons and resulting in demyelination, neuronal death and brain atrophy. [bib_ref] Multiple sclerosis, Compston [/bib_ref] In the most frequent type, the disease is initially characterized by relapses and remissions due to repeated inflammatory attacks in the central nervous system, as demonstrated by the appearance of new T2-weighted-or contrast-enhancing lesions on MRI studies and characterized pathologically by inflammatory infiltrates rich in T cells, macrophages/DCs, and, in certain subforms, also in antibodies and complement (relapsing-remitting phase). The second phase is associated with slow progression of disability, with a progressive decline in inflammation (secondary progressive phase), characterized by microglial activation, but predominantly by axonal/neuronal loss. Some patients follow a progressive course from the onset (primary progressive form). The Extended Disability Scoring Scale is the most commonly used means of assessing function and progression in MS. [bib_ref] Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS), Kurtzke [/bib_ref] First-line treatments are the immunomodulators, such as glatiramer-acetate 118 and b-IFN, [bib_ref] Interferon beta-1b is effective in relapsingremitting multiple sclerosis. II. MRI analysis results..., Paty [/bib_ref] which delay progression of disability. Very recently, the orally available sphingosine 1 phosphate receptor agonist, fingolimod, which is considerably more effective than b-IFN and glatiramer-acetate, [bib_ref] Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis, Cohen [/bib_ref] has also been approved as first-line therapy. Second-line treatments are mitoxantrone 121 and the MoAb, natalizumab. [bib_ref] A controlled trial of natalizumab for relapsing multiple sclerosis, Miller [/bib_ref] Both first-and second-line treatments alter the natural course of disease by targeting the early phase of inflammation, but virtually all failed to halt the build-up of disability when used in the later secondary progressive phase of disease. The administration of such agents is complicated by infrequent, but sometimes serious, adverse events, such as progressive multifocal leukoencephalopathy with natalizumab, serious infections and other adverse events with fingolimod, and cardiomyopathy and secondary leukaemia with mitoxantrone treatment. [bib_ref] Evidence Report: the efficacy and safety of mitoxantrone (Novantrone) in the treatment..., Marriott [/bib_ref] On the horizon are other agents, all aimed at the early inflammatory phase (for example, cladribrine, alemtuzumab, teriflunomide, laquinimod, fumaric acid, ocrelizumab and daclizumab), but those tested in a small population of SPMS (cladribine and alemtuzumab) failed to show effectiveness. Overall, a subset of non-responders has been described in clinical trials with both old and new therapies, associated with the need to maintain long-term immunosuppression. Since 1996, [bib_ref] Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis:..., Fassas [/bib_ref] HSCT has been extensively reported worldwide as a tool for inducing a prolonged restoration of self-tolerance in MS patients progressing despite ongoing, conventional treatments year. [bib_ref] High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe..., Nash [/bib_ref] [bib_ref] Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact..., Saccardi [/bib_ref] [bib_ref] Intense T cell depletion followed by autologous bone marrow transplantation for severe..., Samijn [/bib_ref] [bib_ref] Clinical and MRI outcome after autologous hematopoietic stem cell transplantation in MS, Saiz [/bib_ref] [bib_ref] Autologous stem cell transplantation as rescue therapy in malignant forms of multiple..., Mancardi [/bib_ref] [bib_ref] High-dose immunoablation with autologous haematopoietic stem cell transplantation in aggressive multiple sclerosis:..., Krasulova´e [/bib_ref] [bib_ref] Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse..., Hamerschlak [/bib_ref] [bib_ref] Clinical outcome of autologous peripheral blood stem cell transplantation in opticospinal and..., Xu [/bib_ref] The Autologous Stem cell Transplantation International MS Trial is a multicentre prospective randomized phase II study with a primary MRI end point. Despite a low accrual, 21 patients were included and are now followed up by clinical and MRI assessment. ASTIMS was stopped owing to enrolment difficulties, but a prospective phase III trial comparing autologous HSCT vs best approved/ available therapy is currently under consideration between European and North American experts. [bib_ref] Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and..., Pasquini [/bib_ref] [bib_ref] Panel session report: multiples sclerosis, Freedman [/bib_ref] Most of the patients worldwide have been conditioned with BEAM þ ATG schedule showing satisfactory toxicity/ efficacy equipoise. [bib_ref] Autologous stem cell transplantation for progressive multiple sclerosis: update of the European..., Saccardi [/bib_ref] CY and ATG conditioning was used for autologous HSCT in 21 early relapsing-remitting patients with low (but not negligible) toxicity. After a range 24-48 months follow-up, patients had no deterioration in the Extended Disability Scoring Scale score, 16/21 were free of relapses and significant improvements in neurological disability were reported. [bib_ref] Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase..., Burt [/bib_ref] A larger experience is needed to assess the role of lower intensity regimens and a randomized trial is ongoing (http://www.clinicaltrials. gov). A better outcome in relapsing-remitting over secondary progressive forms, including sustained improvement of the disability, has been recently reported in single centre experiences. [bib_ref] High-dose immunoablation with autologous haematopoietic stem cell transplantation in aggressive multiple sclerosis:..., Krasulova´e [/bib_ref] [bib_ref] Long-term results of stem cell transplantation for MS: a single-center experience, Fassas [/bib_ref] Recommendations In MS, the ideal target patients for autologous HSCT are in the relapsing-remitting phase, showing high inflammatory activity, both clinically and by MRI (Gd þ contrast-enhancing lesions and/or new T2 lesions in two subsequent scans), who are rapidly deteriorating despite the use of one or more lines of approved treatments (level II Systemic sclerosis. SSc is a rare AD of unknown origin, with an incidence of 1 in 100 000 characterized by skin and visceral (lung, gastrointestinal, cardiovascular and renal) fibrosis secondary to excessive collagen deposition.Limited and diffuse cutaneous (dcSSc) forms can be distinguished by the extent of skin and organ involvement and auto-Ab profile. [bib_ref] Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian..., Ferri [/bib_ref] [bib_ref] Scleroderma: from cell and molecular mechanisms to disease models, Abraham [/bib_ref] Rapidly progressing dcSSc within the first 4 years after disease onset, observed in 10-20% of cases, is life-threatening disease with 3-5 years survival between 50 and 80%. [bib_ref] Improved survival in systemic sclerosis is associated with better ascertainment of internal..., Nihtyanova [/bib_ref] [bib_ref] Skin thickness progression rate: a predictor of mortality and early internal organ..., Domsic [/bib_ref] [bib_ref] Mortality in systemic sclerosis: an international meta-analysis of individual patient data, Ioannidis [/bib_ref] Presence of extensive skin thickening (as measured by the Rodnan modified skin score), renal (proteinuria) or lung involvement (as demonstrated by pulmonary functions tests or on CT scan) and high age at onset are important risk factors. [bib_ref] Skin thickness progression rate: a predictor of mortality and early internal organ..., Domsic [/bib_ref] [bib_ref] Mortality in systemic sclerosis: an international meta-analysis of individual patient data, Ioannidis [/bib_ref] [bib_ref] Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French..., Scussel-Lonzetti [/bib_ref] SSc patients only marginally benefit from prolonged oral CY, the only treatment with some proven efficacy. [bib_ref] Cyclophosphamide versus placebo in scleroderma lung disease, Tashkin [/bib_ref] [bib_ref] Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial..., Nannini [/bib_ref] HSCT registry data, case reports and pilot studies in Europe [bib_ref] Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure..., Binks [/bib_ref] [bib_ref] Autologous stem cell transplantation in the treatment of systemic sclerosis: report from..., Farge [/bib_ref] [bib_ref] Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early..., Farge [/bib_ref] and the United States of America [bib_ref] Hematopoietic stem cell transplantation for systemic sclerosis with rapid improvement in skin..., Burt [/bib_ref] [bib_ref] High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes, Mcsweeney [/bib_ref] in dcSSc consistently showed rapid and sustained clinically relevant improvement of functional ability and skin thickening (in the majority of patients, stabilization of organ function (heart, lung, kidney)), but at the expense of toxicity and early TRM [bib_ref] Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure..., Binks [/bib_ref] in the initial studies. Patient eligibility has been broadly similar in different studies, that is, targeting early dcSSc with a Rodnan modified skin score above 15 and some degree of internal organ involvement (mainly lung) or with rapidly progressing skin fibrosis in the first 2 years after AD onset. Different HSCT regimens have been employed, but most included high doses of CY for mobilization (4 g/m 2 ) and conditioning (200 mg/kg total dose with ATG). Comparison with 'historical controls', including those from recent randomized trials of CY vs placebo, suggests that autologous HSCT induces more robust and sustained responses of skin involvement and functional status. [bib_ref] Autologous stem cell transplantation in the treatment of systemic sclerosis: report from..., Farge [/bib_ref] [bib_ref] High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis:..., Nash [/bib_ref] [bib_ref] Autologous non-myeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis, Oyama [/bib_ref] [bib_ref] Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic..., Vonk [/bib_ref] [bib_ref] Autologous stem cell transplantation for systemic sclerosis, Farge [/bib_ref] [bib_ref] Risks of immune system treatments, Burt [/bib_ref] The benefits need to be weighed against the risks of TRM, which appears to be decreasing with increasing experience and better patient selection, 18,99 although definitive statements regarding relative safety and efficacy need to await the final analysis of randomized trials. Two prospective, randomized controlled trials, the multicentre EBMT sponsored ASTIS trial conducted under the auspices of EBMT and European League against Rheumatism in Europe and the single centre ASSIST 204 study, run by the Chicago group, recently completed recruitment and results are expected by the end of 2011. The SCOT trial in North America is still accruing. ASTIS and SCOT are large multicentre RCTs with similar eligibility criteria and comparable outcome measures and include control treatment with 12 monthly i.v. pulses CY, but differ in the conditioning regimen being without (ASTIS) or with (SCOT) irradiation, allowing future comparison between intense immunosuppression vs myeloablation. Long-term follow-up of patients in all of these trials is essential to examine possible divergence of survival and to study late effects of treatment. Although the outcome of juvenile systemic sclerosis is better than the adult form, extensive skin and pulmonary involvement show a 5-year mortality of 10%. [bib_ref] Systemic sclerosis in childhood: clinical and immunologic features of 153 patients in..., Martini [/bib_ref] As with the adult form, immunosuppressive drug strategies may be used, but there is no satisfactory treatment. Autologous HSCT in juvenile systemic sclerosis has been explored in five patients (median age 12 years) incorporated in a larger analysis of SSc. The patients with severe lung disease were treated with CY-based conditioning (120-200 mg/kg) and selected autograft. After a median follow-up of 37 (range 13-67) months, all five children were alive and three of them are in complete and sustained remission. [bib_ref] Autologous stem cell transplantation in the treatment of systemic sclerosis: report from..., Farge [/bib_ref] [bib_ref] Haematpoietic stem cell transplantation in severe autoimmune diseases in children. Results and..., Rabusin [/bib_ref] No published data are available to make recommendations for limited SSc patients in any age group. ## Recommendations Autologous HSCT can be considered as treatment for selected patients with early dcSSc and juvenile systemic sclerosis. Patients to be considered for HSCT include those with diffuse SSc with disease duration p5 years since development of first non-Raynaud's symptoms with a modified Rodnan skin score X15 plus major organ involvement (with documented evidence of onset or clinically significant worsening in the previous 6 months) as defined by at least one of: (a) respiratory involvement with a DLCO and/or forced vital capacity p70% of predicted and evidence of interstitial lung disease (chest X-ray and/or HR-CT scan) (level II) (b) cardiac involvement with conduction disturbances, including second-/third-degree atrioventricular block, intra-ventricular conduction disturbance, left axis deviation, atrial or ventricular rhythm disturbance, pericarditis as defined by p1 cm on cardiac ultrasound (level II) (c) renal involvement with proteinuria 40.3 g/24 h, not explained by other causes than systemic sclerosis (level II). Systemic lupus erythematosus. SLE is a heterogeneous chronic AD with a prevalence of 40-50 per 100 000, predominantly females (485%) with higher frequency among people of African origin. [bib_ref] The association of socio-economic status, race, psychosocial factors and outcome in patients..., Sutcliffe [/bib_ref] [bib_ref] Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a..., Cervera [/bib_ref] [bib_ref] The Euro-lupus project: epidemiology of systemic lupus erythematosus in Europe, Cervera [/bib_ref] The outcome of active severe SLE due to kidney, lung, heart or brain involvement has improved in adults and children with early diagnosis and new immunosuppressive agents combined with overall tighter control of blood pressure and infections. [bib_ref] Improved clinical outcome of lupus nephritis during the past decade: importance of..., Fiehn [/bib_ref] First-line therapies aimed at inducing remission within the first 6-9 months of disease flare include corticosteroids in combination with mycophenolate mofetil or CY using the classical National Institutes of Health regimen [bib_ref] Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome..., Illei [/bib_ref] [bib_ref] Sequential therapies for proliferative lupus nephritis, Contreras [/bib_ref] or the Eurolupus regimen, [bib_ref] Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial..., Houssiau [/bib_ref] with lower CY doses for shorter duration and same efficacy. Among other drugs tested for induction, the use of various MoAbs against T-or B-cell receptors or adhesion molecules all failed to demonstrate their superiority when tested in phase III trials, except for belimumab, an MoAb against Blymphocyte stimulator soluble receptor. [bib_ref] Novel treatments for systemic lupus erythematosus, Gayed [/bib_ref] Response rates to standard therapy vary according to the criteria, extent of visceral involvement, ethnic origin and socio-economic profile. Approximately 20% (10-36%) of active SLE patients fail to respond; 50% (10-65%) relapse after initial treatment, 5-15% evolve towards end-stage disease and 10-15% die at 10 years. [bib_ref] Current causes of death in systemic lupus erythematosus in Europe, Nossent [/bib_ref] [bib_ref] Long-term prognosis and causes of death in systemic lupus erythematosus, Doria [/bib_ref] Initial and persistent renal, cerebral or severe pulmonary involvement along with overall disease activity are important predictors of poor long-term survival. [bib_ref] Long-term prognosis and causes of death in systemic lupus erythematosus, Doria [/bib_ref] [bib_ref] The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and..., Houssiau [/bib_ref] Among 200 autologous HSCT worldwide for SLE, the largest experience comes from retrospective EBMT ADWP registry (n ¼ 53), [bib_ref] Autologous stem cell transplantation for systemic lupus erythematosus, Jayne [/bib_ref] and from the Northwestern University prospective single centre study (n ¼ 50) [bib_ref] Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus, Burt [/bib_ref] with a 50% probability of 5-year disease-free survival in both studies. In addition to a decrease in the overall disease activity and serological responses, autologous HSCT reversed pulmonary dysfunction and anti-phospholipid syndrome with durable treatment-free responses lasting 5 or more years on minimal or no treatment. In terms of safety, the Northwestern University study reported TRM of 4% (2/50, including one death from fungal infection during mobilization), [bib_ref] Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus, Burt [/bib_ref] whereas the first multicentre EBMT analysis showed a more substantial TRM of 12% in early published cohort of 54 patients analyzed up to 2002, [bib_ref] Autologous stem cell transplantation for systemic lupus erythematosus, Jayne [/bib_ref] subsequently decreasing by around half in a later cohort of 28 patients transplanted from 2002 to 2008 (D Jayne, personal communication). In the EBMT registry analysis, severe or fatal infections tend to be more frequent among the 85 SLE patients with autologous HSCT as compared with other groups of patients (39% vs 22%). [bib_ref] Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on..., Farge [/bib_ref] In addition, preliminary analysis of 18 paediatric SLE patients in the EBMT database, with 41 months median follow-up after autologous HSCT, confirmed that nine patients are in CR, while seven relapsed and two died of TRM (M Rabusin, personal communication). An updated analysis of the 85 patients reported to the EBMT is in preparation (D Jayne, personal communication). In summary, in patients with severe SLE refractory to conventional immunosuppressive therapies, autologous HSCT can achieve sustained clinical remissions with qualitative immunological changes 153,154 not seen with other forms of therapy despite significant TRM. Overall prospective and retrospective data highlight the need for careful patient selection, as well as recognition of the intrinsic immune suppression and other risks associated with advanced SLE. Ideally, the role of autologous HSCT in the treatment of severe SLE in both adults and children should be established in adequately powered RCTs. Until larger international RCTs are available, smaller phase II studies and stronger registry analyses should be pursued to help define a core set of clinical data biological sample collection to be collected in every study. ## Recommendations Current uncontrolled data suggest that autologous HSCT can be considered as treatment for carefully selected subpopulations of SLE patients early in their disease course, with reliably predicting poor prognostic factors, according to combinations of demographic, clinical and laboratory markers. Patients to be considered for HSCT would reasonably include those with sustained or relapsed active BILAG category A SLE remaining steroid dependent after at least 6 months of the best standard therapy, using mycophenolate mofetil or CY with or without anti-CD20 and other MoAbs, with documented evidence of visceral involvement or refractory SLE as defined by at least one of: (a) Kidney involvement: meeting the criteria for BILAG category A with a renal biopsy of less than 12 months showing evidence of World Health Organization class III or IV glomerulonephritis (level II). (b) Any other type of vital organ involvement with BILAG neurological category A, cardiovascular or pulmonary category A, vasculitis category A and autoimmune cytopenias category A (level II). (c) Associated anti-phospholipid syndrome with recurrent thromboembolism despite maximal anticoagulation (level III). Crohn's disease. CD is an inflammatory bowel disease affecting both adults and children characterized by a chronic clinical course, with exacerbations and remissions, and by a trans-mural inflammation that may affect different segments of the digestive tract. In developed countries, prevalence of CD is around 0.1%. Recent genetic discoveries have underlined the role of innate and adaptive immunity, as well as epithelial function. Nevertheless, the pathogenesis of CD and the role of environmental factors remain unclear. Current pharmacological treatments based on corticosteroids, immunosuppressants (for example, thiopurines and MTX) and biological therapies (particularly anti-tumour necrosis factor drugs) are used early in the course of the disease. Despite the major recent progress in the treatment of CD, some patients fail all available therapies, including immunosuppressants and biological therapies. There is a subset of patients in whom the disease runs an aggressive course with progressive tissue damage and potentially reduced life expectancy. [bib_ref] Crohn's disease, Shanahan [/bib_ref] [bib_ref] The epidemiology of paediatric inflammatory bowel disease, Cosgrove [/bib_ref] [bib_ref] Association between insertion mutation in NOD2 gene and Crohn's disease in German..., Hampe [/bib_ref] [bib_ref] Disease concordance, zygosity, and NOD2/CARD15 status: follow-up of a population-based cohort of..., Jess [/bib_ref] Surgery may be considered as an option in many cases, but may lead to short bowel syndrome or to a definitive stoma, which may be refused by the patient. Beyond case reports and short series, autologous HSCT as primary treatment for CD has been investigated in several phase II studies, one with extended follow-up. [bib_ref] Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease, Oyama [/bib_ref] [bib_ref] Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn's..., Cassinotti [/bib_ref] [bib_ref] Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory..., Burt [/bib_ref] [bib_ref] Complete remission of Crohn's disease after high-dose cyclophosphamide and autologous stem cell..., Kreisel [/bib_ref] The majority of patients have been adult, although paediatric patients have also been treated [fig_ref] Table 1: EBMT database of autoimmune diseases, June 2011 Abbreviation [/fig_ref]. Responses have been encouraging and prolonged, but the progressive incidence of relapse with long-term follow-up raises questions regarding the benefits over conventional treatments and also in relation to salvage and maintenance treatments post-HSCT. [bib_ref] Crohn disease: remissions but no cure, Nash [/bib_ref] ASTIC is a multicentre, prospective, randomized phase III study for adult patients with CD supported by European Crohn's and Colitis Organization and sponsored by EBMT comparing the relative benefits of autologous HSCT with best available medical therapy. In addition, paediatric specialists have proposed the following consensus criteria for refractory disease (a) corticosteroid-resistant disease, with no response to equivalent prednisolone dose of 1 mg/kg daily (max 60 mg daily) for 8 consecutive weeks, or corticosteroid dependence or relapse within 3 months of stopping treatment and (b) lack of response to, or intolerance of, at least one of; azathioprine or mercaptopurine for 4 consecutive months, MTX for 3 consecutive months, infliximab (5 mg/kg) given as 0, þ 2 and þ 6 weeks regimen infusions, or thalidomide 2 mg/kg for 8 consecutive weeks. [bib_ref] Haematpoietic stem cell transplantation in severe autoimmune diseases in children. Results and..., Rabusin [/bib_ref] ## Recommendations In the absence of results from large studies, autologous HSCT should be reserved for patients with severe CD unresponsive to multiple lines of therapy, including immunosuppressive agents and anti-tumour necrosis factor MoAbs. HSCT may be considered for patients with active CD refractory to immunosuppressants and biologics. The disease activity has to be proven by morphological evaluation (endoscopy, CT scan). Other therapeutic options, including surgery, should be discussed case by case, whenever acceptable. Autologous HSCT may be considered for the following situations (level III): * Active disease, uncontrolled by medical therapies. * Extensive disease in which surgical resection would expose the patient to the risk of small bowel syndrome. * Refractory colonic disease and perianal lesions where coloprotectomy with a definitive stoma not accepted by the patient. Paediatric CD requires special consideration and appropriate expertise in patient selection (level III). ## Orphan diseases and rare indications for autologous hsct In other ADs, the strength of established competing therapies and the limited evidence base have made HSCT a rare consideration. Rare cases of resistant disease may be considered in a multidisciplinary setting within the 'CO' category. Enrolment onto a clinical trial should be pursued, if feasible. Full data reporting to EBMT or equivalent registry is mandatory, and will facilitate prospective noninterventional studies in these indications. Autoimmune cytopenias. The majority of patients with immune cytopenia respond well to treatment, and many require no intervention, but occasionally necessitate high levels of immunosuppression and supportive care with lifethreatening situations. ITP is the most common autoimmune cytopenia, with an incidence of the chronic form of 5.8-6.6 per 100 000 in adults and 0.46 per 100 000 in children. ITP in children follows a chronic course in 25% of patients, and 10% require chronic immunosuppressive therapy. [bib_ref] Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults,..., Anon [/bib_ref] [bib_ref] International consensus report on the investigation and management of primary immune thrombocytopenia, Provan [/bib_ref] Autoimmune haemolytic anaemia (AIHA) is less frequent with an incidence of 2.6/100 000.Paediatric AIHA follows a chronic course in 20% of patients between 2 and 12 years, with a reported mortality rate of 10%. [bib_ref] Management of Evans syndrome, Norton [/bib_ref] Evans' syndrome and thrombotic thrombocytopenic purpura are rarer, but more frequently associated with life-threatening complications with a mortality rate in children up to 30%. [bib_ref] Management of Evans syndrome, Norton [/bib_ref] Among 52 patients with ITP, AIHA and Evans' syndrome in the EBMT registry, who underwent autologous or allogeneic HSCT up to 2008 in 50 centres, OS at 5 years was 61 ± 5%. Analysis of the 24 children with immune cytopenias (19 allogeneic HSCT and 7 autologous HSCT) confirmed a 60% PFS with allogeneic HSCT vs 35% with autologous HSCT, with a TRM of 20% overall. [bib_ref] Haematpoietic stem cell transplantation in severe autoimmune diseases in children. Results and..., Rabusin [/bib_ref] [bib_ref] Panel session report: autoimmune cytopenias, Passweg [/bib_ref] It remains unclear whether symptomatic 'cytopenia-free survival' is best achieved with autologous or allogeneic HSCT, [bib_ref] Haematopoetic stem cell transplantation for refractory autoimmune cytopenia, Passweg [/bib_ref] [bib_ref] International consensus report on the investigation and management of primary immune thrombocytopenia, Provan [/bib_ref] [bib_ref] High-dose cyclophosphamide with autologous lymphocyte-depleted peripheral blood stem cell (PBSC) support for..., Huhn [/bib_ref] but, given the low number of HSCT per centre, it is unlikely that a prospective study can ever be successfully completed. Some patients have clearly benefited and harmonizing procedures may yield more interpretable data in the future through prospective non-interventional protocols. ## Recommendations HSCT may be considered for patients with ITP, AIHA and Evans' syndrome refractory to at least two lines of treatment (including rituximab and TPO receptor agonists for ITP) under the 'CO' criterionJuvenile idiopathic arthritis. JIA is the most common rheumatic disease in children and a major cause of disability. In 5-10% of children with the systemic and polyarticular onset forms, the disease is refractory to nonsteroidal anti-inflammatory drugs and immunosuppressive drugs such as MTX and corticosteroid with an estimated mortality in the whole group of 2-4%. The introduction of biological agents, such as anti-tumour necrosis factor and anti-IL-1 and -6 receptor agents, had a major impact on outcome of children with the polyarticular form, but is less effective in active systemic disease. [bib_ref] Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to..., Quartier [/bib_ref] [bib_ref] Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset..., Yokota [/bib_ref] A retrospective European analysis included 34 JIA patients undergoing autologous HSCT using ATG, and CY±low-dose TBI (4 Gy) and T-cell depletion. [bib_ref] Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical..., De Kleer [/bib_ref] Over half the patients achieved a complete drug-free remission, while another six patients (18%) showed a partial response. The incidence of complications was high with three episodes of fatal haemophagocytic (macrophage activation) syndrome and TRM of 9%. Long-term remission has been confirmed in the majority of patients. [bib_ref] Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical..., De Kleer [/bib_ref] [bib_ref] Autologous stem cell transplantation in children with severe progressive systemic or polyarticular..., Brinkman [/bib_ref] [bib_ref] Current perspectives of autologous stem cell transplantation for severe juvenile idiopathic arthritis, Wulffraat [/bib_ref] [bib_ref] Autologous T cell depleted haematopoietic stem cell transplantation in children with severe..., Abinun [/bib_ref] Recommendations HSCT can be considered as treatment for carefully selected subpopulations of patients with JIA who meet the following inclusion criteria under the 'CO' criterion: * systemic onset with polyarticular course or polyarticular onset, * corticosteroid-resistant disease defined as no response to equivalent prednisone dose of 2 mg/kg per day (max 60 mg daily) for 8 consecutive weeks, * inadequate response to, or intolerance to, at least two disease-modifying antirheumatic drugs, including biological agents such as etanercept, infliximab, adalimumab, anti-IL-1 receptor and anti-IL-6 receptor agents, and * unacceptable toxicity from disease-modifying antirheumatic drugs or corticosteroid therapy (level II). Patients with a history of previous macrophage-activating syndrome or recent systemic disease flare should receive ciclosporin together with maintenance prednisone during the conditioning regimen phase before the transplant (level II). Rheumatoid arthritis. Before the widespread introduction of biological therapy, severe RA was the most common indication for autologous HSCT. The procedure was well tolerated and produced good initial responses, but early relapses were observed necessitating re-introduction of anti-rheumatic treatments. Seronegative disease was more responsive with some prolonged remissions. The EBMT supported the phase III ASTIRA trial to address the role of post transplant maintenance, but, in the midst of emerging biological therapy, it recruited poorly and was closed. Sporadic patients continue to be reported to the registry, but the place of HSCT is unclear. [bib_ref] Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis: a report from..., Snowden [/bib_ref] [bib_ref] A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation..., Moore [/bib_ref] [bib_ref] Reduction of joint damage in severe rheumatoid arthritis by high-dose chemotherapy and..., Verburg [/bib_ref] [bib_ref] Long-term followup of health status in patients with severe rheumatoid arthritis after..., Teng [/bib_ref] [bib_ref] Stem cell transplantation in rheumatoid arthritis, Snowden [/bib_ref] Exceptional patients may be considered on a 'CO' basis, and data registration is a minimum recommendation.. [formula] Systemic [/formula] Dermatomyositis and polymyositis. Among the eight cases of polymyositis and dermatomyositis registered in the EBMT database, there are some encouraging anecdotal responses, especially in children, but others in adults are disappointing. [bib_ref] Autologous stem cell transplantation for rapidly progressive Jo-1-positive polymyositis with long-term followup, Bingham [/bib_ref] [bib_ref] Successful treatment of rapidly progressive interstitial pneumonia with autologous peripheral blood stem..., Oryoji [/bib_ref] [bib_ref] A phase I-II trial of autologous peripheral blood stem cell transplantation in..., Tsukamoto [/bib_ref] [bib_ref] Successful autologous stem cell transplantation in two patients with juvenile dermatomyositis, Holzer [/bib_ref] No definitive recommendations can be made other than that exceptional patients may be considered on a 'CO' basis, and data registration is a minimum recommendation. Chronic demyelinating inflammatory polyneuropathy and neuromyelitis optica. Chronic demyelinating inflammatory polyneuropathy may be chronically disabling and resistant to treatment. In such cases, autologous HSCT has resulted in improvement or stabilization of neurological status and cessation of immunosuppression. [bib_ref] Successful autologous stem cell transplantation in a patient with chronic inflammatory demyelinating..., Vermeulen [/bib_ref] [bib_ref] Chronic inflammatory demyelinating polyradiculoneuropathy: a role for haematopoietic stem cell transplantation?, Kazmi [/bib_ref] [bib_ref] Autologous peripheral blood stem cell transplantation for chronic acquired demyelinating neuropathy, Mahdi-Rogers [/bib_ref] Achieving an accurate diagnosis of chronic demyelinating inflammatory polyneuropathy as per the European Federation of Neurological Societies guidelines with an active inflammatory component is mandatory.Among the limited published and EBMT registry data for HSCT in neuromyelitis optica registered in the EBMT database, anecdotal responses of neuromyelitis optica to HSCT were encouraging, although relapse may not be prevented. [bib_ref] A preliminary result of treatment of neuromyelitis optica with autologous peripheral hematopoietic..., Peng [/bib_ref] [bib_ref] Failure of autologous hematopoietic stem cell transplantation to prevent relapse of neuromyelitis..., Matiello [/bib_ref] The very limited evidence of autologous HSCT in both chronic demyelinating inflammatory polyneuropathy and neuromyelitis optica make any robust clinical recommendations difficult, but given some favorable reported outcomes, treatment-resistant cases may reasonably be considered on a 'CO' basis involving both experienced neurologists and haematologists. ## Recommendations Patients with orphan diseases or rare indications may be considered for treatment as a 'CO', although enrolment onto a prospective clinical trial or prospective non-interventional study is highly recommended, whenever possible (level III). Long-term formalised follow-up of all patients using HSCT registries (for example, EBMT MED-A/B reporting) is a minimum recommendation (level II). Evolving indications for autologous HSCT Type 1 diabetes mellitus. T1D results from a cell-mediated autoimmune attack against pancreatic b-cells. The incidence of T1D in children in Europe varies between 5 and 40 per 100 000 new cases per year. Patients with T1D depend on exogenous insulin administration for survival and the best established treatment is tight control of blood sugar accomplished by either frequent daily injections or continuous s.c. infusion of insulin, that is, intensive insulin therapy, which reduces the risk of retinopathy, nephropathy and neuropathy by 35-90% when compared to conventional therapy with 1-2 insulin injections per day.Autologous HSCT has been explored among other immunotherapeutic approaches aiming at re-inducing tolerance at the time of early onset of T1D and encouraging persistence of b-cell function, which improves outcomes. [bib_ref] B-lymphocyte depletion, and preservation of beta-cell function, Pescovitz [/bib_ref] In Brazil, 20 patients with new onset T1D presenting without ketoacidosis or steroid exposure were treated with autologous HSCT without TRM, 12 patients experiencing sustained insulin independence, normal HbA1C and increased C-peptide levels. [bib_ref] Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes..., Voltarelli [/bib_ref] [bib_ref] C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation..., Couri [/bib_ref] [bib_ref] Autologous hematopoietic stem cell transplantation for type 1 diabetes, Voltarelli [/bib_ref] In the EBMT database, 10 T1D cases are registered with initial outcomes reflecting similar feasibility and safety of autologous HSCT. [bib_ref] Potential role of immunoablation and hematopoietic cell transplantation in the treatment of..., Snarski [/bib_ref] Refractory type II coeliac disease. Coeliac disease affects around 0.5-1% of the population, the vast majority of patients being succesfully managed with a gluten-free diet, [bib_ref] Adult coeliac disease, Hopper [/bib_ref] but a small proportion of patients (2-5%) are refractory. Immunophenotyping of intraepithelial lymphocytes in the small bowel can differentiate refractory type II coeliac disease patients with aberrant phenotype, lacking surface expression of CD3 and CD8, at high risk of developing enteropathy-associated T-cell lymphoma. Based on the poor prognosis of enteropathy-associated T-cell lymphoma, 18 patients with refractory type II coeliac disease resistant to cladribine were identified, and 13 underwent melphalanbased conditioning and autologous HSCT, resulting in improvement in clinical and laboratory parameters, despite one patient suffering TRM and one patient developing enteropathy-associated T-cell lymphoma after 4 years. Improvement in prognosis was supported by mortality from enteropathy-associated T-cell lymphoma in the five patients who did not receive autologous HSCT. [bib_ref] Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T..., Visser [/bib_ref] [bib_ref] Auto-SCT in refractory celiac disease type II patients unresponsive to cladribine therapy, Tack [/bib_ref] Recommendation T1D and coeliac disease are relatively common ADs, but the role of autologous HSCT remains unclear. Patients should only be treated on an IRB/REC-approved prospective clinical trials (level III). Allogeneic and syngeneic HSCT Allogeneic HSCT has rarely been used in the treatment of AD, and syngeneic HSCT, even more rarely. Whereas syngeneic HSCT offers as means of lymphohaemopoietic replacement with risks to the patient no greater than autologous HSCT and potential greater benefit in some, [bib_ref] Sustained remission, possibly cure, of seronegative arthritis after high-dose chemotherapy and syngeneic..., Mccoll [/bib_ref] [bib_ref] Resolution of chronic idiopathic thrombocytopenia purpura following syngeneic peripheral blood progenitor transplant, Zaydan [/bib_ref] [bib_ref] High dose chemotherapy and syngeneic stem cell transplantation in a patient with..., Van Oosterhout [/bib_ref] various forms of allogeneic HSCT are associated with toxicity and TRM risks, which far outweigh the risks of most patients with severe ADs. The area where allogeneic HSCT has mostly been used has been in the context of immune cytopenia, predominantly in the paediatric setting where unrelated and cord blood procedures are reported. [bib_ref] Allogeneic hematopoietic SCT for patients with autoimmune diseases, Daikeler [/bib_ref] [bib_ref] Haematopoetic stem cell transplantation for refractory autoimmune cytopenia, Passweg [/bib_ref] [bib_ref] Successful remission of chronic, refractory autoimmune thrombocytopenic purpura following non-myeloablative allogeneic stem..., Butler [/bib_ref] Donor lymphocyte infusions have also been used to demonstrate the principle of graft-vs-autoimmune effect. [bib_ref] Allogeneic hematopoietic SCT for patients with autoimmune diseases, Daikeler [/bib_ref] [bib_ref] Refractory Evans' syndrome treated with allogeneic SCT followed by DLI. Demonstration of..., Marmont [/bib_ref] [bib_ref] Pure white cell aplasia (PWCA) relapsing after allogeneic BMT and successfully treated..., Marmont [/bib_ref] Some patients clearly benefited from the procedure, despite substantial overall toxicity. It is unclear whether a prospective trial can ever be successfully completed in this area, but harmonising the procedures through a prospective non-interventional international protocol is warranted. Only anecdotal data are available in SSc, SLE, RA and vasculitis, [bib_ref] Induction of remission of severe and refractory rheumatoid arthritis by allogeneic mixed..., Burt [/bib_ref] [bib_ref] Nonmyeloablative stem cell transplant in a patient with advanced systemic sclerosis and..., Khorshid [/bib_ref] [bib_ref] Allogeneic marrow transplantation in patients with severe systemic sclerosis: resolution of dermal..., Nash [/bib_ref] [bib_ref] Nonmyeloablative allogeneic stem cell transplant in a patient with refractory systemic lupus..., Lu [/bib_ref] [bib_ref] Current value of stem-cell transplantation in autoimmune diseases, Ko¨tter [/bib_ref] [bib_ref] Long-term remission in pediatric Wegener granulomatosis following allo-SCT after reducedintensity conditioning, Lawitschka [/bib_ref] precluding any conclusions or recommendations. Given the high risk of TRM and also potential chronic reduction in QoL, previous consensus has discouraged allogeneic HSCT outside of a clinical trial. [bib_ref] Feasibility of allogeneic hematopoietic stem cell transplantation for autoimmune disease: position statement..., Griffith [/bib_ref] ## Recommendations Centres performing donor HSCT for ADs should have appropriate JACIE accreditation or equivalent (level II). Syngeneic HSCT may be considered as an alternative to autologous HSC, with comparable risks and potential greater benefit. Donor-related issues are an important consideration (level II). Allogeneic HSCT outside of a clinical trial is highly discouraged in all ADs. In exceptional circumstances, allogeneic HSCT may be considered for patients with ITP, AIHA and Evans' syndrome refractory to at least two lines of treatment (including rituximab and TPO receptor agonists for ITP) under the 'CO' criterion(level III). In adults under 50 years with life-threatening autoimmune cytopenia, allogeneic HSCT may be considered if an HLA-identical sibling donor is available. In patients for whom no donor can be identified, autologous HSCT is preferred over alternative donor HSCT (level III). In paediatric patients with life-threatening autoimmune cytopenia, allogeneic HSCT may be considered if an HLA-identical sibling donor is available. In Evans' syndrome, unrelated/alternative donor HSCT from a well-matched unrelated donor (with at least 9/10 compatible loci by 4 digit/allele high-resolution typing) may be considered (level III). BM or umbilical cord blood is recommended as graft source for allogeneic HSCT in autoimmune cytopenia (level II). Recommended conditioning for HLA-matched sibling HSCT is with CY 120 mg/kg, fludarabine 150 mg/kg and ATG (or other anti-T-cell serotherapy) (level III). In the paediatric unrelated/alternative donor setting, a sufficiently immunosuppressive regimen should be selected by the responsible clinician. Based on other areas of paediatric HSCT (metabolic disorders and haemoglobinopathies), fludarabine 4 Â 35 mg/m 2 , thiotepa 10 mg/kg and melphalan 140 mg/m 2 þ ATG is one option. Decision making should be individualized based on local experience and donor/recipient factors (level III). ## Conclusions and future directions There is now well 15 years of clinical experience of HSCT in patients with various severe ADs. The field has brought about fruitful multidisciplinary collaborations to address one of the most challenging of groups of patients in clinical practice. In parallel, scientific studies have started to elucidate mechanisms of reset and control of dysfunctional immune systems. However, the evolving industry of biological and smallmolecule drugs has proved a constant challenge to establishing the role of HSCT in severe AD. Only when efficacy is formally demonstrated by controlled studies balancing the acute risks of HSCT vs the toxicity of chronic immunosuppressive treatment will HSCT be perceived as an alternative to, or reasonable escalation step after failure of standard treatment. Lessons previously learnt from the inability to demonstrate benefit of autologous HSCT in breast cancer [bib_ref] Hematopoietic stem cell transplantation: a global perspective, Gratwohl [/bib_ref] are pertinent to HSCT for ADs, although the rarity and heterogeneity of AD warrants a challenging and pragmatically balanced approach. Long-term outcomes of efficacy and 'late effects' [bib_ref] Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for..., Loh [/bib_ref] [bib_ref] Secondary autoimmune diseases occuring after stem cell transplantation for an autoimmune disease:..., Daikeler [/bib_ref] [bib_ref] Reconstitution Graves' disease following autologous haematopoietic stem cell transplantation (HSCT) for severe..., Tailor [/bib_ref] [bib_ref] Follow-up care for young adult survivors of cancer: lessons from pediatrics, Eiser [/bib_ref] [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation:..., Rizzo [/bib_ref] are also of major importance, and health economic considerations should be central to the development of therapeutic strategies. [bib_ref] Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory..., Tappenden [/bib_ref] Ultimately, novel biological, HSCT and other cellular therapy-based approaches should not be mutually exclusive, and optimal outcomes may be achieved with combinations of intensive treatments combined with long-term consolidation and maintenance approaches. For the present time, it is intended that these guidelines and recommendations will promote patient safety and facilitate harmonisation of procedural aspects, patient selection, data collection and coordination of prospective studies, with the aim of identifying the most appropriate clinical niche of HSCT in each AD, as well as supporting basic scientific research endeavours. ## Conflict of interest [table] Table 1: EBMT database of autoimmune diseases, June 2011 Abbreviation: EBMT ¼ European Group for Blood and Marrow Transplantation. a Paediatric ¼ less than 18 years old at HSCT. [/table]	None	https://europepmc.org/articles/pmc3371413?pdf=render	None
dd8854e6ef0cf0c5b0901789484e0509f05ab736	pubmed	Medical Management of Patients After Atypical Femur Fractures: a Systematic Review and Recommendations From the European Calcified Tissue Society	Medical Management of Patients After Atypical Femur Fractures: a Systematic Review and Recommendations From the European Calcified Tissue Society ReuseThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial (CC BY-NC) licence. This licence allows you to remix, tweak, and build upon this work non-commercially, and any new works must also acknowledge the authors and be non-commercial. You don't have to license any derivative works on the same terms. More information and the full terms of the licence here: https://creativecommons.org/licenses/TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request.REPORTS AND RECOMMENDATIONS1682 A ntiresorptive drugs such as bisphosphonates are widely used for the treatment of osteoporosis. Although effective for prevention of osteoporotic fractures, use of bisphosphonates is associated with rare but serious adverse events such as osteonecrosis of the jaw and atypical femur fractures (AFFs). An AFF is a spontaneous or low-trauma, subtrochanteric or femur shaft fracture often complicated by delayed or nonunion (26%-39%) and bilateral occurrence [bib_ref] Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force..., Shane [/bib_ref]. The age-adjusted incidence rate of AFF has been estimated to be 1.8 per 100 0000 person-years in patients on bisphosphonate use under 2 years, increasing to 113 per 100 000 person-years with more than 8 years' duration [bib_ref] Incidence of atypical nontraumatic diaphyseal fractures of the femur, Dell [/bib_ref]. It is thought that decreased bone resorption in bisphosphonate users results in suppressed bone turnover with accumulation of microcracks and homogeneously mineralized bone, making the bone more brittle and allowing the development of a spontaneous femur fracture. However, it is uncertain if bisphosphonates are causally related to AFF, and, incidentally, AFFs do occur in bisphosphonate-naïve individuals [bib_ref] Genetic risk factors for atypical femoral fractures (AFFs): a systematic review, Nguyen [/bib_ref]. Usually, bisphosphonates are discontinued after AFF is diagnosed. It has been shown that the risk of AFF decreases 70% per year from the last use of antiresorptive drugs [bib_ref] Risk of atypical femoral fracture during and after bisphosphonate use, Schilcher [/bib_ref] , although it is not certain that this risk reduction is also seen in patients who have already sustained an AFF. It is unclear if alternative osteoporosis drugs, particularly anabolic drugs, can promote AFF healing. Moreover, there is no guideline on how patients should be treated after an AFF where the risk of causing new atypical fractures should be weighed against the risk of fragility fractures when not treating osteoporosis. It has been proposed that teriparatide, an analog of parathyroid hormone, is a safe option for treatment of osteoporosis in patients with AFF, especially since it may also have a beneicial effect on the healing of AFF itself [bib_ref] Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of..., Shane [/bib_ref]. Teriparatide is the only anabolic osteoporosis drug that is currently globally available. It directly stimulates osteoblasts that might enable the formation of new, heterogeneously mineralized bone at the fracture site of AFF. Besides teriparatide, antiresorptive drugs, other than bisphosphonates, such as raloxifene and denosumab may be considered for osteoporosis treatment in patients with AFF. Denosumab is a human monoclonal antibody to RANKL and a potent inhibitor of bone resorption. Although AFFs have been reported in patients exposed to denosumab in case reports, it has not been clearly established in epidemiological studies how often denosumab, with or without preceding bisphosphonate use, is associated with AFF. The radiological healing or deterioration of AFF while on denosumab treatment is also not known. Raloxifene is a selective estrogen receptor modulator (SERM) that acts as an estrogen agonist in bone, with an antiresorptive effect that is milder than that of bisphosphonates and denosumab. The relationship between raloxifene and the occurrence of AFF has not been investigated. To our knowledge, this is the irst review that explored denosumab and raloxifene in addition to teriparatide for medical management of osteoporosis in patients with AFF. Further, we investigated whether AFF occurs as an adverse event in clinical trials with 2 novel drugs for osteoporosis, romosozumab and abaloparatide. Romosozumab, an antibody to sclerostin with both anabolic and antiresorptive effects, was recently approved in Europe, Japan, and the United States for the treatment of (severe) osteoporosis. Abaloparatide is a synthetic analog of parathyroid hormone-related protein. Strontium ranelate was not included in this review since this drug is no longer available in most countries. We performed a systematic literature review to assess both the occurrence and the radiological healing of AFFs in patients who had used or were using teriparatide, denosumab, or raloxifene. We formulate recommendations for healing of the AFF itself and for osteoporosis management in patients who have sustained an AFF and are at high risk of fragility fractures. # Methods We performed a search using key words related to AFFs and teriparatide, denosumab, and/or raloxifene in Embase, Medline Epub (Ovid), Web of Science and Cochrane Central on May 28, 2018. We separately searched for AFF as an adverse event in clinical trials with romosozumab or abaloparatide. Reviews and articles written in a language other than English were excluded. Conference abstracts and original research articles were included. Articles were reviewed when AFF was diagnosed during or after the use of teriparatide, denosumab, and raloxifene or when the radiological healing of AFF in a speciied amount of time was reported using these drugs. A complete AFF was deined as a noncomminuted subtrochanteric or femur shaft fracture with a predominantly transverse fracture line that may become oblique as it progresses medially, after no or minimal trauma. An incomplete form of AFF was deined as a localized endosteal or periosteal thickening of the lateral cortex of the subtrochanteric femur with or without the presence of a lucent line. When the authors did not describe whether a fracture line was visible, we assessed medical imaging in the article to review the presence of a fracture line. We extracted data on sex, median age, ethnicity, use of bisphosphonates, surgical interventions, and clinical or functional outcome after the AFF as far as this information was available. We assessed the occurrence of newly diagnosed AFF during or after the use of teriparatide, denosumab, or raloxifene. Newly diagnosed AFF could either be the irst clinical presentation of AFF, a second AFF of the contralateral femur, or recurrent AFF at the ipsilateral femur. For the assessment of radiological healing, the results were categorized for each type of drug according to study design (case report, retrospective cohort, and prospective studies) and fracture type (complete AFF, incomplete AFF with or without surgical treatment) . We assessed the total number of AFFs described in the literature with complete radiological healing at 6 months and 12 months after medical management. The number of conservatively treated incomplete AFFs that developed a lucent line or progressed to complete AFF was also noted. We pooled these data on healing from all article types to provide better insight into the effectiveness of the drugs for the healing of AFF. Radiological healing in complete AFFs and surgically treated incomplete AFFs was deined as adequate callus bridging. Radiological healing of an incomplete AFF on conservative management was deined by disappearance of a visible fracture line. Radiological healing of incomplete AFFs without a lucent line included lattening of cortical thickening, disappearance of bone marrow edema on magnetic resonance imaging (MRI) scan, or fading of hotspots on bone scintigraphy. Incomplete AFFs with localized cortical thickening only, without abnormalities on MRI scan or bone scintigraphy, were excluded from assessment of radiological healing because focal cortical thickening can remain unchanged for more than 5 years after diagnosis of incomplete AFF [bib_ref] Long-term radiographic follow-up of bisphosphonate-associated atypical femur fractures, Favinger [/bib_ref]. We give our recommendations for teriparatide, denosumab, and raloxifene in the medical treatment of patients with AFF. In order to address the decision-making in individual cases, we have formulated treatment advice for patients with a new diagnosis of AFF and patients with AFF who have completed a 2-year course of teriparatide. These considerations are based on the indings in this review and our expert opinion. # Results: systematic review Our search retrieved 910 references. We selected 2 conference abstracts and 130 articles after screening of title and abstract. We replaced one conference abstract with the article that was published shortly after our search date [bib_ref] Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy,..., Saag [/bib_ref]. After full-text reading, 67 articles were included for this review. Sections on teriparatide, denosumab, and raloxifene have overlapping references because some case descriptions report on a combination of these treatments in patients with AFF. ## Teriparatide We found 31 case reports, 9 retrospective cohort studies, and 3 prospective studies that have reported the effect of teriparatide on the radiological healing of AFF or occurrence of AFF. There were no published randomized controlled trials (RCTs). Detailed study descriptions of case reports, retrospective cohorts, and prospective studies on teriparatide use in patients with AFF can be found in Supplement 1(1). The demographic characteristics of the patients with AFF on teriparatide in case reports are stated in [fig_ref] Table 1: Continued [/fig_ref]. Clinical variables and main indings from retrospective cohorts and prospective studies are summarized in [fig_ref] Table 2: Summary of Retrospective Cohorts of AFF Patients and Use of Teriparatide [/fig_ref] , respectively. The pooled data on radiological healing of AFF with teriparatide treatment are shown in [fig_ref] Table 4: Radiological Healing of AFF After Teriparatide [/fig_ref]. Teriparatide use and occurrence of AFF. New AFF cases during or after teriparatide use were reported in 8 patients and always occurred in patients with previous bisphosphonate exposure. The new AFFs occurred after 4, 11, 18, and 24 months of teriparatide treatment in 4 patients [bib_ref] A new contralateral atypical femoral fracture despite sequential therapy with teriparatide and..., Nguyen [/bib_ref] [bib_ref] fractures with metachronous presentation, long before a complete fracture occurs, Spyridonidis [/bib_ref] [bib_ref] Hyperpharmacotherapy in ageing cystic ibrosis patients: the irst report of an atypical..., Wa [/bib_ref] [bib_ref] Sequential treatment with teriparatide and strontium ranelate in a postmenopausal woman with..., Lampropoulou-Adamidou [/bib_ref]. The remaining 4 patients were described in a conference abstract that did not report the duration of teriparatide at time of diagnosis, but all developed new incomplete AFFs during teriparatide The country of the afiliation is given when ethnicity of the AFF case was not speciied in the article. d The types of bisphosphonates prior to the occurrence of the irst AFF. When a patient had used several antiresorptive drugs, the total number of years the patient had used this speciic drug is indicated in parentheses. In some cases, type of bisphosphonates was unknown ("bisphosphonates"). For intravenous bisphosphonates, the dosage and treatment interval are given in the table. Alendronate dosages included 70 mg weekly or 10 mg daily. Etidronate was given 400 mg every 2 weeks, ibandronate 150 mg monthly, risedronate 35 mg weekly, and raloxifene 60 mg daily. e The total duration of antiresorptive drugs use prior to the irst diagnosis of AFF is given in years, not including drug holidays. f No access to full-text article. therapy in the same femur in which the irst incomplete AFF was diagnosed [bib_ref] Effect of teriparatide on healing of incomplete atypical femur fractures, Cheung [/bib_ref]. Six of the 8 patients had been diagnosed with another AFF before, but in 2 patients, the AFFs during teriparatide were the irst AFFs [bib_ref] fractures with metachronous presentation, long before a complete fracture occurs, Spyridonidis [/bib_ref] [bib_ref] Hyperpharmacotherapy in ageing cystic ibrosis patients: the irst report of an atypical..., Wa [/bib_ref]. One patient was diagnosed with a complete and contralateral incomplete AFF 2 years after stopping teriparatide without any antiresorptive use in the meantime, but the patient had been treated for 8 years with antiresorptives in the past [bib_ref] fractures with metachronous presentation, long before a complete fracture occurs, Spyridonidis [/bib_ref]. ## Teriparatide use after aff Descriptive data of case reports, retrospective and prospective studies. In 33 patients, a total of 24 incomplete AFFs and 27 complete AFFs were reported at the time of starting teriparatide treatment in 31 case reports. In 13 (54%) incomplete AFFs, a fracture line was described or visible on the images in the publication, while the other cases of incomplete AFFs only showed focal cortical thickening on x-ray. The majority of cases were women (n = 27, 82%). The mean age of all patients with AFF was 67 years, ranging from 21 to 84 years. Only a minority of studies (39%) reported ethnicity in 13 patients, of whom 9 were Caucasian. All cases of AFF were associated with the use of bisphosphonates. A total of 27 (82%) patients were previously exposed to alendronate therapy. The mean treatment duration with antiresorptive drugs was 8.3 years, with a minimum duration of 2 years and a maximum exposure of 17 years. Three patients were diagnosed before the AFF with osteogenesis imperfecta [bib_ref] Atypical femoral fracture in an osteogenesis imperfecta patient successfully treated with teriparatide, Holm [/bib_ref] [bib_ref] Management of atypical femoral fracture in a patient with osteogenesis imperfecta, Tan [/bib_ref] , and 1 patient was genetically tested after the occurrence of bilateral incomplete AFFs that revealed hypophosphatasia [bib_ref] Teriparatide treatment in an adult patient with hypophosphatasia exposed to bisphosphonate and..., Righetti [/bib_ref]. Nine retrospective cohorts that comprised a total of 201 patients with AFF reported the effect of teriparatide use on radiological healing. Five cohorts involved incomplete forms only (15, 20-23), 3 cohorts described complete fractures only [bib_ref] The incidence of atypical femoral fractures in patients with rheumatic disease: Yamagata..., Takakubo [/bib_ref] [bib_ref] Surgical outcome of intramedullary nailing in patients with complete atypical femoral fracture:..., Lee [/bib_ref] [bib_ref] Surgical outcome of atypical subtrochanteric and femoral fracture related to bisphosphonates use..., Yeh [/bib_ref] , and 1 cohort was mixed [bib_ref] Healing of bisphosphonateassociated atypical femoral fractures in patients with osteoporosis: a comparison..., Miyakoshi [/bib_ref]. Six cohorts consisted of entirely Asian populations. In 8 cohorts, all AFF cases were exposed to antiresorptive therapy and 1 cohort had 23% bisphosphonate-naïve patients. Three prospective studies comprised a total of 31 women and 1 man, with a mean age of 73 years, who were treated for bisphosphonate-associated AFFs with teriparatide. Only 1 of these studies had controls (n = 9 patients) without teriparatide treatment [bib_ref] Teriparatide improves bone quality and healing of atypical femoral fractures associated with..., Chiang [/bib_ref]. All 3 studies had a mix of complete and incomplete AFFs. Teriparatide was started immediately after surgery in 1 study and compared with delayed commencement of teriparatide 6 months postoperatively (29) Radiological healing of AFF after teriparatide: pooled data. We pooled indings on fracture union and teriparatide use in case reports and retrospective studies. Apart from deterioration of incomplete AFFs to complete fractures in 2 patients [bib_ref] Responses to treatment with teriparatide in patients with atypical femur fractures previously..., Watts [/bib_ref] , no data on radiological healing from the 3 prospective studies could be used for this analysis because either the fracture type [bib_ref] Teriparatide improves bone quality and healing of atypical femoral fractures associated with..., Chiang [/bib_ref] or time to healing (29, 30) could not be established from these publications. Data on fracture healing of 165 AFFs in 140 patients were pooled in [fig_ref] Table 4: Radiological Healing of AFF After Teriparatide [/fig_ref] , of which 96% were women . Teriparatide treatment was given for 98 (59%) AFFs while 67 AFFs from control groups in the cohort studies (all complete AFFs) did not receive teriparatide. The number of incomplete nonoperated AFFs without teriparatide was too small for comparison (n = 4), and there were no controls for surgically managed incomplete AFF. Healing of the fracture was achieved within 6 months of starting teriparatide in 13 (43%) incomplete nonoperated AFFs, 9 (90%) surgically treated incomplete AFFs, and 44 (76%) complete AFFs. In the non-teriparatide-treated group, 34 (51%) complete AFFs healed within 6 months. Complete AFFs appeared to heal faster with teriparatide compared with controls without teriparatide, but in both groups, nonhealing occurred at 12 months postoperatively in a small portion of patients: 5 (9%) AFFs in the teriparatide users; and 4 (6%) AFFs in those without teriparatide. Teriparatide was started in 11 patients because of signs of delayed healing or nonunion, ranging from 2 months to 2 years after the initial diagnosis of AFF (n = 2 incomplete, conservatively managed AFFs; n = 9 complete AFFs) [bib_ref] Sequential treatment with teriparatide and strontium ranelate in a postmenopausal woman with..., Lampropoulou-Adamidou [/bib_ref] [bib_ref] Atypical femoral fracture in an osteogenesis imperfecta patient successfully treated with teriparatide, Holm [/bib_ref] [bib_ref] Management of atypical femoral fracture in a patient with osteogenesis imperfecta, Tan [/bib_ref] [bib_ref] Surgical outcome of atypical subtrochanteric and femoral fracture related to bisphosphonates use..., Yeh [/bib_ref] [bib_ref] Atypical femoral fractures during prolonged use of bisphosphonates: short-term responses to strontium..., Carvalho [/bib_ref] [bib_ref] Weekly teriparatide for delayed unions of atypical subtrochanteric femur fractures, Fukuda [/bib_ref] [bib_ref] Teriparatide, vitamin D, and calcium healed bilateral subtrochanteric stress fractures in a..., Gomberg [/bib_ref] [bib_ref] Teriparatide for the rapid resolution of delayed healing of atypical fractures associated..., Mastaglia [/bib_ref] [bib_ref] Bilateral atypical femoral fracture in a man on long-term bisphosphonate and glucocorticoid..., Román [/bib_ref] [bib_ref] High revision rate but good healing capacity of atypical femoral fractures. A..., Schilcher [/bib_ref] [bib_ref] Atypical fractures of the femur and ulna and complications of fracture healing..., Stathopoulos [/bib_ref]. Sixteen patients with 18 fractures had not discontinued bisphosphonates immediately after the diagnosis of AFF, ranging from 3 weeks up to 1 year, including 4 AFFs in 4 patients in the teriparatide-treated group (n = 2 incomplete, conservatively managed AFFs; n = 2 complete AFFs) and 12 controls with 14 complete AFFs [bib_ref] The incidence of atypical femoral fractures in patients with rheumatic disease: Yamagata..., Takakubo [/bib_ref] [bib_ref] Surgical outcome of intramedullary nailing in patients with complete atypical femoral fracture:..., Lee [/bib_ref] [bib_ref] Responses to treatment with teriparatide in patients with atypical femur fractures previously..., Watts [/bib_ref] [bib_ref] Atypical femoral fractures during prolonged use of bisphosphonates: short-term responses to strontium..., Carvalho [/bib_ref] [bib_ref] Bisphosphonate long-term treatment related bilateral subtrochanteric femoral fracture. Can teriparatide be useful?, Tarazona-Santabalbina [/bib_ref]. Progression from incomplete to complete AFFs occurred in 4 patients after initiation of teriparatide at varying intervals: 9 days, 2 months, 8 months, and 21 months [bib_ref] High and pointed type of femoral localized reaction frequently extends to complete..., Sato [/bib_ref] [bib_ref] Responses to treatment with teriparatide in patients with atypical femur fractures previously..., Watts [/bib_ref] [bib_ref] Bisphosphonate-induced atypical subtrochanteric femoral fracture, Vaishya [/bib_ref]. ## Denosumab Denosumab use and occurrence of AFF. A total of 31 AFFs in 22 patients were reported after the use of denosumab in 14 case reports and 2 clinical trials. The characteristics of these patients are summarized in [fig_ref] Table 5: Occurrence of AFF During or After the Use of Denosumab [/fig_ref]. Ethnicity was stated only in 3 reports, with subjects of a Caucasian (n = 1) or Japanese (n = 4) background [bib_ref] Atypical femoral fracture associated with bone-modifying agent, Tateiwa [/bib_ref] [bib_ref] Atypical femoral fracture after receiving antiresorptive drugs in breast cancer patients with..., Ota [/bib_ref] [bib_ref] A case of an unusual subtrochanteric fracture in a patient receiving denosumab, Paparodis [/bib_ref]. Eleven patients with 15 AFFs were treated for osteoporosis with denosumab 60 mg half-yearly [bib_ref] Simultaneous bilateral atypical femoral fracture in a patient receiving denosumab: case report..., Selga [/bib_ref] [bib_ref] A case of an unusual subtrochanteric fracture in a patient receiving denosumab, Paparodis [/bib_ref] [bib_ref] Atypical femoral fracture in a patient treated with denosumab, Khow [/bib_ref] [bib_ref] Presence of pyrophosphate in bone from an atypical femoral fracture site: a..., Shabestari [/bib_ref] [bib_ref] An atraumatic femoral fracture in a patient with rheumatoid arthritis and osteoporosis..., Villiers [/bib_ref] [bib_ref] Atypical fracture of the femur in a patient using denosumab-a case report, Schilcher [/bib_ref] [bib_ref] Bilateral atypical femoral fractures in a patient prescribed denosumab -a case report, Thompson [/bib_ref] [bib_ref] Atypical femoral fractures bilaterally in a patient receiving denosumab, Drampalos [/bib_ref] [bib_ref] 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from..., Bone [/bib_ref] [bib_ref] The effect of three or six years of denosumab exposure in women..., Bone [/bib_ref] , while 16 AFFs in 11 patients have been reported after denosumab treatment with a high dose of 120 mg monthly for metastatic bone disease [bib_ref] Atypical femoral fracture associated with bone-modifying agent, Tateiwa [/bib_ref] [bib_ref] Atypical femoral fracture after receiving antiresorptive drugs in breast cancer patients with..., Ota [/bib_ref] [bib_ref] Atypical femoral fractures mimicking metastatic lesions in 2 patients taking denosumab, Austin [/bib_ref] [bib_ref] Impending atypical femoral fracture in patients with medullary thyroid cancer with skeletal..., Koizumi [/bib_ref] [bib_ref] Retrospective review of atypical femoral fracture in metastatic bone disease patients receiving..., Yang [/bib_ref] [bib_ref] Impending atypical femoral fracture in a patient of breast cancer with bone..., Sugihara [/bib_ref]. AFF occurred in 8 patients without prior bisphosphonate use , of which 4 were in patients treated in an oncology setting [bib_ref] Atypical femoral fractures mimicking metastatic lesions in 2 patients taking denosumab, Austin [/bib_ref] [bib_ref] Retrospective review of atypical femoral fracture in metastatic bone disease patients receiving..., Yang [/bib_ref] [bib_ref] Impending atypical femoral fracture in a patient of breast cancer with bone..., Sugihara [/bib_ref] , meaning that only 4 cases were documented of [bib_ref] 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from..., Bone [/bib_ref] [bib_ref] The effect of three or six years of denosumab exposure in women..., Bone [/bib_ref]. The irst patient stopped denosumab and achieved fracture healing within 6 months, while the latter continued denosumab, but no data on the healing of AFF are available in this case (personal communication by Amgen, October 2018). One 60-year-old male who had been on glucocorticoids for asthma for more than 30 years developed an AFF without any previous bisphosphonate use 2 months after the second dose of denosumab, which was given in a RCT of denosumab in patients with glucocorticoidinduced osteoporosis [bib_ref] Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy,..., Saag [/bib_ref]. The fourth case without bisphosphonate exposure concerns an incomplete, medially located AFF after only 1 injection of denosumab and without abnormalities on x-ray but with periosteal reaction on the MRI scan [bib_ref] A case of an unusual subtrochanteric fracture in a patient receiving denosumab, Paparodis [/bib_ref]. Although stress fractures resembling AFF located on the medial instead of the lateral cortex have been described (65) [bib_ref] Atypical femoral fractures mimicking metastatic lesions in 2 patients taking denosumab, Austin [/bib_ref] [bib_ref] Retrospective review of atypical femoral fracture in metastatic bone disease patients receiving..., Yang [/bib_ref] [bib_ref] Impending atypical femoral fracture in a patient of breast cancer with bone..., Sugihara [/bib_ref]. In 2 other cases, the inluence of bisphosphonates on the risk of AFF cannot be excluded, but AFF was preceded by very short bisphosphonate treatment before starting denosumab [bib_ref] Atypical femoral fracture in a patient treated with denosumab, Khow [/bib_ref] [bib_ref] An atraumatic femoral fracture in a patient with rheumatoid arthritis and osteoporosis..., Villiers [/bib_ref]. These 2 cases are very similar, since both patients had used alendronate for just a few weeks before switching to strontium ranelate because of side effects, which was subsequently replaced by denosumab, again because of intolerance to the drug. Both patients developed an AFF after 3 doses of denosumab [bib_ref] Atypical femoral fracture in a patient treated with denosumab, Khow [/bib_ref] [bib_ref] An atraumatic femoral fracture in a patient with rheumatoid arthritis and osteoporosis..., Villiers [/bib_ref]. These reports of AFF after denosumab with minimal or no previous bisphosphonate use are suggestive of a role for denosumab in the development of AFF, but the numbers are small, and AFFs have also been reported rarely in patients never treated for osteoporosis [bib_ref] Bilateral atypical femur fractures without bisphosphonate exposure, Szolomayer [/bib_ref] [bib_ref] Atypical femoral stress fractures in bisphosphonate-free patients, Tan [/bib_ref]. In another report, the AFF appeared to be triggered by 1 dose of denosumab in December 2012 after 5years of alendronate use between 1994 and 1999 (57), followed by a subsequent drug holiday for 13 years. ## Denosumab use after aff We found 7 papers that reported on the use of denosumab after an AFF in 10 patients [bib_ref] Management of atypical femoral fracture in a patient with osteogenesis imperfecta, Tan [/bib_ref] [bib_ref] Bisphosphonate long-term treatment related bilateral subtrochanteric femoral fracture. Can teriparatide be useful?, Tarazona-Santabalbina [/bib_ref] [bib_ref] Atypical femoral fractures bilaterally in a patient receiving denosumab, Drampalos [/bib_ref] [bib_ref] Spontaneous incomplete transverse subtrochanteric femoral fracture with cortical thickening possibly secondary to..., Alfahad [/bib_ref] [bib_ref] Low-energy femoral shaft fractures after long-term alendronate therapy: report of seven cases, Ballas [/bib_ref] [bib_ref] Low-energy atypical femoral shaft and ipsilateral neck fracture: a rare association, Peake [/bib_ref] [bib_ref] Recurrence of bilateral atypical femoral fractures associated with the sequential use of..., Ramchand [/bib_ref]. Bisphosphonates switched to denosumab treatment. Seven patients switched from bisphosphonates to denosumab just before or after the irst AFF. One patient with an incomplete AFF after 4 years of risedronate who underwent preventive placement of an intramedullary gamma nail was switched to denosumab and had delayed healing after 6 and 12 months (68). In a case series of complete AFFs associated with alendronate use (69), 4 patients started denosumab after the irst AFF. There were 4 different outcomes. One patient had delayed fracture healing at 12 months but with minimal pain and almost the same activity level. One patient had a second complete AFF on the contralateral side 1 year after switching to denosumab; this contralateral AFF showed bridging callus formation at 9 months' follow-up. One patient had bridging callus formation at 12 months and was pain-free. One patient had resumed normal daily activities at 18 months of follow-up, and radiographs showed bone healing [bib_ref] Low-energy femoral shaft fractures after long-term alendronate therapy: report of seven cases, Ballas [/bib_ref]. In a case report, 1 patient, who sustained a irst complete AFF after 1 dose of denosumab and 8 years of alendronate [bib_ref] Atypical femoral fractures bilaterally in a patient receiving denosumab, Drampalos [/bib_ref] , continued denosumab treatment but sustained a second complete AFF after 3 more doses of denosumab. The authors describe healing of both AFFs within 5 months postoperatively. Another case is described of denosumab started postoperatively for complete AFF, with full weight-bearing after 3 months and no adverse events at 18 months of follow-up; complete bony union was achieved at 1 year postoperatively [bib_ref] Low-energy atypical femoral shaft and ipsilateral neck fracture: a rare association, Peake [/bib_ref]. Teriparatide switched to denosumab treatment. Three cases are reported of denosumab therapy following teriparatide. One case involved bilateral incomplete AFFs without visible fracture lines after 7 years of oral bisphosphonates and who was treated with teriparatide for 18 months and a subsequent drug holiday of 12 months (71). The cortical thickening had almost completely lattened on x-rays when denosumab was prescribed as treatment for low bone mineral density (BMD). The authors reported that the patient had increasing thigh pain in both upper legs 6 months after the irst dose of denosumab and that x-rays and bone scintigraphy showed recurrent, incomplete bilateral AFFs with presence of a lucent line after which the surgeon decided to perform bilateral internal ixation [bib_ref] Recurrence of bilateral atypical femoral fractures associated with the sequential use of..., Ramchand [/bib_ref]. Two case reports (1 with incomplete AFF and 1 with complete AFF) mention that the initiation of denosumab therapy had a good outcome in the short term (< 1 year) [bib_ref] Management of atypical femoral fracture in a patient with osteogenesis imperfecta, Tan [/bib_ref] [bib_ref] Bisphosphonate long-term treatment related bilateral subtrochanteric femoral fracture. Can teriparatide be useful?, Tarazona-Santabalbina [/bib_ref]. ## Raloxifene ## Raloxifene use and occurrence of aff Six papers [bib_ref] Teriparatide for treatment of patients with bisphosphonate-associated atypical fracture of the femur, Greenspan [/bib_ref] [bib_ref] Severely suppressed bone turnover and atypical skeletal fragility, Visekruna [/bib_ref] [bib_ref] Diaphyseal femoral fatigue fracture associated with bisphosphonate therapy -3 more cases, Osugi [/bib_ref] [bib_ref] Low-energy diaphyseal femoral fractures associated with bisphosphonate use and severe curved femur:..., Sasaki [/bib_ref] [bib_ref] Identiication of a p.Arg708Gln variant in COL1A2 in atypical femoral fractures, Funck-Brentano [/bib_ref] [bib_ref] Atypical femoral fractures-ongoing and history of bone-speciic therapy, concomitant diseases, medications, and..., Muschitz [/bib_ref] stated the use of raloxifene prior to the diagnosis of AFF in 8 patients, although in 4 patients, it was unclear whether this was preceded by bisphosphonate treatment [bib_ref] Identiication of a p.Arg708Gln variant in COL1A2 in atypical femoral fractures, Funck-Brentano [/bib_ref] [bib_ref] Atypical femoral fractures-ongoing and history of bone-speciic therapy, concomitant diseases, medications, and..., Muschitz [/bib_ref]. Two patients had simultaneous use of raloxifene and bisphosphonates during 6 months and 6 years, respectively [bib_ref] Severely suppressed bone turnover and atypical skeletal fragility, Visekruna [/bib_ref] [bib_ref] Diaphyseal femoral fatigue fracture associated with bisphosphonate therapy -3 more cases, Osugi [/bib_ref]. One had had prior bisphosphonate use [bib_ref] Teriparatide for treatment of patients with bisphosphonate-associated atypical fracture of the femur, Greenspan [/bib_ref]. In a case series of surgically treated AFFs from Japan (73), a patient treated with raloxifene only was reported. This concerned a 77-year-old woman who had taken raloxifene and vitamin K2 for only 1 year when she sustained an AFF after a fall from standing height. Because delayed union was suspected, she received low-intensity pulsed ultrasonography 3 months postoperatively, and partial fracture healing was seen 9 months after the surgery [bib_ref] Low-energy diaphyseal femoral fractures associated with bisphosphonate use and severe curved femur:..., Sasaki [/bib_ref]. ## Raloxifene use after aff We found reports of 2 patients treated with raloxifene after AFF, in both cases after teriparatide treatment [bib_ref] Successful teriparatide treatment of atypical fracture after long-term use of alendronate without..., Huang [/bib_ref] [bib_ref] Combined effect of a locking plate and teriparatide for incomplete atypical femoral..., Tsuchie [/bib_ref]. One 63-year-old Asian woman received 10 months of teriparatide after incomplete AFF with a visible fracture line, which was subsequently replaced by raloxifene. The fracture line had already diminished after 3 months of teriparatide and was invisible 15 months after the diagnosis, which was 5 months after starting raloxifene [bib_ref] Successful teriparatide treatment of atypical fracture after long-term use of alendronate without..., Huang [/bib_ref]. One 78-year-old woman with incomplete AFF with a lucent line received teriparatide; the fracture line had almost disappeared 3 months postoperatively. After 12 months of teriparatide, she switched to a SERM, most likely raloxifene, and had an event-free follow-up 3 years after the diagnosis [bib_ref] Combined effect of a locking plate and teriparatide for incomplete atypical femoral..., Tsuchie [/bib_ref]. ## Romosozumab Twelve studies have been performed with romosozumab. Two studies reported 3 cases of AFF. One case of AFF occurred 3.5 months after the irst monthly dose in a phase 3 clinical trial [bib_ref] Romosozumab treatment in postmenopausal women with osteoporosis, Cosman [/bib_ref] , but the association between romosozumab and the AFF is questionable, given that the participant had complained of prodromal pain prior to the irst romosozumab administration. Two cases of AFFs occurred during open-label alendronate treatment after 1 year of monthly romosozumab in another trial [bib_ref] Romosozumab or alendronate for fracture prevention in women with osteoporosis, Saag [/bib_ref]. ## Abaloparatide A total of 9 clinical trials with abaloparatide were published. No cases of AFF were reported in patients who used or had used abaloparatide. # Discussion In clinical practice, there is great uncertainty of how to treat patients after they have sustained an AFF. This relates both to potential (positive or negative) effects of bone agents on the healing of the fracture and to the safety of osteoporosis drugs in those patients, who are still at high risk of fragility fracture after an AFF. Bisphosphonates are usually stopped because patients are considered at risk of an AFF of the other femur since bilaterality is commonly reported, varying from 28% up to 44% [bib_ref] Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of..., Shane [/bib_ref]. In this systematic literature review, we aimed to assess the effects of teriparatide, denosumab, raloxifene, romosozumab, and abaloparatide on both the occurrence and healing of AFF in order to give recommendations for medical management. It is dificult to draw irm conclusions because there are no reported RCTs of treatment in patients with AFF with any of these drugs. Based on descriptions of 165 AFFs treated with teriparatide in observational studies, we made a crude estimate of effects of teriparatide on radiological healing of AFF after 6 and 12 months. The majority of surgically treated incomplete (n = 9, 90%) and complete AFFs (n = 44, 76%) healed within 6 months of teriparatide treatment, in contrast with nonoperated incomplete fractures treated with teriparatide (n = 13, 43%) and complete AFFs that were not treated with teriparatide (n = 34, 51%). The reported data are insuficient for an evidence-based recommendation of the use of teriparatide to accelerate healing of AFF. Yet, keeping in mind the lawed study designs and heterogeneity between studies, the observational data might suggest that teriparatide could have a beneicial effect on the healing time of surgically treated AFF, although nonunion after 1 year can still occur. There is no evidence of improved fracture healing for conservatively managed incomplete AFFs based on these observational data. Our indings clearly show that even during and after teriparatide treatment, a new AFF can occur, either as a irst presentation of AFF or as a second AFF of the contralateral femur, but only in patients previously treated with bisphosphonates. The role of teriparatide for healing of any type of fracture is debated. One metaanalysis of 5 RCTs in patients with osteoporotic fractures found a signiicantly shorter healing time in the teriparatide-treated group [bib_ref] The effect of teriparatide on fracture healing of osteoporotic patients: a meta-analysis..., Lou [/bib_ref] , while another analysis including also nonosteoporotic fractures did not demonstrate any effectiveness for teriparatide with regard to faster union [bib_ref] Effectiveness of teriparatide on fracture healing: a systematic review and meta-analysis, Shi [/bib_ref]. Two RCTs involved subjects with femoral fractures. In one trial with postmenopausal women and low-trauma femoral neck fractures, teriparatide did not improve radiological fracture healing, but the sample size was too small to detect any differences [bib_ref] Does teriparatide improve femoral neck fracture healing: results from a randomized placebocontrolled..., Bhandari [/bib_ref]. The other RCT involved premenopausal women with acute stress fractures of the lower extremities and who showed a tendency toward improved healing on MRI in the teriparatide group (83.3%) in comparison with the control group (57.1%), but this was not statistically signiicant (P = 0.18) [bib_ref] Short-term effects of teriparatide versus placebo on bone biomarkers, structure, and fracture..., Almirol [/bib_ref]. There are no documented cases of AFF with the use of abaloparatide. This drug might have equivalent effects on AFF as teriparatide, given the biological similarity. The results from the literature search were insuficient to assess the effects on AFF healing by denosumab and raloxifene. Despite the lack of epidemiological studies, our analysis of the literature suggests that the absolute risk of AFF when using denosumab or raloxifene for osteoporosis is very low given the limited reports of AFF cases using these drugs, 11 and 8 patients respectively, and they also mostly occurred after previous use of bisphosphonates. However, this risk may be increased in patients who have already had an AFF, suggested by the reports of 2 patients with a second complete AFF (58, 69) on denosumab and in another patient with bilateral recurrent incomplete AFFs on denosumab even after use of teriparatide [bib_ref] Recurrence of bilateral atypical femoral fractures associated with the sequential use of..., Ramchand [/bib_ref]. These cases suggest curtailing use of denosumab treatment after an initial unilateral AFF. Romosozumab is linked to 3 AFF cases in clinical trials, but it remains to be seen if more cases of AFF will develop in patients treated with romosozumab with or without bisphosphonate exposure. Based on our indings, we conclude that there is a clear need for RCTs to evaluate whether teriparatide and/or abaloparatide enhances fracture union of AFF (of any type), since this is the only drug that is not associated with the development of AFF without prior use of bisphosphonates. The observational studies in this review are biased and lack information on confounding factors such as time between diagnosis and starting medical treatment, surgical ixation techniques, smoking, body mass index, fracture localization, use of concomitant medication, and postoperative weight-bearing protocols. Currently, 1 clinical trial is ongoing for patients with incomplete AFF who are randomized to receive either placebo injections or teriparatide. Changes in pain score and physical function using the Western Ontario and McMaster Universities Osteoarthritis scale and the proportion of participants requiring surgery after 12 months serve as primary outcomes. There are no trials registered investigating teriparatide for complete AFF, nonhealing AFF, or electively operated incomplete AFF. Also, no trials are currently evaluating the risks and beneits of antiresorptive therapy compared with placebo in patients with AFF after stopping teriparatide or in patients with AFF managed conservatively or surgically. It is dificult to set up an adequately powered study because of the low incidence of AFF. Therefore, an international registry of AFF cases could be very useful to gain insight into the safety and eficacy of osteoporosis drugs in relation to fracture healing, bone mineral density, bone turnover, and development of new AFFs in these patients, but this is only possible when patients with AFF are referred to specialized centers. ## Recommendations for clinical practice based on expert opinion Based on the results in this review and our expert opinion, we advise on medical treatment for patients with AFF. Our recommendations for medical treatment are summarized in a decision tree [fig_ref] Figure 2: Figure 2 [/fig_ref] , encompassing the occurrence of AFF when using bisphosphonates or denosumab and what to do after a patient with AFF has completed a 2-year course of teriparatide. In any case, extensive monitoring with imaging of both upper legs is advised during the irst 1 or 2 years after the diagnosis of AFF because nonhealing of AFF and contralateral AFF may still occur, even on teriparatide. When AFF is diagnosed during the use of bisphosphonates or denosumab, it is recommended to stop this treatment since continuation may lead to worsening of the AFF or a new contralateral AFF. To prevent a rebound effect, discontinuation of denosumab could be followed by a short course of bisphosphonates or SERMs in patients with surgically treated AFFs. In patients at low fracture risk without prevalent vertebral fractures who have only had 1 or 2 half-yearly injections, consider stopping denosumab treatment without subsequent therapy. After healing of bilateral, surgically managed AFFs, bisphosphonates or denosumab may be continued. It should be kept in mind that discontinuation after 3 or more years of bisphosphonate treatment may result in increased risk of hip fractures and clinical vertebral fractures as shown by some studies [bib_ref] FLEX Research Group. Effects of continuing or stopping alendronate after 5 years..., Black [/bib_ref] [bib_ref] The impact of the duration of bisphosphonate drug holidays on hip fracture..., Curtis [/bib_ref] , although this was not found in another recent retrospective analysis of a population-based cohort [bib_ref] Bisphosphonate drug holiday and fracture risk: a population-based cohort study, Adams [/bib_ref]. Continuation of bisphosphonates might lead to a risk of atypical fractures at skeletal sites other than the femur. Anecdotally, spontaneous fractures of other long bones (eg, ulna, forearm, and tibia) have been reported in relation to bisphosphonate use [bib_ref] Atypical fracture of the tibial diaphysis associated with bisphosphonate therapy: a case..., Bissonnette [/bib_ref] [bib_ref] Effect of long-term use of bisphosphonates on forearm bone: atypical ulna fractures..., Erdem [/bib_ref] [bib_ref] Atypical insuficiency fracture of the tibia associated with long-term bisphosphonate therapy, Breglia [/bib_ref] [bib_ref] Tibial stress reaction presenting as bilateral shin pain in a man taking..., Lim [/bib_ref] [bib_ref] Atypical ulnar fracture associated with long-term bisphosphonate use, Osada [/bib_ref] [bib_ref] Bilateral ulna fractures associated with bisphosphonate therapy, Ang [/bib_ref] [bib_ref] Atypical forearm fractures associated with long-term use of bisphosphonate, Moon [/bib_ref] [bib_ref] Bilateral atypical insuficiency fractures of the proximal tibia and a unilateral distal..., Imbuldeniya [/bib_ref] , but no association has been established, and the potential risk of such atypical fractures does not appear to weigh against the risk of typical osteoporotic fractures. Teriparatide might be started for surgically treated AFFs, although strong evidence for improved fracture union is lacking. Further, teriparatide, SERMs, romosozumab, or abaloparatide may alternatively be considered in patients at high risk of fragility fractures. SERMs are preferably prescribed in relatively young, postmenopausal women who are Decision tree with considerations for medical management after atypical femur fracture (AFF). a Deinition may vary across countries, eg, a hip BMD T-score ≤ -2.5 SD, older age (70-75 years), a recent fragility fracture, other strong risk factors for fracture, or a FRAX fracture risk score that is above country-speciic thresholds [bib_ref] Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task..., Adler [/bib_ref]. d Raloxifene or bazedoxifene are preferably prescribed in relatively young postmenopausal women who are at low risk of hip fractures and deep vein thrombosis [bib_ref] Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society* clinical practice..., Eastell [/bib_ref] , or in women in whom the use of teriparatide is contraindicated. e In case of intolerance to SERMs, hormone replacement therapy or tibolone could be considered in women with a low risk of deep vein thrombosis and breast cancer, without a history of myocardial infarction or stroke [bib_ref] Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society* clinical practice..., Eastell [/bib_ref]. b Switching denosumab to teriparatide may result in progressive BMD loss. c Be aware that antiresorptive therapy may be needed after stopping denosumab. f Calcitonin can be prescribed in patients who are not eligible for bisphosphonates, SERMs, hormone replacement therapy, tibolone, abaloparatide, or teriparatide. Downloaded from https://academic.oup.com/jcem/article-abstract/105/5/1682/5684909 by guest on 09 June 2020 at low risk of hip fractures and deep vein thrombosis [bib_ref] Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society* clinical practice..., Eastell [/bib_ref]. Hormone replacement therapy or tibolone might be considered when SERMs are not tolerated, preferably in younger women (aged < 65 years) who do not have an increased risk of venous thromboembolism and are without a history of myocardial infarction or stroke, also keeping in mind the increased breast cancer risk [bib_ref] Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society* clinical practice..., Eastell [/bib_ref]. If the patient is not eligible for any of the aforementioned drugs, calcitonin can be prescribed as in accordance with the recent guideline of the Endocrine Society on pharmacological management of osteoporosis [bib_ref] Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society* clinical practice..., Eastell [/bib_ref]. The deinition of high risk of fragility fractures varies across countries, but is often deined by a hip BMD T score ≤ -2.5 SD, older age (70-75 years), a recent fragility fracture, other strong risk factors for fracture, or a FRAX (https://www.shefield.ac.uk/FRAX/) fracture risk score that is above country-speciic thresholds [bib_ref] Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task..., Adler [/bib_ref]. After 2 years of teriparatide, subsequent therapy may be given with raloxifene (or hormone replacement therapy) in women and-in those with bilateral surgical ixation of AFF-denosumab or bisphosphonates. In patients at the end of a (short) course of teriparatide who have low bone turnover markers after teriparatide or who are deemed to be at low risk of osteoporotic fractures, teriparatide may be discontinued without further antiresorptive treatment, but close monitoring of BMD and bone turnover markers is recommended. The considerations for each individual drug are given in more detail below. ## Teriparatide There is no evidence-based indication for teriparatide to enhance healing of AFF, but a tendency toward faster healing with teriparatide for surgically managed AFFs is seen in the limited, observational data. Hence, teriparatide 20 ug daily, when reimbursed, might be considered for surgically treated AFF, both incomplete AFF and complete AFF. Even during the use of teriparatide, nonunions do still occur in surgically managed AFF. The limited data on conservatively managed incomplete forms of AFF and use of teriparatide do not demonstrate improved fracture healing, but should be interpreted with caution, pending the result of an RCT that is awaiting results. When teriparatide is given for the sole purpose to enhance fracture healing of AFF, a short treatment duration of 3 to 6 months may sufice. Teriparatide is a reasonable treatment option for patients who have had an AFF and are still at high risk for fragility fractures. A big clinical dilemma is what to do after a full 2-year course of teriparatide treatment. Normally, antiresorptive therapy is advised after 2 years of teriparatide because the positive effects on bone mass and strength will in time disappear, as with any drug without skeletal retention. Some patients with AFF may have inherent low bone turnover, for example, due to an underlying monogenetic disease [bib_ref] Abnormal bone turnover in individuals with low serum alkaline phosphatase, López-Delgado [/bib_ref] or due to previous long-term use of bisphosphonates. It can be speculated that accelerated bone loss after cessation of teriparatide may not occur in these cases. A few studies describe the effect of teriparatide on bone turnover in patients with AFF, but the results are inconclusive. Administration of teriparatide during 6 months has been associated with a signiicant increase in bone turnover markers in patients with AFF [bib_ref] Teriparatide improves bone quality and healing of atypical femoral fractures associated with..., Chiang [/bib_ref] [bib_ref] Responses to treatment with teriparatide in patients with atypical femur fractures previously..., Watts [/bib_ref] and values returned almost to baseline level after 2 years of teriparatide [bib_ref] Responses to treatment with teriparatide in patients with atypical femur fractures previously..., Watts [/bib_ref] , but pretreatment values varied widely [bib_ref] Responses to treatment with teriparatide in patients with atypical femur fractures previously..., Watts [/bib_ref] [bib_ref] Bisphosphonate-associated atypical sub-trochanteric femur fractures: paired bone biopsy quantitative histomorphometry before and..., Miller [/bib_ref] and bone turnover markers did not correlate with histomorphometric indings from bone biopsies before and after teriparatide treatment in patients with AFF [bib_ref] Bisphosphonate-associated atypical sub-trochanteric femur fractures: paired bone biopsy quantitative histomorphometry before and..., Miller [/bib_ref]. We suggest monitoring bone turnover markers on a regular basis in patients with AFF before, during, and after teriparatide treatment and considering antiresorptive drugs when levels start to increase or when BMD starts to decrease in patients at high risk of fractures. In this situation, we suggest either a SERM, romosozumab, calcitonin, tibolone, estrogens, denosumab, or bisphosphonates, based on sex and on bilaterality of surgical intervention (see below). ## Denosumab When a patient sustains an AFF during the use of denosumab, the risk of a rebound effect with rapid loss of BMD and potential risk of multiple vertebral fractures following cessation of denosumab (98) must be weighed against the potentially increased risk of a contralateral AFF when continuing denosumab. Patients who have already had vertebral fractures appear to be at greatest risk of developing multiple vertebral fractures after denosumab discontinuation. In general, a course of bisphosphonates is recommended after stopping denosumab [bib_ref] Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement..., Tsourdi [/bib_ref]. This is not advisable for a conservatively managed incomplete AFF, but a short course of a SERM or bisphosphonates may be considered in patients with bilateral surgically treated AFFs or a unilateral surgically treated AFF without any radiological signs of incomplete AFF of the contralateral femur. Denosumab could be stopped without follow-up therapy in patients at low risk of fragility fractures without prevalent vertebral fractures, especially in those who have only had 1 or 2 half-yearly injections of 60 mg subcutaneously. For patients at high risk of fragility fractures, a switch to teriparatide or a SERM could be considered. However, the rebound effect after stopping denosumab might still occur since teriparatide increases bone turnover. One should also be aware of a decrease in BMD, especially at cortical sites, as was seen in osteoporotic women who transitioned to teriparatide after 2 years of denosumab in the DATA-switch study [bib_ref] Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of..., Leder [/bib_ref]. Alternatively, hormone replacement therapy or tibolone can be considered in women in absence of contraindications such as a high risk of breast cancer or deep vein thrombosis, history of stroke, or myocardial infarction. Calcitonin is an option if the patient does not tolerate any of the aforementioned drugs [bib_ref] Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society* clinical practice..., Eastell [/bib_ref]. Denosumab could be continued or initiated when the patient has bilateral surgically treated AFFs and a persistently high risk of fragility fractures, including those who have completed 2 years of teriparatide. Denosumab therapy for up to 10 years has been associated with increasing BMD and low fracture incidence [bib_ref] 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from..., Bone [/bib_ref]. Long-term use of denosumab could especially be considered in elderly patients with a life expectancy of less than 10 years, for whom this may serve as life-long osteoporosis treatment. ## Raloxifene Raloxifene could be considered as follow-up therapy after teriparatide when bone turnover markers are high in postmenopausal women who do not have a history of venous thromboembolic events. Preferably, it is given to women who are relatively young and are at lower risk of hip fractures. As mentioned above, it could also be considered in patients who have to stop denosumab because they are at risk of another AFF and to potentially prevent the rebound in bone turnover and risk of multiple vertebral fractures, especially when they have already had vertebral fractures. However, no studies have been performed using SERMs to prevent rebound after stopping denosumab. Because it has a weaker antiresorptive effect than bisphosphonates or denosumab, and few cases of AFF have been reported on raloxifene, this may be a preferred option after teriparatide [bib_ref] Effect of raloxifene after recombinant teriparatide [hPTH(1-34)] treatment in postmenopausal women with..., Adami [/bib_ref] [bib_ref] Sequential treatment of severe postmenopausal osteoporosis after teriparatide: inal results of the..., Eastell [/bib_ref]. Yet it should be kept in mind that raloxifene is not regularly prescribed for osteoporosis, hence a low number of AFFs associated with raloxifene does not guarantee a lower risk of AFF compared with other antiresorptive drugs. [fig] Figure 2: Figure 2. Decision tree with considerations for medical management after atypical femur fracture (AFF). a Deinition may vary across countries, eg, a hip BMD T-score ≤ -2.5 SD, older age (70-75 years), a recent fragility fracture, other strong risk factors for fracture, or a FRAX fracture risk score that is above country-speciic thresholds (95). d Raloxifene or bazedoxifene are preferably prescribed in relatively young postmenopausal women who are at low risk of hip fractures and deep vein thrombosis (94), or in women in whom the use of teriparatide is contraindicated. e In case of intolerance to SERMs, hormone replacement therapy or tibolone could be considered in women with a low risk of deep vein thrombosis and breast cancer, without a history of myocardial infarction or stroke (94). b Switching denosumab to teriparatide may result in progressive BMD loss. [/fig] [table] Table 2: Summary of Retrospective Cohorts of AFF Patients and Use of Teriparatide [/table] [table] Table 3: Summary of Prospective Studies on AFF Patients and Use of TeriparatidePercentage of women, mean age, antiresorptive use and mean duration of antiresorptive treatment were based on the whole cohort, including controls. AFF, atypical femur fracture; AR, antiresorptive; NS, not stated; TPT, teriparatide. a The number of patients is given. b 7 immediate postsurgery, 6 on teriparatide 6 months postoperatively.Downloaded from https://academic.oup.com/jcem/article-abstract/105/5/1682/5684909 by guest on 09 June 2020 weeks to just over 1 year after the diagnosis of AFF(28,30). The study by Greenspan et al included 4 individuals with periprosthetic fractures(29), which strictly does not adhere to the diagnostic criteria for AFF as formulated by the American Society forBone and Mineral Research (3). [/table] [table] Table 4: Radiological Healing of AFF After Teriparatide: Pooled Data [/table] [table] Table 5: Occurrence of AFF During or After the Use of Denosumab [/table]	None	https://academic.oup.com/jcem/article-pdf/105/5/1682/36645431/dgz295.pdf	Abstract Context Atypical femur fractures (AFFs) are serious adverse events associated with bisphosphonates and often show poor healing. Evidence acquisition We performed a systematic review to evaluate effects of teriparatide, raloxifene, and denosumab on healing and occurrence of AFF. Evidence synthesis We retrieved 910 references and reviewed 67 papers, including 31 case reports, 9 retrospective and 3 prospective studies on teriparatide. There were no RCTs. We pooled data on fracture union (n = 98 AFFs on teriparatide) and found that radiological healing occurred within 6 months of teriparatide in 13 of 30 (43%) conservatively managed incomplete AFFs, 9 of 10 (90%) incomplete AFFs with surgical intervention, and 44 of 58 (75%) complete AFFs. In 9 of 30 (30%) nonoperated incomplete AFFs, no union was achieved after 12 months and 4 (13%) fractures became complete on teriparatide. Eight patients had new AFFs during or after teriparatide. AFF on denosumab was reported in 22 patients, including 11 patients treated for bone metastases and 8 without bisphosphonate exposure. Denosumab after AFF was associated with recurrent incomplete AFFs in 1 patient and 2 patients of contralateral complete AFF. Eight patients had used raloxifene before AFF occurred, including 1 bisphosphonate-naïve patient. Conclusions There is no evidence-based indication in patients with AFF for teriparatide apart from reducing the risk of typical fragility fractures, although observational data suggest that teriparatide might result in faster healing of surgically treated AFFs. Awaiting further evidence, we formulate recommendations for treatment after an AFF based on expert opinion.
ae1f778514b015be3fbf8b9815be84208a1681e1	pubmed	Carrier screening in individuals of Ashkenazi Jewish descent	Carrier screening in individuals of Ashkenazi Jewish descent Disclaimer: This guideline is designed primarily as an educational resource for medical geneticists and other 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. Genet Med 2008:10(1):54 -56. Diseases commonly grouped together as "Jewish Genetic Disorders" (JGDs) range in incidence from 1/900 to 1/40,000 in the Jewish community, specifically those individuals of Ashkenazi (eastern European) heritage. Although some of these disorders in isolation would be considered rare, the overall carrier rate in this population is significant, with between 1 in 4 and 1 in 5 Ashkenazi Jews carrying a mutation for any one of these disorders. Because of genetic drift in combination with historical and social factors, certain autosomal recessive disorders have been found to occur at a higher incidence (e.g., Tay-Sachs disease) or almost exclusively in this population (e.g., familial dysautonomia) whereas other disorders may be as common as in other high risk groups (e.g., cystic fibrosis). However, the commonality for JGDs is that all exhibit the founder mutation phenomenon whereby only 1-3 mutations account for the vast majority of deleterious alterations found in this specific population. Over 30 years ago, the development of an accurate and reliable biochemical test led to a remarkably successful community carrier screening program for Tay-Sachs disease. The subsequent widespread adoption of Tay-Sachs carrier screening resulted in a significant drop in this disease among the Ashkenazi Jewish population. Today, the vast majority of children born with Tay-Sachs disease have non-Jewish parents. Advances in our understanding of the molecular biology of Tay-Sachs disease and other Jewish genetic disorders have resulted in the identification of many of the "founder" mutations present in this population [fig_ref] Table 1: Jewish genetic disorders for which testing should be offered [/fig_ref]. As technology has improved, our ability to perform carrier screening for an increasing number of disorders has likewise expanded. However, there has been debate as to which disorders should be included in preconception/prenatal carrier screening panels and what criteria should be used to determine how this selection is made. In addition, it is important to take into account the needs of the community for which screening is intended (see commentary in this issue, page 33). Although there is no definitive mechanism whereby any individual or organization can speak for a population as a whole, experience both in the United States and Israel points to overall acceptance of carrier screening in the Jewish population if done with sensitivity and respect for cultural and religious differences. Several support groups have taken it upon themselves to educate the community and professionals about the need for comprehensive testing and prevention. The ultra-orthodox Dor Yeshorim program has advocated for broad-based testing for decades and the Central Conference of American Rabbis, the rabbinic arm of the Reform Movement, North America's largest Jewish denomination, has passed a resolution urging all Reform Rabbis to counsel prospective couples on the availability of testing. Thus, the community focus is on the accuracy of the test and its ability to prevent significant disease as opposed to "cherry picking" disorders based on overall incidence or rarity. This document seeks to provide guidance to clinicians regarding prenatal/preconception carrier screening for Ashkenazi Jewish individuals; however, new discoveries and technological advances will inevitably result in the availability of additional tests and revised recommendations in the future. ## Recommendations 1. We recommend that carrier screening for cystic fibrosis, Canavan disease, familial dysautonomia, and Tay-Sachs disease be offered to all Ashkenazi Jews who are pregnant or considering pregnancy, according to current American College of Medical Genetics and/or the American College of Obstetricians and Gynecologists (ACOG) guidelines. In addition, we recommend that carrier screening be offered for Fanconi anemia (Group C), Niemann-Pick (Type A), Bloom syndrome, mucolipidosis IV, and Gaucher disease. Carrier screening for these disorders should include testing for the specific mutations listed in [fig_ref] Table 1: Jewish genetic disorders for which testing should be offered [/fig_ref] , which will result in a carrier detection rate Ն 95% for most disorders. As a result, even in disorders that are relatively less common, expected mutation-specific carrier frequencies are relatively high. 2. Additional disorders will be considered for addition to this panel based on the following: a. The natural history of the disorder should be well understood and carry a potential for significant morbidity and/or mortality in the homozygous or compound heterozygous state. b. Based on available scientific literature there should be either Ͼ 90% detection rate or an allele frequency of Ն1% in the Ashkenazi Jewish population. Although there may be sound reasons to reconsider these thresholds in the future, they appear to be rational and appropriate at this time. As always, any such testing should meet the highest standards of quality as detailed in the companion laboratory guidelines. 3. The offering of such testing should ideally take place before pregnancy, thereby giving individuals time to make appropriate reproductive decisions based on their own personal choices and cultural backgrounds. Currently, the majority of testing takes place in the primary care obstetrical setting and not in the medical genetic specialty environment. However, regardless of the clinical setting, adequate counseling should be provided to anyone considering testing so that choices are truly "informed." Counseling should include the following: a. A general description of the disorders should be provided. Audiovisual materials are available and brochures, videos etc., can supplement the discussion. b. Whereas some of these disorders are associated with consistent symptoms and findings, others have imprecise phenotype/genotype correlations with the possibility of mild disease. c. Although detection rates are excellent overall, counseling must include an understanding that in the case of a negative test, a residual risk remains. d. A carrier of a gene mutation for an autosomal recessive disorder is a healthy individual who is not at risk of developing the disease but has a risk of passing the gene mutation to his/her offspring. e. The success of the Tay-Sachs screening program has resulted in the possible misperception that the Tay-Sachs gene is no longer present in the Ashkenazi Jewish community. Because a carrier is asymptomatic, screening by necessity should occur in every generation. Furthermore, some individuals are aware that they or their parents may have been tested for Tay-Sachs disease in the past, possibly through community testing programs. If documentation is not available, it is appropriate to offer repeat testing. f. Formal genetic counseling and medical genetic consultation should be readily available to anyone desiring this service. 4. If only one member of a couple is of Ashkenazi Jewish background, testing should still be offered. Ideally, the Jewish member of the couple should be tested first. If the Jewish partner has a positive test result, the other partner (regardless of background) should be screened for that particular disorder. In the case of Tay-Sachs disease, testing can be performed using the biochemical assay, which has an excellent detection rate regardless of ethnic or racial background. The mutation detection rate and carrier frequency among different ethnic/racial groups is known for cystic fibrosis; however, for the other disorders, a discussion should include the lack of a precise residual risk in the case where the non-Jewish partner is negative on mutation analysis. 5. Generally, individuals self-identify themselves as Jewish and whether or not they are of eastern European origin. One Jewish grandparent is sufficient to offer testing. However, if someone is unsure as to their precise lineage, it is recommended to offer testing. At this time, there is no specific panel of tests available for Jews from non-Ashkenazi background. However, a proper family history and ethnic origin should still be obtained and appropriate testing offered (e.g., hemoglobinopathy screening for those from the Mediterranean basin). 6. In the case where someone is identified as a carrier, genetic counseling should be readily available to discuss the findings and possible reproductive options. Furthermore, a discussion regarding the importance of genetic counseling for other family members should be stressed. Although the provider can not contact family members directly, the individual should be encouraged to discuss the findings with his or her family if possible and appropriate. 7. At present, many laboratories offer these tests as a panel, testing for several disorders as a group, in a single multiplex assay. This approach is practical from a technical and cost standpoint. However, the ethical concept of respect for persons necessitates that physicians only order tests for those diseases that have been consented to by the patient. If a patient does not provide informed consent for all tests included in a multiplex panel, then the requested tests should be ordered individually. ## Resources [table] Table 1: Jewish genetic disorders for which testing should be offered (see Technical Standards and Guidelines for Reproductive Screening in the Ashkenazi 98% is reflective of a homogenous Ashkenazi background where all four grandparents are likely of Ashkenazi Jewish heritage. 92% may be more reflective of more diverse populations. c 89% is based on the allele frequencies in Ashkenazi Gaucher disease Type 1 patients. 94.6% is adjusted to account for the presence of N370S homozygous asymptomatic individuals who would not be identified by screening affected patients. [/table]	None	https://www.nature.com/articles/gim20088.pdf	Disclaimer: This guideline is designed primarily as an educational resource for medical geneticists and other 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.
58640502de10c030fc7724109ca8fd601dc57544	pubmed	A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis	A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis MethodologyThis guideline was compiled according to the British Society for Haematology (BSH) process at b-s-h.org.uk. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of the recommendations. surgery and management. The search covered the period from 2005, the date of last version of the guideline (McMullin et al, 2005), to February week 3 2017. Exclusions included articles not in English, studies not in humans, single case reports and small case series. A total of 6062 articles were identified which, with exclusions and duplications, resulted in 1215 articles which were reviewed.Review of manuscriptReview of the manuscript was performed by the BSH Guidelines committee General Haematology Task Force, the BSH Guidelines Committee and the General Haematology sounding board of BSH. It was also placed on the members section of the BSH website for comment. A patient representative from MPN-Voice (www.mpnvoice.org.uk) participated in the guideline writing meeting. The guideline has been reviewed by MPN-Voice; this organisation does not necessarily approve or endorse the contents. # Introduction The previous BSH guideline for the management of erythrocytosis was published in [bib_ref] Pregnancy and its management in the Philadelphia negative myeloproliferative diseases, Harrison [/bib_ref] [bib_ref] Guidelines for the diagnosis, investigation and management Guideline ª 2018 The Authors, Mcmullin [/bib_ref] and amended in [bib_ref] Amendment to the guideline for diagnosis and investigation of polycythaemia/erythrocytosis, Mcmullin [/bib_ref]. Here, we re-evaluate the literature formulate guidance on the management of specific situations encountered in polycythaemia vera and the management of the other types of secondary erythrocytosis. Recommendations for the diagnostic pathway of investigation of an erythrocytosis, risk stratification and management of PV are in the accompanying guideline [bib_ref] A guideline for the diagnosis and management of polycythaemia vera. A British..., Mcmullin [/bib_ref]. We review evidence and outline guidance on management of acute thrombotic events and secondary prevention of thrombosis in PV. The unusual thrombotic events, splanchnic vein and cerebral vein thromboses are discussed and haemorrhage. The specific situations of surgery and pregnancy and guidance on management of pruritus are included. The evidence for the management of other causes of erythrocytosis, including idiopathic erythrocytosis, congenital erythrocytosis, hypoxic pulmonary disease and posttransplant erythrocytosis, is reviewed and recommendations made. ## Management of specific situations in polycythaemia vera Thrombosis Thrombotic events are the major cause of morbidity and mortality in PV, and their prevention is the main objective of treatment. About one-third of patients present with a thrombotic event [bib_ref] Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia, Elliott [/bib_ref] [bib_ref] Risk and cause of death in patients diagnosed with myeloproliferative neoplasms in..., Hultcrantz [/bib_ref] [bib_ref] Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German..., Kaifie [/bib_ref] and younger patients diagnosed with PV have an increased risk of early death from cardiovascular disease over the general population, accounting for 45% of all deaths in PV [bib_ref] Vascular and neoplastic risk in a large cohort of patients with polycythemia..., Marchioli [/bib_ref] [bib_ref] Risk and cause of death in patients diagnosed with myeloproliferative neoplasms in..., Hultcrantz [/bib_ref]. Arterial thrombosis involving large arteries and peripheral vascular disease are more common than venous thromboembolism in PV. A prospective study [bib_ref] Vascular and neoplastic risk in a large cohort of patients with polycythemia..., Marchioli [/bib_ref] found that three quarters of PV patients who experience a thrombotic event had arterial and one quarter venous thrombosis. Concerning the management of thrombosis: cardiovascular risk factors should be assessed and controlled, particularly hyperlipidaemia and hypertension, smoking and diabetes mellitus. The long-term cardiovascular risk should be formally assessed at baseline and annually using a validated score, such as that determined by the computerised scoring tool, QRISK, although the impact of myeloproliferative neoplasms (MPN) on this score is not defined (National Institute for Health and Care Excellence. This assessment is usually conducted in primary health care, but the results should be used in primary and secondary care to optimise the management of vascular risk factors. Risk stratification for thrombosis identifies age ≥65 years and previous thrombosis as high-risk factors for further thrombosis. The role of thrombocytosis as a risk factor in PV is less clear than in essential thrombocythaemia (ET) [bib_ref] The haematocrit and platelet target in polycythemia vera, Di Nisio [/bib_ref]. The mechanism behind thrombosis is complex and factors include functional cellular changes, such as increased leucocyte-platelet aggregation and endothelial activation, and the overexpression of activation and adhesion molecules by the neoplastic cells. Some of these factors may explain the increased incidence of thrombosis at unusual sites, such as splanchnic vein thrombosis (SVT) and cerebral venous thrombosis (CVT). Factor V Leiden (F5 R506Q) and prothrombin gene mutation (F2 G20210A) have been associated with thrombosis in PV and ET [bib_ref] The relationship between factor V Leiden, prothrombin G20210A, and MTHFR mutations and..., Trifa [/bib_ref]. However, routine testing for inherited or acquired thrombophilia is not recommended as it has is no impact on treatment and standard guidelines for thrombophilia testing should be applied for PV patients. Both primary and secondary prevention should include control of cardiovascular risk factors in accordance with current recommendations. Of interest, there is some evidence that angiotensin-converting enzyme inhibitors (ACEi), as anti-hypertensive agents, may have an additional role in controlling the haematocrit (Hct) . In accordance with evidence for the management of PV, low-dose aspirin should be offered to all patients [bib_ref] Efficacy and safety of low-dose aspirin in polycythemia vera, Landolfi [/bib_ref]. Low-dose aspirin, which describes various doses (e.g. 75, 81 or 100 mg) used in different countries, is the only dose to have been assessed in recent clinical trials. The risk of major bleeding, particularly gastro-intestinal, increases with age, and proton pump inhibitors should be given to patients over 75 years of age as well as to those a with high bleeding risk. The role of the ADP-receptor antagonist, clopidogrel, in the long-term prevention of MPNrelated thrombosis has not been investigated although it is widely used as an alternative in those who cannot tolerate aspirin. The Hct should be maintained below 0Á45 in accordance with evidence from the Cytoreductive therapy in PV (CYTO-PV) study [bib_ref] Cardiovascular events and intensity of treatment in polycythemia vera, Marchioli [/bib_ref]. ## Management of acute thrombotic events Acute thrombotic events should be managed according to current guidelines. Cytoreductive therapy should be instituted to ensure control of blood counts to the therapeutic target. Venesection to reduce the Hct to <0Á45 should be undertaken if it is not controlled at the time of acute thrombosis. For arterial thrombosis, low dose aspirin should be offered to all patients, and specialist advice should be sought. For venous thromboembolism (VTE), anticoagulation should be commenced. Low molecular weight heparin (LMWH) remains the first choice in the acute setting, followed by vitamin K antagonists (VKA) as per guidelines. Direct oral anticoagulants (DOACs) are increasingly used in the non-MPN population for prophylaxis and VTE therapy. However, there is limited data for their specific use in MPN, where they appear to be safe and efficacious . ## Secondary prevention of thrombosis Indefinite anticoagulation for VTE is recommended because of the presence of continuing risk [bib_ref] Guideline on aspects of cancer-related venous thrombosis, Watson [/bib_ref] [bib_ref] Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report, Kearon [/bib_ref]. In MPN, the role of continuing Guideline anticoagulation, particularly in VTE, has been assessed by several studies. Around a third of patients who stop anticoagulation after initial treatment suffer a recurrence [bib_ref] Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and..., Barosi [/bib_ref] [bib_ref] Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German..., Kaifie [/bib_ref]. Two retrospective studies [bib_ref] Oral anticoagulation to prevent thrombosis recurrence in polycythemia vera and essential thrombocythemia, Hern Andez-Boluda [/bib_ref] [bib_ref] High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and..., De Stefano [/bib_ref] showed that cessation of VKA after 3 months of treatment for a first VTE in MPN patients increased the risk of recurrent thrombosis compared with continued treatment. The later study also suggested a role for VKA in reducing the risk of arterial thrombotic recurrence and the possible benefit of adding aspirin to VKA to prevent recurrent arterial thrombosis. We are unable to make a specific recommendation about the addition of aspirin to VKA when a secondary thrombosis occurs in a patient already on VKA, as there is not yet evidence to support this. However, trials of this combination are in progress in other conditions and evidence may emerge. For unprovoked VTE, where there is no physical precipitating factor, we therefore recommend indefinite anticoagulation to reduce the incidence of recurrence. In a significant number of patients with recurrent thrombosis , cell counts were sub-optimally controlled. Cytoreduction should therefore be reviewed to ensure optimal counts are achieved. For recurrent arterial events, specialist advice should be sought from cardiovascular, stroke or vascular physicians. ## Recommendations: thrombosis ## Splanchnic vein thrombosis Unusual sites of venous thrombosis are more common in patients with MPN, especially in younger patients. The splanchnic circulation is particularly vulnerable in patients with JAK2 V617F mutation. SVT comprises thrombosis of hepatic, portal, superior mesenteric and splenic veins singly or in combination. The incidence of SVT during the course of PV ranges from 0Á8 to 7Á8% [bib_ref] Splanchnic vein thrombosis in myeloproliferative neoplasms, Sekhar [/bib_ref]. Overall, portal-mesenteric axis venous thrombosis is commoner than hepatic vein thrombosis or Budd Chiari Syndrome (BCS), however BCS is more prevalent in PV [bib_ref] Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a metaanalysis, Smalberg [/bib_ref]. The mortality of MPN-SVT is high, at 20-40% at 10 years, due to the index occurrence or recurrent thrombosis, bleeding or leukaemic transformation [bib_ref] Long-term follow-up of patients with portal vein thrombosis and myeloproliferative neoplasms, Hoekstra [/bib_ref] [bib_ref] Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry, Ageno [/bib_ref]. The presence of hypersplenism, SVT-related haemodilution and iron deficiency due to blood loss and/or masked polycythaemia can artificially lower the blood counts and a normal Hct may be found despite a high red cell mass. Therefore, it is important to investigate all patients presenting with SVT without attributable local pathology, such as malignancy, sepsis or pancreatitis, for the presence of JAK2 V617F mutation, which is present in 80-90% of patients with MPN-SVT, and if this is negative, testing should be done for a CALR mutation, which is present in about 2Á5% [bib_ref] Calreticulin mutations and their importance in splanchnic vein thrombosis, Sekhar [/bib_ref]. Although PV is commoner in males, PV-related SVT is commoner in young females. The reason for the predilection of splanchnic venous circulation to thrombosis in MPN is not clear. Many series report co-existing inherited or acquired thrombophilia in 25-30% patients, especially protein S deficiency which has been associated with unusual site thrombosis in MPN patients . In patients with SVT or cerebral vein thrombosis (CVT), testing for inherited and acquired thrombophilia should be considered if it would influence management decisions, such as intensity and duration of anticoagulation in the face of higher risks of bleeding [bib_ref] Guidelines on the investigation and management of venous thrombosis at unusual sites, Tait [/bib_ref]. Anticoagulation treatment in the acute phase should be undertaken with LMWH unless there are compelling contraindications [bib_ref] Guidelines on the investigation and management of venous thrombosis at unusual sites, Tait [/bib_ref]. In addition, the treatment of acute phase SVT includes interventions to recanalize the blocked veins, such as thrombolysis and insertion of stents. Optimal management results in long-term survival of 85% at 10 years in BCS. Patients requiring liver transplantation have a high mortality [bib_ref] Long-term outcome of liver transplant patients with Budd-Chiari syndrome secondary to myeloproliferative..., Potthoff [/bib_ref]. The management of PV-related SVT therefore needs close coordination between hepatologists, interventional radiologists and haematologists to achieve an accurate diagnosis, anti-coagulate effectively, undertake interventional procedures and optimise cytoreduction in the acute phase. Recurrence risk is high and prevention is important because of significant morbidity and mortality associated with recurrence. Overall 25-30% of MPN-SVT patients suffer a recurrence by 10 years [bib_ref] Long-term follow-up of patients with portal vein thrombosis and myeloproliferative neoplasms, Hoekstra [/bib_ref] [bib_ref] Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry, Ageno [/bib_ref]. Although recurrence is more likely in the splanchnic circulation [bib_ref] Prognostic factors in noncirrhotic patients with splanchnic vein thromboses, Amitrano [/bib_ref] , it can occur in other venous or arterial locations. Anticoagulant practice in MPN-SVT is heterogeneous [bib_ref] Treatment of thromboembolic events coincident with the diagnosis of myeloproliferative neoplasms: a..., Ellis [/bib_ref]. Current VTE guidelines recommend continuing anticoagulation in the presence of continuing active risk [bib_ref] Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, Kearon [/bib_ref] [bib_ref] Guidelines on the investigation and management of venous thrombosis at unusual sites, Tait [/bib_ref]. On this basis, PVrelated SVT is an indication for long-term anticoagulation. Several prospective and retrospective registry studies conclude that long-term anticoagulation reduces recurrence risk at splanchnic and other sites with an acceptable level of bleeding complications [bib_ref] Prognostic factors in noncirrhotic patients with splanchnic vein thromboses, Amitrano [/bib_ref] [bib_ref] Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry, Ageno [/bib_ref]. Recurrence in the arterial circulation has been observed in patients not on anti-platelet agents [bib_ref] Long-term follow-up of patients with portal vein thrombosis and myeloproliferative neoplasms, Hoekstra [/bib_ref]. The strategy of using anti-platelet agents in addition to VKA is followed in selected patients with BCS with stents in-situ but registry data do not suggest any benefit from this combination for prevention of recurrence of thrombosis outside of this group. Concerning anticoagulation with DOACs, 20% of patients with non-cirrhotic SVT suffered thrombosis or haemorrhage at 2 years (De Gottardi et al, 2017). These agents have not been studied in MPN-related SVT where LMWH followed by warfarin is the standard of care. The impact of cytoreduction in MPN with SVT has not been systematically studied. Cytoreduction was used in 40-70% patients across registries and did not uniformly influence recurrence risk. However, abnormally high blood counts due to inadequate cytoreduction were present in over half the patients with recurrent thrombosis (De Stefano et al, 2016b) indicating the need for rigorous clinical monitoring of patients on cytoreduction. Venesection alone is not appropriate to treat PV and cytoreduction should be undertaken in the presence of SVT. Patients with PV-related SVT are younger and interferon may be suitable as a first line agent, however data on interferon in this group of patients are not yet available. There are no data to guide therapeutic targets of cytoreductive treatment. In particular, whether more aggressive cytoreduction offsets the residual risk of recurrent thrombosis is not known. One strategy is to use standard targets for treatment of PV with an aim to achieving normal Hct, white blood cell (WBC), neutrophil and platelet counts [bib_ref] Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet, Barbui [/bib_ref]. An alternative strategy is to use lower targets, as defined by experts in the ongoing trial of pegylated interferon 2 alpha in MPN including MPN-SVT aiming for a Hct ≤0Á42, WBC count between 2 and 8 9 10 9 /l, and platelet count between 100 and 200 9 10 9 /l [bib_ref] Pegylated Interferon Alfa-2a salvage therapy in high risk Polycythemia Vera (PV) or..., Hoffman [/bib_ref]. As this study is not yet complete the evidence for the use of these targets is weak. Nevertheless, the fact that these patients do develop thrombosis with normal counts suggests functional thrombogenicity, which may be altered by using diseasemodifying agents to achieve these lower targets. Small doses of cytoreductive agents are often sufficient to achieve therapeutic targets and care must be taken to avoid significant thrombocytopenia in the face of continuing anticoagulation. Treatment with ruxolitinib was found to reduce the volume of spleen in a third of MPN-SVT patients after 2 years . Complications of treatment include bleeding, especially gastrointestinal haemorrhage and, in particular, variceal haemorrhage [bib_ref] Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry, Ageno [/bib_ref]. A quarter of major bleeds are intracranial. Other than thrombocytopenia, cytoreduction does not have any impact on bleeding risk. Bleeding risk can be minimized by careful management of oesophageal varices and concurrent use of proton pump inhibitors. ## Cerebral vein thrombosis Cerebral vein thrombosis occurs in about 1% of MPN patients, primarily in those with ET bearing the JAK2 V617F mutation [bib_ref] Cerebral vein thrombosis in patients with Philadelphia-negative myeloproliferative neoplasms. An European Leukemia..., Martinelli [/bib_ref]. In selected patients with unexplained CVT, testing for JAK2 V617F can identify the aetiology and assist management. Recurrence rates are higher in MPN-CVT, especially in spontaneous CVT, and a third of patients suffer recurrence despite anticoagulation and cytoreduction [bib_ref] Venous thromboembolic events after cerebral vein thrombosis, Miranda [/bib_ref] [bib_ref] Cerebral vein thrombosis in patients with Philadelphia-negative myeloproliferative neoplasms. An European Leukemia..., Martinelli [/bib_ref]. Recurrence is systemic, affecting venous and arterial circulation and often involves splanchnic veins. Patients with PV-related CVT should be treated with long-term anticoagulation and cytoreduction. The role of aspirin and JAK inhibitors have not been studied in this group of patients. ## Recommendations: splanchnic vein thrombosis and cerebral vein thrombosis ## Haemorrhage Haemorrhage is both a less frequent and generally less severe clinical complication of PV than thrombosis. The reported incidence varies greatly between studies [bib_ref] Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia, Elliott [/bib_ref] [bib_ref] Vascular and neoplastic risk in a large cohort of patients with polycythemia..., Marchioli [/bib_ref] [bib_ref] Bleeding complications in BCR-ABL negative myeloproliferative neoplasms: prevalence, type, and risk factors..., Kander [/bib_ref] [bib_ref] Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German..., Kaifie [/bib_ref]. The principal sites affected are skin, mucous membranes and gastrointestinal tract. Patients with SVT are at a particularly high risk of bleeding from gastro-oesophageal varices. Factors contributing to bleeding in patients with PV include extreme thrombocytosis (platelet counts >1500 9 10 9 /l) [bib_ref] Natural history and risk factors for thrombosis in 360 patients with antiphospholipid..., Finazzi [/bib_ref] and associated acquired von Willebrand syndrome (aVWS). This has been reported to affect 12% of PV patients, usually those with high platelet counts, and does not always correlate with bleeding [bib_ref] Bleeding complications in BCR-ABL negative myeloproliferative neoplasms: prevalence, type, and risk factors..., Kander [/bib_ref] [bib_ref] Factors predisposing to acquired von Willebrand syndrome during the course of polycythemia..., Mital [/bib_ref]. Other platelet function defects are reported in PV but they are not predictive of bleeding. However, the risk of bleeding is likely to be higher with combined use of anti-platelet therapies, such as dual anti-platelet therapy or anti-platelet therapy and VKA [bib_ref] Use of single and combined antithrombotic therapy and risk of serious upper..., Hallas [/bib_ref] [bib_ref] Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German..., Kaifie [/bib_ref]. Other studies have reported splenomegaly [bib_ref] Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German..., Kaifie [/bib_ref] and a high leucocyte count [bib_ref] Leukocytosis in polycythemia vera and splenomegaly in essential thrombocythemia are independent risk..., Chou [/bib_ref] [bib_ref] Prediction of thrombotic and hemorrhagic events during polycythemia vera or essential thrombocythemia..., Lim [/bib_ref] as predictors of haemorrhage. Blood counts should therefore be optimised. Other measures to consider include adjustment of any concomitant anti-platelet and/or anticoagulant therapy. Clinically significant bleeding may, paradoxicall,y require platelet transfusionand a role for tranexamic acid has been suggested [bib_ref] The optimal management of polycythaemia vera, Spivak [/bib_ref]. The utility of recombinant activated factor VII (rFVIIa) is unknown in MPN patients with uncontrolled life-threatening bleeding and perhaps worthy of further study. ## Peri-operative management Polycythaemia vera patients undergoing surgery are, paradoxically, at risk of both haemorrhage and thrombosis. Even in treated PV patients with well controlled counts, there is an increased risk of haemorrhage, demonstrated by their increased transfusion requirements [bib_ref] Perioperative blood product administration and thromboembolic events in patients with treated polycythemia..., Weingarten [/bib_ref] compared to non-PV patients . VTE incidence was increased 5-fold despite prophylaxis. It is therefore important that PV patients are assessed pre-operatively and abnormal counts optimised, balancing the acute need for surgical procedure against the risk of bleeding and thrombosis. Polycythaemia vera patients who bleed may have significant qualitative platelet abnormalities. Patients with a prior history of bleeding should be tested for platelet function and for aVWS preoperatively. Anti-thrombotic prophylaxis should be administered according to standard postoperative guidelines. There is a little evidence that use of cytotoxic agents impairs wound healing: their use in the 4-6 weeks after surgery needs to be considered based on thrombotic and haemorrhagic risk and could be avoided if venesection alone is sufficient. ## Recommendations: surgery - Pre-operative planning should involve a haematologist to optimise count control and individualise peri-operative plan. (GRADE 1B) - Use standard protocols for managing antithrombotic prophylaxis. (GRADE 1B) - If the patient has a bleeding history, screen for coagulation tests, aVWS and platelet function tests pre-operatively. (GRADE 2C) ## Pregnancy Polycythaemia vera is uncommon in females of reproductive age, occurring in less than 0Á3 per 100 000 [bib_ref] Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/ myeloproliferative neoplasms in..., Srour [/bib_ref]. There are only small case series describing the management of pregnancy in patients with PV [bib_ref] Pregnancy and its management in the Philadelphia negative myeloproliferative diseases, Harrison [/bib_ref] [bib_ref] The management and outcome of 18 pregnancies in women with polycythemia vera, Robinson [/bib_ref] [bib_ref] Management of Philadelphia negative chronic myeloproliferative disorders in pregnancy, Griesshammer [/bib_ref]. Larger case series are published for pregnancy management in patients with ET or cohorts of patients with all MPNs [bib_ref] Pregnancy outcomes in myeloproliferative neoplasms: UK prospective cohort study, Alimam [/bib_ref] [bib_ref] Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic..., Skeith [/bib_ref]. The guidance detailed here refers to these case series, practices extrapolated from the management of pregnant patients with ET and personal practice. Pregnancy is a prothrombotic state with increased risk of thromboembolism in patients with PV. Consequently, there is a significant risk of obstetric complications, such as fetal loss throughout all trimesters, intra-uterine growth retardation, prematurity, maternal thromboembolism and haemorrhage. Previously significant fetal loss and maternal morbidity was seen, but a recent prospective study of pregnancy outcomes in MPNs showed better outcomes. There were no maternal deaths or thrombotic events [bib_ref] Pregnancy outcomes in myeloproliferative neoplasms: UK prospective cohort study, Alimam [/bib_ref]. This improvement in pregnancy outcomes is probably partly due to a more protocol-based management and a multidisciplinary approach. Pregnancies in patients with PV should be managed under the joint care of an obstetrician experienced in the care of high-risk patients and a haematologist experienced in MPNs. Management should start with preconceptual planning for both male and female patients. The Hct should be kept within a gestational-appropriate range and potentially teratogenic medications (such as hydroxycarbamide) should be stopped a minimum of 3 months prior to planned conception in males and females. There is insufficient data regarding the safety of anagrelide during pregnancy and it should therefore be withdrawn at least 3 months prior to conception in females. Interferon should be considered for those patients who require cytoreductive therapy, though patients should be counselled regarding the potential for interferon to reduce fertility. All patients should receive low dose aspirin (unless there are patient-specific contraindications) throughout pregnancy and the postpartum period. Patients with high risk pregnancies should be identified [fig_ref] Table I: Management of risk factors during pregnancy [/fig_ref]. These are patients with previous arterial or venous thrombosis or haemorrhage attributed to PV, previous pregnancy complications (>3 first trimester losses, >1 s or third trimester loss, birth weight <5th centile for gestation, intrauterine death or stillbirth, pre-eclampsia), extreme thrombocytosis before or during pregnancy, diabetes mellitus or hypertension requiring pharmacological treatment. Those patients with a prior history of thrombosis and/or fetal morbidity should commence cytoreduction therapy with interferon and prophylactic LMWH in addition to aspirin. The dose and frequency of LMWH should be adjusted according to renal function, body weight and previous history. For those patients of normal body weight, no renal impairment and with a history of previous venous thrombosis or fetal morbidity, standard dose thromboprophylaxis (e.g. enoxaparin 40 mg/day) should be commenced as soon as pregnancy is confirmed. This should be increased to intermediate dose thromboprophylaxis (e.g. twice daily enoxaparin 40 mg) at 16-20 weeks. Patients with a previous history of arterial thrombosis should be commenced on intermediate dose prophylaxis (e.g. twice daily enoxaparin 40 mg) throughout pregnancy [bib_ref] Pregnancy and its management in the Philadelphia negative myeloproliferative diseases, Harrison [/bib_ref]. Interferon should be initiated for those patients with a history of PV-associated haemorrhage, extreme thrombocytosis (>1500 9 10 9 /l) before or during pregnancy and/or diabetes mellitus or hypertension requiring pharmacological treatment. All other patients (standard risk pregnancy) should receive low dose aspirin throughout pregnancy with the addition of once daily prophylactic dose LMWH for 6 weeks postpartum. During pregnancy, the Hct should be maintained within the normal range for gestation with venesection [fig_ref] Table I: Management of risk factors during pregnancy [/fig_ref]. Interferon can be considered if venesection fails to adequately control the Hct or is not tolerated. Patients should be reminded to avoid iron supplementation in the absence of proven iron depletion. Where supplementation is offered, this should be at a low dose with regular monitoring. The full blood count, blood pressure and urinalysis should be checked every 4 weeks until 24 weeks and then every 2 weeks. Fetal growth should be assessed by regular ultrasound. Uterine Dopplers should be performed at 20 weeks' gestation to assess placental function by measuring the mean pulsatile index. If the index is >1Á4, the frequency of growth scans should be increased and consideration given to escalating treatment to include LMWH and interferon. Dehydration should be avoided in all patients during labour and the third stage of labour should be actively managed. Thromboembolic deterrent (TED) stockings are advisable during labour and if immobile during the postpartum period. LMWH and aspirin should be stopped prior to elective caesarean section or once spontaneous labour has begun, as per local guidelines. Low molecular weight heparin should be restarted at the earliest opportunity post-partum provided there is no significant bleeding. The dose of LMWH should be once daily and should be continued for 6 weeks post-partum. Aspirin should be continued throughout the post-partum period. Breastfeeding is safe with both aspirin and LMWH, and permissible with interferon. The Hct should be monitored in the post-partum period and maintained at less than 0Á45. Attention should be paid to the platelet count, as a rebound thrombocytosis may develop, necessitating the introduction of cytoreductive therapy. There is no evidence regarding the management of PV during fertility treatment. Ovarian hyperstimulation is associated with an increased risk of thrombosis and therefore cytoreductive therapy (with interferon) and thromboprophylaxis with LMWH should be considered. It can occur spontaneously or be precipitated by water or changes in temperature and can have a significant negative impact on quality of life, affecting sleep, participation in social activities and bathing [bib_ref] Aquagenic pruritus in polycythemia vera: characteristics and influence on quality of life..., Siegel [/bib_ref]. The intensity of pruritus varies but can be severe causing emotional depression, anxiety and even suicide ideation. The pathogenesis of pruritus in PV is not clear. Mechanisms involving basophils [bib_ref] The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from..., Pieri [/bib_ref] and mast cells [bib_ref] Pivotal role of mast cells in pruritogenesis in patients with myeloproliferative disorders, Ishii [/bib_ref] have been postulated. It can also be associated with the iron deficiency that commonly results from frequent venesection therapy. Pruritus has been found to be correlated with granulocyte JAK2 V617F homozygosity and allele burden [bib_ref] Pruritus in polycythemia vera is associated with a lower risk of arterial..., Gangat [/bib_ref]. The mechanism for this association is unclear though it may relate to cytokine levels. ## Recommendations: pregnancy management The management of pruritus is challenging. Symptoms can improve or resolve with control of blood counts, using venesection alone or with cytoreductive therapy (Le Gall- [bib_ref] Administration of direct oral anticoagulants in patients with myeloproliferative neoplasms, Ianotto [/bib_ref]. Improvement in pruritus has been reported with hydroxycarbamide [bib_ref] Treatment of polycythemia vera with hydroxyurea, Sharon [/bib_ref] , interferon (although this drug can also worsen pruritus) [bib_ref] Interferon alpha in the treatment of polycythemia vera, Lengfelder [/bib_ref] , busulfan and 32 P [bib_ref] Skin mast cells in polycythaemia vera: relationship to the pathogenesis and treatment..., Jackson [/bib_ref]. Trials of ruxolitinib in PV have shown this agent to be effective in controlling pruritus in patients who have failed to respond to hydroxycarbamide [bib_ref] Ruxolitinib versus standard therapy for the treatment of polycythemia vera, Vannucchi [/bib_ref] [bib_ref] The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib..., Mesa [/bib_ref] [bib_ref] Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2):..., Passamonti [/bib_ref]. In those who are severely iron deficient as a result of venesection, pruritus may improve with iron replacement, if this is possible, but iron replacement must be undertaken with extreme caution and close supervision of blood counts. However, pruritus can persist in patients with PV once their blood counts have normalised [bib_ref] Pruritus in polycythemia vera is associated with a lower risk of arterial..., Gangat [/bib_ref]. Antihistamines (both H1 and H2 receptor antagonists) are commonly prescribed though demonstrate mixed results [bib_ref] The use of cimetidine for the treatment of pruritus in polycythemia vera, Weick [/bib_ref] [bib_ref] Aquagenic pruritus, Steinman [/bib_ref] and combination therapy at high doses may be required to be effective. Other adjunctive therapy that have been shown to be of benefit include selective serotonin reuptake inhibitors (SSRIs) [bib_ref] Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated..., Tefferi [/bib_ref] and anticonvulsants (such as gabapentin and pregabalin). Tricyclic antidepressants, thalidomide and naltrexone have also been found to be beneficial [bib_ref] Antipruritic treatment with systemic l-opioid receptor antagonists: a review, Phan [/bib_ref]. Sometimes creams containing menthol can also provide some relief [bib_ref] Menthol: a refreshing look at this ancient compound, Patel [/bib_ref]. From a practical point of view, it is advisable to cut nails to reduce skin damage. Joint management with a dermatologist should be considered for refractory symptoms and for those patients requiring narrow-band-ultraviolet (UVB) or ultraviolet A (UVA) [bib_ref] Ultraviolet phototherapy for pruritus, Rivard [/bib_ref]. The addition of oral psoralen to UV light (PUVA) is only occasionally used. In patients who do not require cytoreductive therapy, the above options should be tried prior to initiating cytoreductive therapy just to control pruritus. ## Recommendations ## Management of secondary erythrocytosis ## Idiopathic erythrocytosis Idiopathic erythrocytosis (IE) is a diagnosis of exclusion. It is an absolute erythrocytosis of no identifiable cause that is more frequent in males [bib_ref] Idiopathic erythrocytosis: a study of a large cohort with a long follow-up, Randi [/bib_ref]. Every effort should be made to exclude identifiable primary and secondary causes of erythrocytosis (including PV and congenital erythrocytosis) before a diagnosis of IE is made. Erythropoietin (EPO) levels are unhelpful as they are below normal in a third of patients, suggesting a primary erythrocytosis, and elevated in two-thirds, suggesting a secondary erythrocytosis. Recent studies using sequencing analysis have identified a number of patients who were previously diagnosed with IE as having mutations in either erythrocytosis-associated genes or novel genes [bib_ref] Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis..., Camps [/bib_ref] , suggesting that at least some of these cases have a genetic basis. Although previous data suggested that the risk of thrombosis and/or haemorrhage was considerably elevated in IE, these observations were based on old evidence that predated the identification of the JAK2 V617F mutation and therefore some patients with PV are likely to have been included in the study cohorts. More contemporary data suggests that the risk of thrombosis/bleeding is low in IE [bib_ref] Thrombotic and hemorrhagic complications in idiopathic erythrocytosis, Bertozzi [/bib_ref]. There are no clinical studies evaluating the use of aspirin or venesection in IE and therefore evidence-based recommendations cannot be made. Cytoreductive therapy is not indicated in patients with IE. The thrombotic risk factors should be evaluated in each case and, in selected cases, the Hct can be controlled by venesection. There is no evidence on which to determine the target Hct as relevance of data from PV patients for IE is unclear. A pragmatic approach is required for these patients with rigorous control of vascular risk factors, such as diabetes mellitus, hypertension and smoking and use of aspirin in cases where this would be otherwise clinically indicated for primary or secondary prevention. It would be reasonable to venesect patients with an arbitrary target Hct of <0Á55, although a lower target Hct of <0Á45 may be appropriate for a patient with a history of thrombosis considered to be related to the erythrocytosis. Recommendations: idiopathic erythrocytosis ## Congenital erythrocytosis Germ-line defects can result in a congenital erythrocytosis, which is usually diagnosed in children or young adults, often in those with a family history of erythrocytosis. A wide range of defects have been described leading to primary and secondary erythrocytosis including high oxygen affinity haemoglobins [bib_ref] Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis..., Camps [/bib_ref]. These conditions are rare and clinical events and outcomes are poorly described. In Chuvash polycythaemia, where affected individuals have a homozygous mutation in the VHL gene increased thrombotic complications have been reported [bib_ref] Prospective study of thrombosis and thrombospondin-1 expression in Chuvash polycythemia, Sergueeva [/bib_ref]. Major thrombotic events have also been reported to occur in young individuals with other types of congenital erythrocytosis. There are also reports of increased pulmonary artery pressure in both Chuvash polycythaemia and other congenital erythrocytosis [bib_ref] Endothelin-1, vascular endothelial growth factor and systolic pulmonary artery pressure in patients..., Bushuev [/bib_ref] [bib_ref] Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary physiology, Smith [/bib_ref]. Recently, somatic gain-of-function mutations in EPAS1 (HIF2A) have been associated with neuroendocrine tumours in the presence of erythrocytosis [bib_ref] Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia, Zhuang [/bib_ref] and, therefore, it may be advised to screen for these events in individuals with known mutations. There is little hard evidence to advise on management of congenital erythrocytosis. Low-dose aspirin is of benefit in myeloproliferative neoplasms in the prevention of thromboembolic events [bib_ref] Efficacy and safety of low-dose aspirin in polycythemia vera, Landolfi [/bib_ref] and, by extrapolation, may be of benefit in congenital erythrocytosis. Venesection can be used to reduce the Hct but it must be considered that the raised Hct is in keeping with the physiological consequences of the mutation and in Chuvash polycythaemia there are suggestions that venesection may be detrimental. However, in those with symptoms for which the raised Hct may be contributory or if a previous thrombotic episode has occurred, or in individuals who are asymptomatic but who have affected family members with the same genetic lesion and a thrombotic episode, venesection to a target of 0Á52 is suggested. This advice particularly pertains to those with high oxygen affinity haemoglobins [bib_ref] High oxygen affinity hemoglobins, Mangin [/bib_ref]. In Chuvash polycythaemia the VHL protein is a SOCS1coperative regulator of JAK2 and JAK2-targeted therapy may be of benefit in this disorder [bib_ref] Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies..., Russell [/bib_ref]. Recently there have been reports of clinical improvement in patients with Chuvash polycythaemia on ruxolitinib [bib_ref] Clinical improvement with JAK2 inhibition in Chuvash polycythemia, Zhou [/bib_ref] and ruxolitinib may therefore be considered for the management of this specific cause of congenital erythrocytosis. ## Recommendations: congenital erythrocytosis ## Hypoxic pulmonary disease Erythrocytosis can be associated with advanced chronic obstructive pulmonary disease (COPD) and with obstructive sleep apnoea syndrome (OSA). In both conditions, erythrocytosis is relatively rare. In COPD, the incidence of erythrocytosis, usually defined as Hct > 0Á55, ranges from 6 to 8% [bib_ref] Prognostic value of the hematocrit in patients with severe COPD receiving long-term..., Chambellan [/bib_ref] [bib_ref] Haemoglobin level and its clinical impact in a cohort of patients with..., Cote [/bib_ref]. Incidences of 1Á7-8% are reported in OSA [bib_ref] Polycythemia is rarely caused by obstructive sleep, Gangaraju [/bib_ref]. The prognostic significance of erythrocytosis in hypoxic pulmonary disease (HPD) is not known but the development of an erythrocytosis in patients with HPD is associated with an increased risk of the development of cor pulmonale and poor median survival of 2-3 years [bib_ref] Effects of long-term oxygen therapy on mortality and morbidity, Criner [/bib_ref]. However, in a retrospective analysis of severe COPD patients on long term oxygen treatment, a Hct ≥ 0Á55 was associated with better prognosis compared to COPD patients with anaemia [bib_ref] Prognostic value of the hematocrit in patients with severe COPD receiving long-term..., Chambellan [/bib_ref] [bib_ref] Haemoglobin level and its clinical impact in a cohort of patients with..., Cote [/bib_ref]. The risk of PE in this setting is also unclear [bib_ref] Prevalence of venous thromboembolism in patients with secondary polycythemia, Nadeem [/bib_ref] as an increased Hct in the general population is also associated with increased VTE risk [bib_ref] Hematocrit and risk of venous thromboembolism in a general population. The Tromso..., Braekkan [/bib_ref]. A recent study suggests that patients with COPD at low risk of VTE had increased incidence of pulmonary embolism if they had concurrent erythrocytosis [bib_ref] Relationship between polycythemia and in-hospital mortality in chronic obstructive pulmonary disease patients..., Guo [/bib_ref]. Additional risk factors affecting circulatory compromise and tissue oxygen delivery include carbon monoxide in smokers, extent of hypercapnia, renal blood flow, acid-base balance (pH), capacity of the bone marrow to respond to erythropoietic drive, position on the oxygen dissociation curve and changes in the peripheral vascular circulation. Furthermore, for an individual patient, co-existent age-related vascular disease may also affect thrombotic risk. The evidence base for recommendations for the management of erythrocytosis in HPD remains limited. However, treatment of the underlying hypoxia reduces the Hct. Long term oxygen therapy improves survival in patients with COPD and severe hypoxaemia (PaO 2 below 7Á3 kPa or <8Á0 kPa with nocturnal hypoventilation) [bib_ref] Survival on long-term oxygen therapy in chronic airflow limitation: from evidence to..., Crockett [/bib_ref]. All patients with erythrocytosis consequent upon HPD should therefore be evaluated by a respiratory physician for consideration of long-term oxygen therapy or alternative methods of improving oxygenation. If they are smokers they should be strongly advised to stop. In addition to supplemental oxygen, nocturnal oxygenation may also be improved by the use of non-invasive ventilation. Therefore, failure to achieve adequate oxygenation in HPD should not be accepted without review by a specialist respiratory physician. Of benefit regarding limited venesection in patients with HPD, reducing the Hct to 0Á50-0Á52 led to an improvement in exercise tolerance but a further staged reduction of Hct to 0Á45 did not give additional benefit as discussed in the previous guideline [bib_ref] Guidelines for the diagnosis, investigation and management Guideline ª 2018 The Authors, Mcmullin [/bib_ref]. However, a Hct lower than 0Á45 is detrimental to these patients, and associated with poorer outcome [bib_ref] Prognostic value of the hematocrit in patients with severe COPD receiving long-term..., Chambellan [/bib_ref]. It is of interest that ACEi [bib_ref] Association of angiotensinconverting enzyme inhibitor therapy initiation with a reduction in hemoglobin..., Leshem-Rubinow [/bib_ref] have the ability to reduce the Hct in this setting. In the case of obstructive sleep apnoea, erythrocytosis is associated with nocturnal oxygen desaturation and such patients should be referred for appropriate investigation. Long term non-invasive continuous positive airway pressure (CPAP) has been shown to reduce erythrocytosis [bib_ref] Long-term compliance with nasal continuous positive airway pressure (CPAP) in obstructive sleep..., Krieger [/bib_ref]. ## Recommendations: hypoxic pulmonary disease - Patients with hypoxic pulmonary disease who develop erythrocytosis should be evaluated by a respiratory physician for consideration of long-term oxygen therapy or alternative therapy. (GRADE 1A) - Patients who are symptomatic as a result of hyperviscosity or have a Hct >0Á56 should be considered for venesection to reduce this to 0Á50-0Á52. (GRADE 2C) ## Post-transplant erythrocytosis The definition of post-transplant erythrocytosis (PTE) varies across publications, which impacts on the estimate of incidence. A Hct over 0Á51 lasting more than a month after renal transplantation is a commonly used definition [bib_ref] Posttransplant erythrocytosis, Vlahakos [/bib_ref] ; however, gender-specific cut-offs (males, Hct > 0Á52; females >0. 50), use of haemoglobin concentration in the definition (>170 g/l) and variable duration (>1 month, 3 months, 6 months) have also been used. The incidence of post-renal transplant erythrocytosis is between 5% and 20% and is decreasing. PTE also occurs in approximately 1% of patients after haematopoetic stem cell transplantation (HSCT) [bib_ref] Erythrocytosis following allogeneic hemopoietic SCT in three cases of aplastic anemia, Ahmed [/bib_ref] [bib_ref] A rare complication after allogeneic stem cell transplantation: posttransplant erythrocytosis, Atilla [/bib_ref] and after combined pancreatic-renal transplant, with a reported incidence of 16% [bib_ref] Elevated incidence of posttransplant erythrocytosis after simultaneous pancreas kidney transplantation, Guerra [/bib_ref]. Post-transplant erythrocytosis following renal transplantation is a benign, often self-limiting condition which typically develops within the first year following transplantation, although it can occur at 2-4 years [bib_ref] Factors predisposing to post-renal transplant erythrocytosis: a retrospective study, Charfeddine [/bib_ref]. Spontaneous resolution can occur over a period of 1-4 years [bib_ref] Erythrocytosis after renal transplantation: review of 101 cases, Einollahi [/bib_ref] and treatment with ACEi or angiotensin receptor blockers (ARB) successfully reduces the Hct in the majority [bib_ref] Factors predisposing to post-renal transplant erythrocytosis: a retrospective study, Charfeddine [/bib_ref]. Indeed, the increasing use of these drugs for hypertension at earlier stages after transplantation has been deemed responsible for the falling incidence of PTE. Risk factors for developing erythrocytosis include male gender, retained native kidney, hypertension, renal artery stenosis, a short period of pre-transplant dialysis, reduced need for pretransplant use of EPO or being transfused. Studies also list good allograft function, diabetes, rejection-free course and use of ciclosporin adversely affecting the incidence and use of mycophenolate mofetil favourably affecting the incidence. Symptoms due to high viscosity, comprising dizziness, malaise, headache, lethargy and plethora, are reported. No thrombosis or mortality has been reported in recent studies. Venesection has been used by some in patients with persistently high Hct (>0Á57-0Á60) and helps reduce the Hct but does not reduce the incidence of thrombosis [bib_ref] Factors predisposing to post-renal transplant erythrocytosis: a retrospective study, Charfeddine [/bib_ref]. Aspirin use has been variable and its effect is not clear. Mechanisms of post-renal transplant erythrocytosis have been reviewed [bib_ref] Posttransplant erythrocytosis, Vlahakos [/bib_ref]. Recipient-related, rather than donor-related, features underlie the development of PTE. The erythrocytosis is EPO-responsive, with high EPO levels at onset reducing to lower levels after suppression of the renin-angiotensin-system (RAS) using ACEi, ARBs or native kidney nephrectomy; recurrence after discontinuation of these drugs is accompanied by increased EPO levels [bib_ref] Posttransplant erythrocytosis, Vlahakos [/bib_ref]. Retention of native kidneys is thought to lead to a 'hyper-erythropoietinaemia'. Unlike suppression of the RAS, venesection increases EPO levels. The renin-angiotensin, androgen and adrenergic systems increase erythropoiesis and sensitivity of erythroid progenitors to EPO. The likely common pathway is via insulinlike growth factor-1 (IGF1) which increases erythropoiesis. ACEi reduce IGF1 levels thus reducing erythropoiesis. Pancreatic plus renal transplant increases IGF1 levels, and use of systemic venous drainage (as opposed to portal venous drainage) was associated with a higher incidence and earlier onset of PTE [bib_ref] Elevated incidence of posttransplant erythrocytosis after simultaneous pancreas kidney transplantation, Guerra [/bib_ref]. These patients also required more frequent venesection to maintain a stable Hct. Treatment with ACEi or ARB reduces Hct to a nadir level at 3 months with stable results for several years. Discontinuation usually leads to recurrence of post-transplant erythrocytosis, but 20-30% of patients maintain a normal Hct after cessation. The use of aggressive venesection leads to iron deficiency. Haematopoetic stem cell transplantation-related erythrocytosis has been observed in about 1% of patients transplanted for aplastic anaemia but also in other conditions, including myelodysplastic syndromes and acute leukaemia [bib_ref] Erythrocytosis following allogeneic hemopoietic SCT in three cases of aplastic anemia, Ahmed [/bib_ref] [bib_ref] A rare complication after allogeneic stem cell transplantation: posttransplant erythrocytosis, Atilla [/bib_ref]. Patients who developed PTE did not have total body irradiation and were mostly men. Erythrocytosis was asymptomatic, with no thrombosis or mortality reported. All were treated with venesection on an ongoing basis. PTE after HSCT starts, on average, about 11 months after the transplant and can be self-limiting, lasting approximately 6 months. Persistent post-transplant erythrocytosis unresponsive to ACEi, ARB or venesection requires further investigation to define underlying causes, including JAK2 V617F mutation analysis. ## Recommendations ## Cyanotic congenital heart disease Patients with congenital cyanotic heart disease are best managed by specialist cardiology clinics. Decisions about venesection for these patients should not be made in a haematology clinic. # Conclusion Using the available evidence and best practice we have suggested practical guidance for the management of specific situations and complications of polycythaemia vera. # Declaration of interests The BSH paid the expenses incurred during the writing of this guidance. All authors have made a declaration of interests to the BSH and Task Force Chairs which may be reviewed on request. [fig] •: Patients presenting with splanchnic vein thrombosis (SVT) not associated with local malignancy should be tested for the presence of JAK2 V617F mutation and if negative, CALR mutation. (GRADE 1A) Patients with SVT should be treated with long-term anticoagulation. (GRADE 1B) Patients with CVT should be treated with long-term anticoagulation. (GRADE 2C) Cytoreduction and control of blood counts should be undertaken in keeping with management of high-risk polycythaemia vera. (GRADE 1A) Patients should be managed in a multidisciplinary setting in conjunction with interventional radiology and hepatology. (GRADE 1B) [/fig] [table] Table I: Management of risk factors during pregnancy. [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bjh.15647	The previous BSH guideline for the management of erythrocytosis was published in 2005 (McMullin et al, 2005) and amended in 2007 (McMullin et al, 2007). Here, we re‐evaluate the literature formulate guidance on the management of specific situations encountered in polycythaemia vera (PV) and the management of the other types of secondary erythrocytosis. Recommendations for the diagnostic pathway of investigation of an erythrocytosis, risk stratification and management of PV are in the accompanying guideline (McMullin et al, 2018). We review evidence and outline guidance on management of acute thrombotic events and secondary prevention of thrombosis in PV. The unusual thrombotic events, splanchnic vein and cerebral vein thromboses are discussed and haemorrhage. The specific situations of surgery and pregnancy and guidance on management of pruritus are included. The evidence for the management of other causes of erythrocytosis, including idiopathic erythrocytosis, congenital erythrocytosis, hypoxic pulmonary disease and post‐transplant erythrocytosis, is reviewed and recommendations made.
1139851acdfea28bf002269dc3ac44c191c3c21e	pubmed	WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus	WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus Recent spread of avian infl uenza A (H5N1) virus to poultry and wild birds has increased the threat of human infectionswith H5N1 virus worldwide. Despite international agreement to stockpile antivirals, evidence-based guidelines for their use do not exist. WHO assembled an international multidisciplinary panel to develop rapid advice for the pharmacological management of human H5N1 virus infection in the current pandemic alert period. A transparent methodological guideline process on the basis of the Grading Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to develop evidence-based guidelines. Our development of specifi c recommendations for treatment and chemoprophylaxis of sporadic H5N1 infection resulted from the benefi ts, harms, burden, and cost of interventions in several patient and exposure groups. Overall, the quality of the underlying evidence for all recommendations was rated as very low because it was based on small case series of H5N1 patients, on extrapolation from preclinical studies, and high quality studies of seasonal infl uenza. A strong recommendation to treat H5N1 patients with oseltamivir was made in part because of the severity of the disease. Similarly, strong recommendations were made to use neuraminidase inhibitors as chemoprophylaxis in high-risk exposure populations. Emergence of other novel infl uenza A viral subtypes with pandemic potential, or changes in the pathogenicity of H5N1 virus strains, will require an update of these guidelines and WHO will be monitoring this closely. # Introduction Highly pathogenic avian infl uenza A (H5N1) virus causes rapid and fatal illness in many bird populations. Of all infl uenza A viruses circulating in birds, H5N1 is currently of greatest public-health concern because it has caused severe and fatal human infections with mortality ranging from 33% to over 50% since the fi rst known outbreak in Hong Kong in 1997. [bib_ref] Avian infl uenza A (H5N1) infection in humans, Beigel [/bib_ref] The spread of H5N1 in poultry and wild birds in many countries has raised concerns about the increased risk of transmission of H5N1 virus to human beings. Clinicians, public-health offi cers, and policymakers worldwide are faced with uncertainty about the best pharmacological management options of human beings infected with H5N1 virus. In view of its mandate to provide international advice on public-health questions, WHO published interim clinical guidelines for the use of antivirals for H5N1 infection in February, 2004.These interim guidelines were updated in 2005 following an expert consultation [bib_ref] Avian infl uenza A (H5N1) infection in humans, Beigel [/bib_ref] and there has been general international agreement to stockpile antivirals for potential use during an infl uenza pandemic. [bib_ref] Preparing for pandemic infl uenza: should hospitals stockpile oseltamivir?, Cinti [/bib_ref] To provide evidence-based guidelines, [bib_ref] Practice guidelines: a new reality in medicine. I. Recent developments, Woolf [/bib_ref] WHO convened a rapid advice panel in March, 2006, on the pharmacological management of human infection with avian infl uenza A (H5N1) virus. Because of their publichealth implications, the full guidelines were initially made available on the internet by WHO on The guidelines are based on the current situation with sporadic H5N1 human infections and household clusters, and do not apply to a pandemic scenario. # Methods The methods used to develop these guidelines adhered to the suggested principles for developing transparent, evidence-based WHO guidelines. [bib_ref] Improving the use of research evidence in guideline development: introduction, Oxman [/bib_ref] [bib_ref] WHO: strengthening the road to renewal, Horton [/bib_ref] The decision to convene an international rapid advice guidelines panel for the treatment and chemoprophylaxis of H5N1 virus infection was made in January, 2006; review and preparation of the evidence summaries began in ; and the panel met on . ## Group composition The group developing the guidelines included clinicians with experience in treating H5N1 patients, infectious disease experts, infl uenza specialists, basic scientists, public-health offi cers, and methodologists as shown in panel 1. 10 ## Formulation of questions and rating the importance of outcomes Questions were initially identifi ed by clinicians managing patients with H5N1 infections and refi ned by the panel members. An evidence profi le was prepared for each question using the Grading Recommendations Assessment, Development and Evaluation (GRADE) approach. [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] Eight potentially important outcomes were initially identifi ed by two reviewers (MK, ADO). This list was circulated to the panel chair (HJS), WHO staff , and the scientifi c reviewers by email for independent scoring of the relative importance of each outcome. Scores were rated on a scale from 1 to 9: a rating of 7-9 indicated the outcome was critical for a decision or Review recommendation, 4-6 indicated that it was important, and 1-3 indicated that it was not important. Because the relative importance of some outcomes depended on whether a drug was being used for treatment or chemoprophylaxis, these two methods were considered separately. For all ratings, the means of the panel members' ratings established the relative importance of the outcomes. The Cochrane Consumers network was consulted and this generated four responses, but the ratings did not diff er substanially from those of the panel. ## Preparation of evidence profi les A group of independent scientifi c reviewers (panel 1) with expertise in the conduct of systematic reviews of the literature and preparation of evidence summaries compiled the evidence (MK, RB, LS, GEV, ADO). The clinical and public-health questions covered by the guidelines were developed from suggestions by clinicians and public-health offi cers and are listed in panel 2. The underlying considerations included the selection of appropriate clinical outcomes, target populations, and dosing regimens for treatment and chemoprophylaxis. ## Evidence summaries and quality ratings The evidence summaries were based on systematic reviews supplemented with recent randomised trials for the treatment and chemoprophylaxis of any infl uenza virus infection; and case series, animal, and in-vitro studies for the treatment or chemoprophylaxis of H5N1 virus infection. The search strategy is described elsewhere. [bib_ref] Rapid Advice Guidelines on pharmacological management of humans infected with avian infl..., Who [/bib_ref] Original controlled studies not included in the systematic reviews and published before 2005 or after February, 2006, were not included. However, panel members were asked to identify relevant published studies that became available between February, 2006, and the meeting date and these were considered if provided in full to the panel 2 weeks before the meeting. Adverse event data from trials were supplemented by reports from the Uppsala Monitoring Centre and from manufacturers' reports. Evidence summaries were created using the GRADE approach [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] with GRADE profi ler software (v1.12, http:// www.gradeworkingroup.org). Evidence is classifi ed as "high", "moderate", "low", or "very low" quality, based on its methodological characteristics for a specifi c healthcare problem. Assessments of the quality of evidence for each important outcome took into account the study design, limitations of the studies, consistency of the evidence across studies, the directness of the evidence, and the precision of the estimate. Based on the GRADE system the overall quality of evidence is determined by the lowest quality for critical outcomes, and thus the overall quality of evidence was very low for each of the clinical questions. ## Panel meeting One meeting of the guideline panel, chaired by a clinical epidemiologist with experience in respiratory medicine, was held to discuss the results of the evidence review and to develop recommendations. WHO was represented at the group's meeting and provided scientifi c input and guidance. The panel agreed recommendations would be based on a consensus of the panel and that voting would be used if agreement could not be reached. Panel members declared their potential confl icts of interest according to WHO rules in writing before and verbally at the meeting as described elsewhere. [bib_ref] Rapid Advice Guidelines on pharmacological management of humans infected with avian infl..., Who [/bib_ref] [bib_ref] WHO Rapid Advice Guidelines: quick and transparent, Schünemann [/bib_ref] Balance of benefi ts, harms, burden, and cost and developing recommendations Formulating the recommendations included explicit consideration of the quality of evidence, benefi ts, harms, burdens, costs, and values. A high value was placed on antiviral resistance to specifi c drugs for most questions. The panel considered several diff erent patient and exposure groups and assessed the balance of benefi ts and drawbacks of interventions for each group. Recommendations are classifi ed as "strong" or "weak" recommendations, as recommended by the GRADE working group. [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] [bib_ref] An offi cial ATS statement: grading the quality of evidence and strength..., Schünemann [/bib_ref] Agreement on the type and wording of the recommendations was also reached during the panel meeting by consensus. However, two recommendations required voting to decide the strength of the recommendation or whether the recommendation should be given at all. # Results Evidence profi les were prepared for each of the clinical questions shown in panel 2 and are available from the WHO website. [bib_ref] Rapid Advice Guidelines on pharmacological management of humans infected with avian infl..., Who [/bib_ref] disease was considered indirect, because the populations, viruses, and possibly even drug eff ects were diff erent. Therefore, the rating of quality of evidenceie, confi dence in the estimates of eff ect-for all important effi cacy outcomes was lowered by two quality levels. The rate and severity of adverse eff ects, however, were judged to be similar. Sparse data lowered the quality of evidence for some of the other critical outcomes (eg, lower respiratory tract infections) by another level. ## Treatment For treatment of H5N1 infection, the fi nal list of critical outcomes comprised mortality, duration of hospitalisation, incidence of lower respiratory tract complications, antiviral drug resistance existing before treatment, and serious adverse events. The panel placed a low value on the potential of developing resistance during therapy, adverse outcomes, and cost. In judging strength of the recommendations, the panel considered the high case fatality and the paucity of possible pharmacological alternatives in all of the recommendations. ## Panel 2: clinical questions - Should oseltamivir be used for treatment or prophylaxis? - Should zanamivir be used for treatment or prophylaxis? - Should amantadine or rimantadine be used for treatment or prophylaxis? - Should ribavirin be used for treatment? - Should corticosteroids, immunoglobulin, or interferon be used for treatment? - Should broad-spectrum antibiotics be used for the prevention of secondary pneumonia? Direct data came from the most recent case series that described 37 H5N1 patients, of whom 25 were treated with oseltamivir (19 deaths) and 12 patients did not receive oseltamivir (nine deaths). [bib_ref] Avian infl uenza A (H5N1) infection in humans, Beigel [/bib_ref] Treatment regimens diff ered across these patients, beginning between days 4 to 22 of the illness. Three cases of resistance to oseltamivir developing after treatment of H5N1 patients have been published, one of whom received a prophylaxis dose. [bib_ref] Oseltamivir resistance during treatment of infl uenza A (H5N1) infection, De Jong [/bib_ref] [bib_ref] Avian fl u: isolation of drugresistant H5N1 virus, Le [/bib_ref] In fi ve similarly designed studies in otherwise healthy adults with seasonal infl uenza (n=1644), lower respiratory tract complications (including pneumonia) were reduced (relative risk [RR] 0·15, 95% CI 0·03-0·69) but there were only 11 events. [bib_ref] Impact of oseltamivir treatment on infl uenza-related lower respiratory tract complications and..., Kaiser [/bib_ref] This analysis also reported a signifi cant reduction (RR 0·40, 95% CI 0·18-0·88) in all-cause hospitalisations within 30 days of diagnosis in oseltamivir recipients compared with placebo. Rare cases of anaphylaxis and serious skin reactions were reported during post-marketing experience, and data from regulatory trials reported nausea and vomiting as the most frequent adverse event. [bib_ref] Safety and pharmacology of oseltamivir in clinical use, Dutkowski [/bib_ref] Even allowing for the sparse direct evidence, most panel members judged that oseltamivir should be used as treatment and made a strong recommendation (recommendation 1; see below) following a vote (one abstention and one vote for a weak recommendation out of 13 panel members). It was noted that even small relative risk reductions could lead to large net benefi t in mortality. Recommended treatment regimens are shown in the table. There were no clinical data to recommend higher drug doses or more prolonged treatment, but the panel noted that two-fold higher doses did not provide greater antiviral or clinical eff ects in adults with uncomplicated seasonal infl uenza. [bib_ref] Effi cacy and safety of oseltamivir in treatment of acute infl uenza:..., Nicholson [/bib_ref] [bib_ref] Effi cacy and safety of the oral neuraminidase inhibitor oseltamivir in treating..., Treanor [/bib_ref] Should H5N1 patients receive treatment with zanamivir? Direct evidence for the use of zanamivir in H5N1 patients currently does not exist. Zanamivir is active in vitro and in vivo against H5N1 viruses including the oseltamivirresistant H5N1 virus that contains the H274Y mutation. 14 Indirect evidence derives from zanamivir studies for treatment of seasonal infl uenza, but there are too few events in these studies to provide evidence of a benefi t in terms of mortality or duration of hospitalisation. Lower respiratory tract complications were not signifi cantly reduced (odds ratio [OR] 0·83, 95% CI 0·24-2·26) in three trials (n=2299 patients with 46 events) that described this outcome in otherwise healthy adults with seasonal infl uenza. [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] [bib_ref] Zanamivir in the prevention of infl uenza among healthy adults: a randomized..., Monto [/bib_ref] [bib_ref] Zanamivir: a signifi cant reduction in viral load during treatment in military..., Puhakka [/bib_ref] An increased incidence of bronchospasm was reported particularly for patients with airway disease. [bib_ref] From the food and drug administration: revised labeling for zanamivir, Henney [/bib_ref] No information on resistance of H5N1 viruses to zanamivir exists. There was uncertainty about the adequacy of drug delivery with the commercial formulation of inhaled zanamivir in patients with viral pneumonia or possible extra-pulmonary viral spread. Although there is limited evidence of a possible net clinical benefi t of inhaled zanamivir, because H5N1 infection is associated with a high case fatality the panel made a weak recommendation for the use of zanamivir in H5N1 patients (recommendation . ## Should h5n1 patients receive treatment with m2 ion channel inhibitors? No controlled clinical trial has evaluated amantadine or rimantadine for the treatment of H5N1 infection, although there are published case study data for ten patients in whom amantadine was used as treatment. [bib_ref] Avian infl uenza A (H5N1) infection in humans, Beigel [/bib_ref] All four of the patients who received amantadine within 5 days of symptom onset survived, and two of the six patients who were treated after 5 days of illness survived. Six of eight patients who did not receive amantadine survived, but no conclusions can be drawn from these uncontrolled clinical data. There is insuffi cient evidence in the studies on seasonal infl uenza to evaluate the eff ects of amantadine or rimantadine on mortality or duration of hospitalisation. A Cochrane review of M2 inhibitor treatment and chemoprophylaxis reports adverse eff ects (gastrointestinal and central nervous system) with both agents. [bib_ref] Amantadine and rimantadine for infl uenza A in adults, Jeff Erson [/bib_ref] Moderate to severe central nervous system side-eff ects appear to be more frequent with amantadine. [bib_ref] Amantadine and rimantadine for preventing and treating infl uenza A in adults, Jeff Erson [/bib_ref] [bib_ref] A controlled trial of amantadine and rimantadine in the prophylaxis of infl..., Dolin [/bib_ref] The development of antiviral resistance during treatment is a frequent problem with amantadine and rimantadine. Primary (pretreatment) resistance appears to be common in clade 1 H5N1 virus isolated from human beings in Thailand, Vietnam, and Cambodia, [bib_ref] Oseltamivir resistance during treatment of infl uenza A (H5N1) infection, De Jong [/bib_ref] [bib_ref] Avian fl u: isolation of drugresistant H5N1 virus, Le [/bib_ref] and resistance has occurred in some clade 2 H5N1 viruses, particularly those isolated in Indonesia. [bib_ref] Oseltamivir resistance during treatment of infl uenza A (H5N1) infection, De Jong [/bib_ref] [bib_ref] Avian fl u: isolation of drugresistant H5N1 virus, Le [/bib_ref] Resistance has been found in H1N1 viruses from the preamantadine era. [bib_ref] Generation and characterization of recombinant infl uenza A (H1N1) viruses harboring amantadine..., Abed [/bib_ref] Thus, amantadine or rimantadine do not off er greater net clinical benefi t as fi rst-line agents in the treatment of H5N1 infection compared with the neuraminidase inhibitors, and drug resistance is a major limitation. This assessment of possible net benefi t under certain circumstances led to conditional and weak recommendations only when neuraminidase inhibitors are not available (recommendations 4 and 6). The recommendation includes considerations of possible development of drug resistance and the incidence of toxic eff ects. ## Should h5n1 patients receive combination treatment of neuraminidase inhibitors and m2 ion channel inhibitors? Insuffi cient data exist to assess the possible benefi t of combination treatment of neuraminidase inhibitors and M2 ion channel inhibitors on mortality, duration of hospitalisation, complications, or resistance emergence in either seasonal infl uenza or H5N1 infection. Without convincing evidence of clinical benefi t, combination therapy might be used only in the context of prospective Review data collection (recommendation 7) at the same time as doses described for monotherapy . ## Chemoprophylaxis For chemoprophylaxis, the critical outcomes were infl uenza cases, outbreak control, drug resistance, and serious adverse events. The panel developed risk categorisations for exposure to assist countries in prioritising use of antivirals where availability is limited and to avoid chemoprophylaxis of individuals not considered at risk (panel 3). ## Should oseltamivir be used for the chemoprophylaxis of h5n1 infection? Although oseltamivir has been used in the fi eld for chemoprophylaxis of H5N1 infection, there are no controlled human studies. For seasonal infl uenza, two systematic reviews and health technology assessments have reported eff ects of oseltamivir (for 1-6 weeks) as chemoprophylaxis. [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] [bib_ref] Systematic review and economic decision modelling for the prevention and treatment of..., Turner [/bib_ref] Three randomised controlled trials of the eff ect of oral oseltamivir on post-exposure infl uenza incidence found large reductions in laboratoryconfi rmed infl uenza (RR reductions of 50% to 89%). [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] No diff erences in prophylactic effi cacy were found between 75 mg once-daily and 75 mg twice-daily dosing in seasonal infl uenza in adults. Two trials found that oseltamivir was also eff ective for chemoprophylaxis of household contacts of infl uenza cases, when taken for 7-10 days after exposure to an index case. [bib_ref] Management of infl uenza in households: a prospective, randomized comparison of oseltamivir..., Hayden [/bib_ref] [bib_ref] Eff ectiveness of oseltamivir in preventing infl uenza in household contacts: a..., Welliver [/bib_ref] Overall the evidence for pharmacological chemoprophylaxis of H5N1 infection with oseltamivir was rated as very low quality and indirect. However, oseltamivir has shown large eff ects on infl uenza incidence as post-exposure chemoprophylaxis for seasonal infl uenza and is active as pre-exposure prophylaxis in animal models of H5N1 infection. [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] Oselta mivir might eff ectively provide an important reduction in H5N1 virus transmission. The panel, therefore, recom mended that chemoprophylaxis courses should begin as soon as possible after exposure status is known and be used continuously for 7-10 days after the last known exposure (recommendations 8 to 11), but the strength of the recommendation diff ers by risk group. ## Should zanamivir be used for the chemoprophylaxis of h5n1 infection? Two randomised controlled trials investigating the eff ect of inhaled zanamivir on post-exposure infl uenza incidence in healthy adults found large reductions in laboratory-confi rmed seasonal infl uenza (OR 0·19, 95% CI 0·09-0·38). [bib_ref] Systematic review and economic decision modelling for the prevention and treatment of..., Turner [/bib_ref] A similar eff ect was seen in two trials of seasonal chemoprophylaxis. [bib_ref] Systematic review and economic decision modelling for the prevention and treatment of..., Turner [/bib_ref] Trials assessing the combination of both intranasal (not commercially available) and inhaled zanamivir in healthy adults,and in elderly and high-risk adults showed no additive benefi t for any critical outcome. 31 ## Panel 3: risk stratifi cation for the provision of chemoprophylaxis of h5n1 virus infection Antiviral chemoprophylaxis should generally be considered according to the risk stratifi cation described below. It is based on observational data for reported cases of human infection with avian infl uenza A (H5N1) virus and on high quality data from studies of seasonal human infl uenza virus infection. High-risk exposure groups are currently defi ned as: - Household or close family contacts* of a strongly suspected or confi rmed H5N1 patient, because of potential exposure to a common environmental or poultry source as well as exposure to the index case Moderate-risk exposure groups are currently defi ned as: - Individuals with unprotected and very close direct exposure † to sick or dead H5N1 infected animals or to particular poultry that have been implicated directly in human cases - Persons involved in handling sick animals or decontaminating known infected animals or environments, if personal protective equipment might not have been used properly - Health-care personnel in close contact with strongly suspected or confi rmed H5N1 patients, for example during intubation or performing tracheal suctioning, or delivering nebulised drugs, or handling inadequately screened/sealed body fl uids without any, or with insuffi cient, personal protective equipment. This also includes laboratory personnel who might have an unprotected exposure to virus-containing samples ‡ Low-risk exposure groups are currently defi ned as: - Health-care workers not in close contact (distance greater than 1 m or no direct contact with infectious material) with a strongly suspected or confi rmed H5N1 patient - Health-care workers who used appropriate personal protective equipment during exposure to H5N1 patients - Personnel involved in culling non-infected or likely noninfected animal populations to prevent viral spread - Personnel involved in handling sick animals or decontaminating known infected animals or environments, who used proper personal protective equipment In the absence of sustained human-to-human transmission, the general population is currently not considered at risk. *A close contact may be defi ned as an individual sharing a household with, or remaining unprotected while within speaking distance (<1 m) of, or in the care of, a patient with confi rmed or strongly suspected H5N1 infection. †Examples of high-risk exposure based on confi rmed transmission to humans include: unprotected exposure to infected animal products such as consumption of blood from H5N1 infected ducks, preparation of food from infected animals (eg, plucking feathers), or prolonged exposure to infected birds in a confi ned space, such as playing with pets. ‡This defi nition of moderate risk is based on very few cases recognised under these situations to date. Because circumstances could change rapidly, it would be reasonable to consider the moderate and high-risk groups together for prophylaxis decisions. If a particular patient has been implicated in possible human-to-human transmission, then these examples of exposures could be defi ned as high risk. ## Review Although the evidence for chemoprophylaxis of H5N1 infection with zanamivir is of very low quality and indirect, trials in seasonal infl uenza [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] have shown quite large reductions in the incidence of infl uenza cases. On the basis of extrapolation from these trials, zanamivir might provide reductions in cases of H5N1 infection (recommendations 12 to 15). ## Should m2 ion channel inhibitors be used for the chemoprophylaxis of h5n1 infection? No direct data on the use of M2 ion channel inhibitors in human H5N1 virus infection exist. 11 randomised controlled trials investigating the eff ect of oral amantadine on seasonal infl uenza A incidence in healthy adults found large reductions in laboratoryconfi rmed infl uenza A (RR reductions of 61%, 95% CI 35-76). [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] Eff ects on mortality were not reported. High quality evidence for the use of amantadine as postexposure chemoprophylaxis for H5N1 infection in any population does not exist. The eff ect of oral rimantadine in reducing laboratoryconfi rmed cases of infl uenza A in healthy adults in three randomised placebo controlled trials was not signifi cant (RR 0·28, 95% CI 0·08-1·08), but head to head trials against amantadine showed no diff erence between the two active treatments. [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] Overall, amantadine and rimantadine appear not to be of greater net clinical benefi t as a fi rst-line agent for chemoprophylaxis of H5N1 infection compared with the neuraminidase inhibitors. However, based on extrapolation from trials in seasonal infl uenza, amantadine and rimantadine might have net clinical benefi t as a fi rst-line agent for chemoprophylaxis of H5N1 infection when neuraminidase inhibitors are not available and the virus is known or likely to be susceptible (recommendations 17 and 21). ## Recommendations for treatment of patients with confi rmed or strongly suspected infection with avian infl uenza a (h5n1) in a non-pandemic situation ## Recommendation 1 In patients with confi rmed or strongly suspected H5N1 infection, clinicians should administer oseltamivir treatment as soon as possible (strong recommendation, very low quality evidence). ## Remarks This recommendation places a high value on the prevention of death in an illness with a high case fatality. It places relatively low values on adverse reactions, the development of resistance, and costs of treatment. Despite the lack of controlled treatment data for H5N1, this is a strong recommendation, in part, because there is a lack of known eff ective alternative pharmacological interventions at this time. The recommendation applies to adults, including pregnant women and children. Until further information becomes available, the current treatment regimen for H5N1 is as recommended for early treatment of adults, special patient groups (eg, those with renal insuffi ciency), and children with seasonal infl uenza. ## Recommendation 2 In patients with confi rmed or strongly suspected infection with avian infl uenza A (H5N1) virus, clinicians might administer zanamivir (weak recommendation, very low quality evidence). ## Remarks This recommendation places a high value on the prevention of death in an illness with high case fatality. It places a relatively low value on adverse eff ects (including bronchospasm), the potential development of resistance, and costs of treatment. The bioavailability of zanamivir outside of the respiratory tract is lower than that of oseltamivir. Zanamivir might be active against some strains of oseltamivir-resistant H5N1 virus. The recommendation applies to adults, including pregnant women, and children. Use of zanamivir requires that patients are able to use the diskhaler device. Until further information becomes available, the current treatment regimen for H5N1 infection is the same as recommended for early treatment of adults and children with seasonal infl uenza. Although the quality of evidence when considered on a continuum is lower for the use of zanamivir compared with oseltamivir, the overall quality of evidence in the fourcategory grading system is very low for both interventions. ## Recommendation 3 If neuraminidase inhibitors are available, clinicians should not administer amantadine alone as a fi rst-line treatment to patients with confi rmed or strongly suspected human infection with avian infl uenza H5N1 (strong recommendation, very low quality evidence). ## Remarks Although recognising that the illness is severe, this recommendation places a high value on the potential development of resistance and avoiding adverse eff ects. This is a strong recommendation in part, because of the availability of other options for treatment that might be more eff ective. ## Recommendation 4 If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, clinicians might administer amantadine as a fi rst-line treatment to patients with confi rmed or strongly suspected infection with avian infl uenza A (H5N1) virus (weak recommendation, very low quality evidence). ## Remarks This recommendation places a high value on the prevention of death in an illness with a high case fatality. ## Review It places a relatively low value on adverse eff ects and the development of resistance in a situation without alternative pharmacological treatment. Until further infor mation becomes available, the current treatment regimen for (H5N1) infection is the same as recommended for early treatment of adults and children with seasonal infl uenza. The use of amantadine should be guided by knowledge about local resistance patterns, and special consideration of the benefi ts and harms to patients at higher risk for adverse outcomes (eg, pregnant patients). ## Recommendation 5 If neuraminidase inhibitors are available, clinicians should not administer rimantadine alone as a fi rst-line treatment to patients with confi rmed or strongly suspected infection with avian infl uenza A (H5N1) virus (strong recommendation, very low quality evidence). ## Remarks Although recognising that the illness is severe, this recommendation places a high value on the potential development of resistance and avoiding adverse eff ects. This is a strong recommendation in part, because of the availability of other options for treatment that might be more eff ective. ## Recommendation 6 If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, clinicians might administer rimantadine as a fi rstline treatment to patients with confi rmed or strongly suspected infection with avian infl uenza A (H5N1) virus (weak recommendation, very low quality evidence). ## Remarks This recommendation places a high value on the prevention of death in an illness with a high case fatality. It places a relatively low value on adverse eff ects and the development of resistance. The use of rimantadine should be guided by knowledge about local antiviral resistance patterns, and special consideration of the benefi ts, harms, burdens, and cost in patients at higher risk for adverse outcomes. Rimantadine has generally a more favourable side-eff ect profi le than amantadine. ## Recommendation 7 If neuraminidase inhibitors are available and especially if the virus is known or likely to be susceptible, clinicians might administer a combination of neuraminidase inhibitor and M2 inhibitor to patients with confi rmed or strongly suspected infection with avian infl uenza A (H5N1) virus (weak recommendation, very low quality evidence). This should only be done in the context of prospective data collection. ## Remarks This recommendation places a high value on the prevention of death in an illness with a high case fatality. It places a relatively low value on adverse eff ects, the potential development of resistance, and costs associated with therapy. The use of combination therapy should be guided by knowledge about local antiviral resistance patterns under special consideration for the benefi ts and shortcomings in patients at higher risk for adverse outcomes. Combination therapy should only be done if detailed and standardised clinical and virological data collection is in place at the start of therapy (prospective data collection). Clinicians should carefully establish which patients (eg, severely ill patients) could receive combination therapy. ## Recommendations for chemoprophylaxis of avian infl uenza a (h5n1) For antiviral chemoprophylaxis, the panel devised an exposure-based assessment of risk (panel 3) developed from observational data for reported cases of H5N1 infection. These categories of risk were based on expert interpretation of existing evidence of the current situation with sporadic H5N1 infections in the prepandemic era. Decisions to initiate antiviral chemoprophylaxis should generally be guided by this risk stratifi cation and specifi c recommendations for chemoprophylaxis are shown below. ## Recommendation 8 In high-risk exposure groups oseltamivir should be administered as chemoprophylaxis continuing for 7-10 days after the last known exposure (strong recommendation, very low quality evidence). ## Remarks This recommendation places a high value on preventing an illness with high case fatality. It places a relatively low value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be used continuously for 7-10 days after last known exposure. Oseltamivir has been used for as long as 8 weeks for chemoprophylaxis of seasonal infl uenza. The dose of oseltamivir for H5N1 chemoprophylaxis should be that used in seasonal infl uenza. This recommendation also applies to pregnant women in the high-risk exposure group. ## Recommendation 9 In moderate-risk exposure groups oseltamivir might be administered as chemoprophylaxis, continuing for 7-10 days after the last known exposure (weak recommendation, very low quality evidence). ## Remarks This recommendation places a high value on preventing an illness with high case fatality. It places a relatively low Review value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be used continuously for 7-10 days after last known exposure. Oseltamivir has been used for as long as 8 weeks for chemoprophylaxis of seasonal infl uenza. The dose of oseltamivir for H5N1 chemoprophylaxis should be that used in seasonal infl uenza. This recommendation applies to pregnant women in the moderate-risk exposure group. ## Recommendation 10 In low-risk exposure groups oseltamivir should probably not be administered for chemoprophylaxis (weak recommendation, very low quality of evidence). ## Remarks This recommendation places a high value on avoiding adverse eff ects and cost. It places a lower value on preventing the low risk of H5N1 disease. ## Recommendation 11 Pregnant women in the low exposure risk groups should not receive oseltamivir for chemoprophylaxis (strong recommendation, very low quality of evidence). ## Remarks This recommendation places a high value on avoiding possible but uncertain harm associated with oseltamivir chemoprophylaxis during pregnancy. It places a lower value on preventing the low risk of H5N1 disease. ## Recommendation 12 In high-risk exposure groups zanamivir should be administered as chemoprophylaxis continuing for 7-10 days after the last known exposure (strong recommendation, very low quality evidence). ## Remarks This recommendation places a high value on preventing an illness with high case fatality. It places a relatively low value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be used continuously for 7-10 days after last known exposure. The dose of zanamivir should be that used for the chemoprophylaxis of seasonal infl uenza. The bioavailability of zanamivir outside of the respiratory tract is lower than that of oseltamivir. Zanamivir might be active against some strains of oseltamivir-resistant H5N1 virus. Consequently, it might be a reasonable choice for healthcare workers with a high-risk exposure to an oseltamivirtreated H5N1 patient. This recommendation also applies to pregnant women who have high-risk exposure. ## Recommendation 13 In moderate-risk exposure groups, zanamivir might be administered as chemoprophylaxis continuing for 7-10 days after the last known exposure (weak recommendation, very low quality evidence). ## Remarks This recommendation places a high value on preventing an illness with high case fatality. It places a relatively low value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be continued for 7-10 days after the last known exposure. The bioavailability of zanamivir outside of the respiratory tract is lower than that of oseltamivir. Zanamivir might be active against some strains of oseltamivir-resistant H5N1 virus. This recommendation also applies to pregnant women in the moderate-risk exposure group. ## Recommendation 14 In low-risk exposure groups, zanamivir should probably not be administered for chemoprophylaxis (weak recommendation, very low quality of evidence). ## Remarks This recommendation places a high value on avoiding adverse eff ects, possible development of resistance, and cost. It places a lower value on preventing the low risk of H5N1 disease. ## Recommendation 15 Pregnant women in the low-risk exposure group should not receive zanamivir for chemoprophylaxis (strong recommendation, very low quality of evidence). ## Remarks This recommendation places a high value on avoiding possible but uncertain harm associated with zanamivir during pregnancy. It places a lower value on preventing the low risk of H5N1 disease. ## Recommendation 16 If the virus is known or likely to be an M2 inhibitorresistant H5N1 virus, amantadine should not be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus (strong recommendation, very low quality evidence). ## Remarks This recommendation places a high value on avoiding adverse eff ects in a situation when no drug effi cacy would be expected. ## Recommendation 17 If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, amantadine might be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus in high or moderate-risk exposure groups (weak recommendation, very low quality evidence). ## Review ## Remarks This recommendation does not apply to pregnant women, the elderly, people with impaired renal function, and individuals receiving neuropsychiatric medication, or with neuropsychiatric or seizure disorders. It places a high value on preventing an illness with high case fatality. It places a relatively low value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be continued for 7-10 days after the last known exposure. Amantadine has been used for as long as 6 weeks for chemoprophylaxis of seasonal infl uenza A. This recommendation applies when neuraminidase inhibitors are not available or have limited availability. ## Recommendation 18 If neuraminidase inhibitors are not available and even if the virus is known or likely to be susceptible, amantadine should probably not be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus in low-risk exposure groups (weak recommendation, very low quality evidence). ## Remarks This recommendation places a high value on avoiding adverse events, development of resistance, and cost. It places a lower value on preventing the low risk of H5N1 disease. ## Recommendation 19 In pregnant women, the elderly, people with impaired renal function, and individuals receiving neuropsychiatric medication or with neuropsychiatric or seizure disorders amantadine should not be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus (strong recommendation, very low quality of evidence). ## Recommendation 20 If the H5N1 virus is known or likely to be M2 inhibitorresistant, rimantadine should not be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus (strong recommendation, very low quality evidence). ## Remarks This recommendation places a high value on avoiding adverse eff ects in a situation when no drug effi cacy would be expected. ## Recommendation 21 If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, rimantadine might be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus in high or moderate-risk exposure groups (weak recommendation, very low quality evidence). ## Remarks This recommendation places a high value on preventing an illness with high case fatality. It places a relatively low value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be continued for 7-10 days after the last known exposure. Rimantadine has been used for as long as 7 weeks for chemoprophylaxis of seasonal infl uenza A. This recommendation applies when neuraminidase inhibitors are not available or have limited availability. This recommendation does not apply to pregnant women. ## Recommendation 22 If neuraminidase inhibitors are not available and even if the virus is known or likely to be susceptible, rimantadine should probably not be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus in low-risk exposure groups (weak recommendation, very low quality evidence). ## Remarks This recommendation places a high value on avoiding adverse events, development of resistance, and cost. It places a lower value on preventing the low risk of H5N1 disease. ## Recommendation 23 In pregnant women rimantadine should not be administered for chemoprophylaxis of human infection with avian infl uenza A (H5N1) virus (strong recommendation, very low quality of evidence). The recommended dose and duration of treatment and chemoprophylaxis are shown in the table. ## Other recommendations In addition to the recommendations of antiviral use, the panel evaluated other pharmacological management options but made only one detailed recommendation (strong recommendation based on very low quality evidence against the use of ribavirin in pregnancy because of known adverse eff ects). Recommendations relating to antibiotic use are provided on the WHO website. 7 A number of research recommendations including the need for detailed prospective data collection on all H5N1 cases, exploration of combination therapy, and parenteral administration modes were also made. 7 # Discussion This review summarises the clinical recommendations from the WHO Rapid Advice Guidelines on pharmacological management of human beings infected with avian infl uenza A (H5N1) virus. [bib_ref] Rapid Advice Guidelines on pharmacological management of humans infected with avian infl..., Who [/bib_ref] These guidelines were developed by a panel involving relevant stakeholders including clinicians who cared for patients with H5N1 disease. ## Review One of the strengths of these guidelines is the transparent, evidence-based development approach. Another strength is the explicit description of the values that infl uence the recommendations. The main weakness is the very limited amount of direct evidence pertaining to human H5N1 infections, and the lack of data on resource use, which render more detailed cost-eff ectiveness analyses infeasible. Making strong recommendations-implying that they should be followed in most situations-in the face of evidence rated as very low quality demands explanation. First, the disease is deadly for a very high proportion of patients. Second, neuraminidase inhibitors are the most promising pharmacological treatments at present, despite the uncertainty about their effi cacy. However, even a hypothetical and small reduction in the relative risk of death in the order of 10% would require only 15-30 patients to be treated to prevent one H5N1 death. Third, in the absence of important adverse outcomes, the panel judged that the potential benefi ts clearly outweigh the associated harm, burden, and cost during the treatment of relatively few patients worldwide. Overall, these considerations highlight the importance of separating the rating of evidence from determining the strength of recommendations in any guideline process. Prospective clinical research is needed to assess the effi cacy of neuraminidase and M2 ion channel inhibitors, the dose and duration, and the potential role of combination therapy for the treatment of H5N1 patients. The development of resistance to these drugs is a major concern and this aspect requires careful monitoring. The results of such work will help to establish whether these current recommendations will remain applicable. In view of the current uncertainty, clinicians will ask which other measures should be taken to treat H5N1 patients. Early antiviral treatment and supportive care remain key features in the management of H5N1 patients.Policymakers will ask whether the strong recommendation for treatment with oseltamivir leads to stockpiling. Because these recommendations were developed in the context of the current pandemic alert period without sustained human-to-human transmission, extrapolation to stockpiling decisions related to pandemic preparedness is limited, since diff erent criteria for judgment are likely to apply including changing estimates of benefi t and harm. For chemoprophylaxis, resource considerations are of even greater concern. Users of these guidelines should apply the risk stratifi cation presented in these guidelines for allocation of oseltamivir. The panel strongly recommended chemoprophylaxis with neuraminidase inhibitors only for high-risk exposure groups and pointed out that chemoprophylaxis should be seen in the context of standard infection control measures including the proper use of adequate personal protective equipment. Zanamivir is listed as a reasonable alternative in view of the limited availability of oseltamivir and since the evidence base for chemoprophylaxis with zanamivir is stronger than for treatment with this agent. Moreover, in certain situations of limited or no availability of neuraminidase inhibitors clinicians might consider the use of M2 inhibitors (recommendations 4, 6, 17, and 21), although no activity would be expected for resistant viruses. Guideline users must be aware, however, that the risk stratifi cation is based on weak evidence from small observational studies as well as observations of expert clinicians. These guidelines off er many advantages over previous advice because of the structured development process including explicit question formulation and evidence summaries. For example, the Health Evidence Network (HEN) reportprovides comprehensive, evidence-based information and recommendations ranging from vaccination to stockpiling antivirals, but the report does not provide the level of detail that clinicians and other decision makers need for making decisions about the pharmacological management in exposed or infected patients. [bib_ref] Pandemic infl uenza: using evidence on vaccines and antivirals for clinical decisions..., Granados [/bib_ref] The latter was not the mandate of the HEN report on avian infl uenza, and therefore the current document presents important new information. These guidelines were developed with the aim of allowing simple implementation. The greatest barrier to implementation results from the limited availability of the neuraminidase inhibitors and the lack of resistance data. However, the clear description of the guiding principles of the panel's values and preferences will facilitate their application by clinicians treating H5N1 patients. In particular, weak recommendations will require careful evaluation of values and resources before they can be implemented. WHO will begin collecting feedback from user countries on the practicality of these guidelines. Emergence of novel human infl uenza A viral subtypes or a change in the pathogenicity or transmissibility of H5N1 virus strains, availability of new pharmacological agents, or important clinical research data on H5N1 will necessitate an update of these guidelines. In view of the potential for rapid change in the situation in relation to avian infl uenza, WHO will continue to monitor these factors carefully before deciding when to revise or update the recommendations. ## Confl icts of interest This guideline project was funded by WHO. Panel members made the following declarations regarding possible confl icts of interest according to WHO rules for the period 2002-2006. JB declares no personal funding, but is an investigator (through the National Institutes of Health) on trials with Roche and Biocrest; CDM declares funding for trials in unrelated therapeutic area, not in the last 4 years; FGH declares receipt of research grants for trials of antivirals and vaccines from Roche, Abbotts, Biocrest and Merck; HJS declares no personal funding, but research grants and honoraria deposited into research accounts or received by a research group that he belongs to from Pfi zer, Amgen, Roche, and AstraZeneca for development or consulting regarding quality of life instruments for chronic respiratory diseases; NS declares receipt of travel grants from Roche to attend meetings on avian infl uenza; YY delares no personal funding, but is an investigator on trials with Tibotec Pharmaceutical, and has received travel grants from GlaxoSmithKline, Roche, Boehringer, Bristol-Myers Squibb, Pfi zer, Abbot, and Gilead to attend scientifi c meetings. All other members of the panel declare that they have no confl icts of interest. [table] Table: The recommended dose and duration of treatment and chemoprophylaxis for management of human infection of avian infl uenza A (H5N1) virus [/table]	None	http://www.thelancet.com/article/S1473309906706843/pdf	None
571dd384fdf956a594256e056e555972dfa7d078	pubmed	Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: Background☆1☆2☆3☆4☆5☆6☆7☆8	Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: Background☆1☆2☆3☆4☆5☆6☆7☆8 [bib_ref] Clinical syndromes in adults caused by respiratory infection, Evans [/bib_ref] [bib_ref] Diagnosis of acute bronchitis in adults: a national survey of family physicians, Oeffinger [/bib_ref] [bib_ref] Ambulatory Care Visits to Physician Offices, Hospital Outpatient Departments, and Emergency Departments:..., Schappert [/bib_ref] [bib_ref] Current Estimates from the National Health Interview Survey, United States, Adams [/bib_ref] [bib_ref] What's in a name? Public knowledge, attitudes, and experiences with antibiotic use..., Gonzales [/bib_ref] [bib_ref] Ambulatory Care Visits to Physician Offices, Hospital Outpatient Departments, and Emergency Departments:..., Schappert [/bib_ref] [bib_ref] Ambulatory Care Visits to Physician Offices, Hospital Outpatient Departments, and Emergency Departments:..., Schappert [/bib_ref] [bib_ref] National Ambulatory Medical Care Survey: 1992 Summary, Schappert [/bib_ref] [bib_ref] National Ambulatory Medical Care Survey, Schappert [/bib_ref] [bib_ref] National Ambulatory Medical Care Survey: United States, 1975-81 and, Nelson [/bib_ref] [bib_ref] Principles of appropriate antibiotic use for treatment of acute respiratory tract infections..., Gonzales [/bib_ref] ## Evaluation of acute cough illness Principle 1. The evaluation of adults with an acute cough, illness, or a presumptive diagnosis of uncomplicated acute bronchitis should focus on ruling out serious illness, particularly pneumonia. ## A wide variety of infections and inflammatory disorders can lead to an acute cough illness. the american College of Chest Physicians defines acute cough illness, in contrast to chronic or persistent cough, as lasting less than 3 weeks. [bib_ref] Managing cough as a defense mechanism and as a symptom, Irwin [/bib_ref] Acute upper respiratory tract infection accounted for approximately 70% of primary diagnoses in adults presenting for an ambulatory office visit with a chief symptom of cough. 14 Asthma and pneumonia were the next most common diagnoses, assigned to 6% and 5% of patients, respectively. The predominance of cough and accompanying clinical features suggestive of an acute upper respiratory tract infection, such as sore throat or rhinorrhea, is usually used to distinguish bronchitis from other acute upper respiratory tract infections. [bib_ref] Clinical syndromes in adults caused by respiratory infection, Evans [/bib_ref] As one might expect, clinicians are inconsistent in assigning each diagnosis. [bib_ref] Diagnosis of acute bronchitis in adults: a national survey of family physicians, Oeffinger [/bib_ref] For example, some clinicians diagnose acute bronchitis only when productive cough is present; others insist on the presence of purulent sputum. 1.2 Previously undiagnosed asthma is a consideration in patients presenting with an acute cough illness. However, in the setting of acute cough ( <2 to 3 weeks' duration), the diagnosis of asthma is difficult to establish because many patients with acute bronchitis will have transient bronchial hyperresponsiveness (and abnormal results on spirometry). No guidelines have been established for distinguishing transient from chronic bronchial hyperresponsiveness, and long-term follow-up studies suggest that abnormalities on pulmonary function testing in patients with uncomplicated acute bronchitis typically resolve after 2 to 3 weeks, although they may last as long as 2 months. [bib_ref] Pulmonary function tests in acute bronchitis: evidence for reversible airway obstruction, Williamson [/bib_ref] [bib_ref] Reversible airflow limitation in adults with respiratory infection, Melbye [/bib_ref] [bib_ref] Acute bronchitis in the community: clinical features, infective factors, changes in pulmonary..., Boldy [/bib_ref] The diagnosis of cough-variant asthma, in contrast, is generally reserved for patients with persistent cough ( >2 to 3 weeks' duration), lack of wheezing, and (usually) normal results on pulmonary function tests. [bib_ref] Cough variant asthma: a review of the clinical literature, Johnson [/bib_ref] [bib_ref] Cough-variant asthma in children and adults: case reports and review, Pender [/bib_ref] Cough-variant asthma should be suspected in adults with persistent cough that worsens at night or after exposure to cold or exercise; the diagnosis relies on improvement of symptoms with bronchodilator treatment or a positive result on a methacholine challenge test. Therefore, in the absence of severe airflow obstruction, it is prudent to limit evaluation for possible chronic asthma or cough-variant asthma to patients with cough illness lasting longer than 3 weeks. ## 1.3 When evaluating an otherwise healthy adult with uncomplicated acute cough illness, the primary diagnostic objective should be to exclude the presence of pneumonia. Four prospective studies (1984 to 1990) examined the accuracy of patient history and physical examination for diagnosing radiographic pneumonia in adults with acute respiratory illness in outpatient and emergency department settings, and a clinical decision tool to determine the need for radiography was developed. 20-23 A subsequent validation study done by an independent group of investigators found that the specificity (about 67%) but not the sensitivity (about 75%) of these prediction rules for detecting radiographic pneumonia exceeded that of physician judgment (specificity, 58%). [bib_ref] Comparison of physician judgment and decision aids for ordering chest radiographs for..., Emerman [/bib_ref] An evidence-and quality-based review of these studies [bib_ref] Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical..., Metlay [/bib_ref] concluded that the absence of abnormalities in vital signs (heart rate ≥100 beats/min, respiratory rate ≥24 breaths/ min, or oral temperature ≥38°C) and chest examination (focal consolidation-for example, rales, egophony, or fremitus) sufficiently reduces the likelihood of pneumonia to the point where further diagnostic testing is usually not necessary [A]. (Letters in square brackets are evidence ratings. See the background document in this issue 12 for explanation.) Notably absent from all of the rules is the presence of purulent sputum. Many patients and physicians seem to believe that purulent sputum signifies that a bacterial infection is present and antibiotic therapy is indicated. [bib_ref] Colour of respiratory discharge and antibiotic use, Mainous [/bib_ref] [bib_ref] Patient knowledge of upper respiratory infections: implications for antibiotic expectations and unnecessary..., Mainous [/bib_ref] [bib_ref] The relation between purulent manifestations and antibiotic treatment of upper respiratory tract..., Gonzales [/bib_ref] Purulence primarily occurs when inflammatory cells or sloughed mucosal epithelial cells are present, and it can result from either viral or bacterial infection. [bib_ref] Green sputum, Robertson [/bib_ref] [bib_ref] Adult bacterial nasopharyngitis: a clinical entity?, Heald [/bib_ref] 1.4 Specific patient and epidemiologic circumstances should be taken into account before this recommendation is applied. Although all of the studies on which this recommendation is based included elderly persons and patients with chronic lung disease, subgroup analyses serology, or polymerase chain reaction. Specific viruses most frequently associated with acute bronchitis include those that produce primarily lower respiratory tract disease (influenza B, influenza A, parainfluenza 3, and respiratory syncytial virus), as well as viruses that more commonly produce upper respiratory tract symptoms (corona virus, adenovirus, and rhinoviruses). Unless bacterial superinfection is present (defined as pneumonia with an infiltrate on chest radiography), antibiotic treatment does not affect the clinical course of viral respiratory infections. ## 2.2 To date, only Bordetella pertussis, Mycoplasma pneumoniae, and C. pneumoniae (TWAR) have been established as nonviral causes of uncomplicated acute bronchitis in adults. As a group, these agents are associated with 5% to 10% of all cases of uncomplicated acute bronchitis in adults. They are recovered more frequently (10% to 20% of cases) in studies of adults with chronic or persistent cough. [bib_ref] Pertussis infection in adults with persistent cough, Wright [/bib_ref] [bib_ref] Prevalence of positive serology for acute Chlamydia pneumoniae infection in emergency department..., Wright [/bib_ref] [bib_ref] Prevalence and incidence of adult pertussis in an urban population, Nennig [/bib_ref] The diagnoses in these studies are frequently based on serologic conversion, an event that can also occur in asymptomatic persons and may not be related to the clinical illness in question. More recent studies using polymerase chain reaction have reported similar frequencies of recovery of these agents in adults with acute bronchitis. No evidence indicates that Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis produces acute bronchitis in adults without underlying lung disease. Studies reporting an association between these encapsulated bacteria and acute bronchitis have failed to distinguish between colonization and acute infection. Since Gram stain and culture of sputum do not reliably detect M. pneumoniae, C. pneumoniae, or B. pertussis, these tests are not recommended in the evaluation of patients with uncomplicated acute bronchitis. ## Treatment of uncomplicated acute bronchitis ## Principle 2. routine antibiotic treatment of uncomplicated acute bronchitis is not recommended, regardless of duration of cough [a]. ## 3.1 On the basis of the microbiology of acute bronchitis, it should not be surprising that randomized, placebocontrolled trials have failed to support a role for antibiotic treatment of uncomplicated acute bronchitis . [bib_ref] Randomised controlled trial of antibiotics in patients with cough and purulent sputum, Stott [/bib_ref] [bib_ref] Effectiveness of erythromycin in the treatment of acute bronchitis, King [/bib_ref] [bib_ref] A randomized, controlled trial of doxycycline in the treatment of acute bronchitis, Williamson [/bib_ref] [bib_ref] Effects of doxycycline in patients with acute cough and purulent sputum: a..., Verheij [/bib_ref] [bib_ref] Erythromycin in the treatment of acute bronchitis in a community practice, Brickfield [/bib_ref] [bib_ref] The treatment of acute bronchitis with trimethoprim and sulfamethoxazole, Franks [/bib_ref] [bib_ref] A placebo-controlled, double-blind trial of erythromycin in adults with acute bronchitis, Dunlay [/bib_ref] [bib_ref] Double-blind trial of early demethylchlortetracycline in minor respiratory illness in general practice, Howie [/bib_ref] [bib_ref] Doxycycline in acute bronchitis: a randomized doubleblind trial, Scherl [/bib_ref] By the mid-1990s, published reviews of randomized, placebo-controlled trials 51,52 had concluded that routine antibiotic treatment of acute bronchitis does not have a consistent impact on duration or severity of illness or on potential complications, such as development of pneumonia. Consistent with these conclusions, the U.S. Food and Drug Administration removed uncomplicated acute bronchitis (or "secondary bacterial infections of acute bronchitis") as an indication for randomized, controlled trials of antimicrobial therapy in 1998. Since then, three were not performed; a high index of suspicion for pneumonia therefore remains warranted in these patient groups, given the increased likelihood for atypical disease presentation. [bib_ref] Influence of age on symptoms at presentation in patients with community-acquired pneumonia, Metlay [/bib_ref] [bib_ref] Risk factors for 30-day mortality in elderly patients with lower respiratory tract..., Houston [/bib_ref] Conversely, even when vital sign abnormalities are detected in the absence of chest auscultatory findings, chest radiography may not be indicated in patients with other clinical features consistent with a viral illness (such as influenza, parainfluenza, or respiratory syncytial virus) or features that are inconsistent with pneumonia (such as streptococcal pharyngitis or chronic sinusitis). Cough lasting longer than 3 weeks exceeds the case definition for acute bronchitis; such patients should be considered to have persistent cough or chronic cough illness. Irwin and colleagues have developed a welldefined approach to the adult with persistent cough [D]. [bib_ref] Managing cough as a defense mechanism and as a symptom, Irwin [/bib_ref] ## Microbiology of uncomplicated acute bronchitis The vast majority of cases ( ≥90%) of uncomplicated acute bronchitis have a nonbacterial cause. We reviewed the MEDLINE database (1966 to October 1999) by using Medical Subject Headings and keyword searches that included microbiology and bronchitis and analyzed references from review articles and chapters in textbooks on infectious disease to identify studies of the microbiology of acute bronchitis. We excluded studies involving patients with chronic lung disease, malignant conditions, or immunosuppression, as well as those conducted during confirmed outbreaks of a pathogen (for example, a Chlamydia pneumoniae outbreak at a single university). We limited our selection to English-language studies of consecutive, unselected adolescents or adults enrolled in nonreferral, ambulatory settings. In the mid-1980s, it was established that a specific species of C. pneumoniae (TWAR) could cause uncomplicated acute bronchitis. Therefore, estimates of the proportion of cases with a potential bacterial cause are limited to studies published since this discovery. [bib_ref] A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections, Grayston [/bib_ref] [bib_ref] Evidence that Chlamydia pneumoniae causes pneumonia and bronchitis, Grayston [/bib_ref] 2.1 As in community-acquired pneumonia, microbiological study of uncomplicated acute bronchitis identifies a pathogen in the minority of cases, ranging from 16% to 40%. [bib_ref] Acute bronchitis in the community: clinical features, infective factors, changes in pulmonary..., Boldy [/bib_ref] [bib_ref] Prospective study of aetiology and outcome of adult lower-respiratory-tract infections in the..., Macfarlane [/bib_ref] [bib_ref] Acute viral infections of upper respiratory tract in elderly people living in..., Nicholson [/bib_ref] [bib_ref] Acute bronchitis in adults. How close do we come to its aetiology..., Jonsson [/bib_ref] This variability is most likely due to the epidemic nature of agents that produce uncomplicated acute bronchitis and limitations in viral and bacterial identification techniques. Noninfectious causes of uncomplicated acute bronchitis, such as occult asthma exacerbation or toxic fume inhalation, should also be considered, although the prevalence of these conditions in adults with acute cough illness has not been well studied. In epidemiologic studies, respiratory viruses, particularly influenza, appear to cause the large majority of cases of uncomplicated acute bronchitis according to culture, antibody [bib_ref] A placebo-controlled, double-blind trial of erythromycin in adults with acute bronchitis, Dunlay [/bib_ref] productive cough of any times daily for 10 days group (n = 24) vs. 1.8 in antibiotic group (n = 24) (P < .01); duration proportion of patients with congestion at day 10, 75% vs. 38%; proportion of patients taking cough or cold medicines at day 10, 38% vs. 3% (P < .05); no difference between groups for day cough, night cough, productive cough, sore throat, feeling poor or unable to work or carry out daily routine at day 10; no differences among smokers Scherl et al, Kentucky Persons >12 years of age with Doxycycline, 100 mg twice Mean (± SD) duration of cough, 10.8 ± 1.2 days in placebo 1987 [bib_ref] Doxycycline in acute bronchitis: a randomized doubleblind trial, Scherl [/bib_ref] self-described cough daily on day 1, then 100 mg/d group vs. 9.4 ± 1.5 days in antibiotic group; mean duration producing purulent sputum for 7 days of sputum, [bib_ref] National Ambulatory Medical Care Survey, Schappert [/bib_ref] to decrease shedding of the pathogen and spread of disease, since antibiotic treatment does not appear to hasten resolution of symptoms if it is initiated 7 to 10 days after onset of illness. [bib_ref] Factors influencing the spread of pertussis in households, Wirsing Von Konig [/bib_ref] [bib_ref] Prevention of secondary transmission of pertussis in households with early use of..., Sprauer [/bib_ref] [bib_ref] Erythromycin in the treatment of pertussis: a study of bacteriologic and clinical..., Bergquist [/bib_ref] Because of the public health implications of pertussis, antibiotic treatment of suspected pertussis should always be accompanied by a diagnostic test. Diagnostic tests for pertussis are not routinely available; one could inquire at local or state health departments or academic medical centers for further assistance. ## Influenza Because influenza is the most common pathogen isolated in patients with uncomplicated acute bronchitis, it is worthwhile discussing recent advances in diagnosis and treatment of influenza. Although amantadine and rimantidine have been available for more than 30 years, 60,61 the recent development and direct-to-consumer marketing of neuraminidase inhibitor therapy has generated immense public and physician interest in pharmacologic treatment of influenza.A Cochrane Collaborationsponsored systematic review of neuraminidase inhibitors for the treatment of influenza in healthy adults was recently performed. [bib_ref] Neuraminidase inhibitors for preventing and treating influenza in healthy adults, Jefferson [/bib_ref] Inhaled (zanamivir) and oral (oseltamivir) formulations of neuraminidase inhibitors have demonstrated some efficacy in reducing illness duration [bib_ref] Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of..., Hayden [/bib_ref] [bib_ref] Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of..., Monto [/bib_ref] in adults with naturally acquired influenza A and B if treatment begins within 48 hours of symptom onset. The major clinical advantage of neuraminidase inhibitor therapy relates to activity against influenza A and B; amantadine and rimantidine, in contrast, have activity only against influenza A. The relative proportion of cases due to each type of influenza varies substantially from year to year. In the 1999-2000 influenza season, 99% of influenza cases from surveillance facilities in the United States were due to influenza A. All drugs appear to have a similar impact on influenzal illness: about 1 less day of illness, and about a half-day quicker return to normal activities. On the basis of the Cochrane Collaboration's calculations, adverse effects are modestly more frequent with rimantadine (in about 32% of patients; most cases are related to the central nervous system) than oral neuraminidase inhibitor (in about 24% of patients; most cases are gastrointestinal) or placebo (in about 19% of patients). Neuraminadase inhibitors are likely to be much more costly to health plans and patients than rimantadine, although formularies are likely to vary considerably. For any of these antiviral agents to be effective, influenza must be diagnosed and therapy initiated within 48 hours (preferably <30 hours) of symptom onset. During documented influenza outbreaks, the positive predictive value of clinical diagnosis based on clinician judgment appears meta-analyses have also been published. [bib_ref] Quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for..., Fahey [/bib_ref] [bib_ref] Are antibiotics effective treatment for acute bronchitis? A meta-analysis, Smucny [/bib_ref] [bib_ref] Antibiotics in acute bronchitis: a meta-analysis, Bent [/bib_ref] These meta-analyses are plagued by lack of uniformity in outcome measures used in each of the randomized, placebocontrolled trials and by inclusion of poor-quality studies. In one of the meta-analyses, [bib_ref] Are antibiotics effective treatment for acute bronchitis? A meta-analysis, Smucny [/bib_ref] no statistically significant benefit of antibiotic treatment was observed when cough duration was treated as a continuous variable. However, when cough was treated as a dichotomous variable (proportion of patients with cough at a follow-up visit), the investigators reported a significant difference (relative risk, 0.69 [95% CI, 0.49 to 0.98]). Another meta-analysis [bib_ref] Antibiotics in acute bronchitis: a meta-analysis, Bent [/bib_ref] transformed heterogenous outcome measures to calculate a "standardized effect size" and reported that antibiotic therapy decreases the duration of cough and sputum by 0.5 day (over a 7-day period). The third meta-analysis 53 excluded three trials that were included in the previous meta-analyses on the basis of poor quality 45 or lack of information on loss to follow-up [bib_ref] Effectiveness of erythromycin in the treatment of acute bronchitis, King [/bib_ref] [bib_ref] Erythromycin in the treatment of acute bronchitis in a community practice, Brickfield [/bib_ref] ; those investigators reported no benefit of antibiotic treatment on cough duration. All three meta-analyses reported no impact of antibiotic treatment on duration of illness, limitation of activity, or loss of work, and all concluded that routine antibiotic treatment of acute bronchitis in adults is not justified. Identification of cases of bacterial or mycoplasmaassociated bronchitis might seem to be a reasonable strategy for selecting patients in whom antimicrobial therapy would be beneficial. However, studies to date have been unable to distinguish bacterial bronchitis from viral bronchitis on clinical grounds. Furthermore, the single randomized, placebo-controlled trial in which subgroup analysis of patients with probable mycoplasma infection (based on a single rapid serology test) was done did not find a consistent benefit of antibiotic treatment. However, the sample was fairly small (42 and 49 patients in the placebo and treatment groups, respectively). [bib_ref] Effectiveness of erythromycin in the treatment of acute bronchitis, King [/bib_ref] 3.2 The one uncommon circumstance for which evidence supports antibiotic treatment of patients with uncomplicated acute bronchitis is suspicion of pertussis. Selected studies have recovered pertussis in up to 10% to 20% of patients with cough lasting longer than 2 to 3 weeks. [bib_ref] Pertussis infection in adults with persistent cough, Wright [/bib_ref] [bib_ref] Prevalence of positive serology for acute Chlamydia pneumoniae infection in emergency department..., Wright [/bib_ref] Unfortunately, no clinical features allow clinicians to distinguish adults with persistent cough due to pertussis, primarily because pertussis in adults with previous immunity does not lead to the classic features of whooping cough seen in patients (usually children) with primary infection. [bib_ref] Pertussis in the 1990s: diagnosis, treatment, and prevention, Pasternack [/bib_ref] Therefore, clinicians should limit suspicion and treatment of adult pertussis to adults with a high probability of exposure to pertussis-for example, during documented outbreaks. Antimicrobial therapy for suspected pertussis in adults is recommended primarily to be good and to perform as well as available rapid diagnostic tests for influenza; reported sensitivities of these tests range from 63% to 81%. [bib_ref] Performance of virus isolation and Directigen Flu A to detect influenza A..., Kaiser [/bib_ref] [bib_ref] Optical immunoassay test for rapid detection of influenza A and B viruses:..., Mitamura [/bib_ref] [bib_ref] Comparison of a new neuraminidase detection assay with an enzyme immunoassay, immunofluorescence,..., Noyola [/bib_ref] Reports from the Management of Influenza in the Southern Hemisphere Trialists study, which evaluated neuraminidase treatment of community-acquired influenza, suggest that clinical diagnosis or suspicion of influenza is correct approximately 70% of the time during documented influenza outbreaks. 66 Although this study was not adequately designed to evaluate the true sensitivity or specificity of clinical diagnosis, which would have required measuring the rate of influenza infection in patients in whom it was not suspected, the findings probably accurately reflect clinical practice. Accurate clinical diagnosis of influenza outside the annual outbreak period is more difficult. As a result, diagnostic testing for influenza outside outbreaks, when suspected, may be considered for epidemiologic purposes. ## Symptomatic therapy What symptomatic therapy should we offer patients seeking care for uncomplicated acute bronchitis? The first task is to identify which symptoms are most bothersome to the patient. In most cases, cough is the major symptom for which patients seek relief. Randomized, controlled trials have demonstrated a consistent benefit of therapy with albuterol versus placebo for uncomplicated acute bronchitis in reducing the duration and severity of cough (in one study, the "placebo" was erythromycin). [bib_ref] A comparison of albuterol and erythromycin for the treatment of acute bronchitis, Hueston [/bib_ref] [bib_ref] Albuterol delivered by metered-dose inhaler to treat acute bronchitis, Hueston [/bib_ref] [bib_ref] Symptomatic effect of inhaled fenoterol in acute bronchitis: a placebo-controlled double-blind study, Melbye [/bib_ref] Approximately 50% fewer patients report the presence of cough after 7 days of treatment. The efficacy of bronchodilators in patients with uncomplicated acute bronchitis makes sense given the frequent finding of bronchial hyperresponsiveness in these patients. The randomized, placebo-controlled trials of albuterol have reported mixed results in identification of subsets of patients most likely to benefit from treatment; therefore, treatment should be individualized in patients without clinical evidence of bronchial hyperresponsiveness (such as wheezing or bothersome cough). [bib_ref] Symptomatic effect of inhaled fenoterol in acute bronchitis: a placebo-controlled double-blind study, Melbye [/bib_ref] 3.5 The literature evaluating the efficacy of antitussive treatments is problematic because treatment benefit appears to depend on the cause of the cough illness. Acute or early cough due to colds or other viral upper respiratory tract infections does not appear to respond to dextromethorphan or codeine, whereas chronic cough (duration >3 weeks), cough associated with underlying lung disease, or experimentally induced cough seems to respond to these two agents. In patients with uncomplicated acute bronchitis (in whom the average duration of cough is 2 to 3 weeks), preparations containing dex-tromethorphan or codeine probably have a modest effect on severity and duration of cough. Although evidence from randomized, placebo-controlled trials is lacking, other low-cost and low-risk actions, such as elimination of environmental cough triggers (for example, dust and dander) and vaporized air treatments (particularly in low-humidity environments, such as high altitude) are also reasonable options, given the underlying pathophysiology of uncomplicated acute bronchitis. Principle 3. Patient satisfaction with care for acute bronchitis depends most on physician-patient communication rather than whether an antibiotic is prescribed . 4.0 Clinicians caring for patients with uncomplicated acute bronchitis should be encouraged to discuss the lack of benefit of antibiotic treatment for uncomplicated acute bronchitis and stop prescribing antibiotics for this condition as a standard of practice. Patients frequently expect to receive antibiotics for uncomplicated acute bronchitis [bib_ref] What's in a name? Public knowledge, attitudes, and experiences with antibiotic use..., Gonzales [/bib_ref] [bib_ref] Antibiotics and respiratory infections: are patients more satisfied when expectations are met?, Hamm [/bib_ref] ; however, this expectation appears to derive from previous receipt of antibiotics for uncomplicated acute bronchitis. [bib_ref] What's in a name? Public knowledge, attitudes, and experiences with antibiotic use..., Gonzales [/bib_ref] Mounting evidence indicates that patient satisfaction with the office encounter for uncomplicated acute bronchitis does not depend on receipt of antibiotic therapy but instead is related to the patient-centered quality of the encounter (for example, believing that the provider spent enough time and explained the illness and treatment plan). [bib_ref] Antibiotics and respiratory infections: are patients more satisfied when expectations are met?, Hamm [/bib_ref] A combined patient and physician educational intervention that reduced antibiotic use for acute bronchitis did not lead to greater utilization of services (such as nonantibiotic prescriptions or return visits), 74 greater patient dissatisfaction, or longer duration of illness. [bib_ref] Reducing antibiotic use in ambulatory practice: impact on patient-centered outcomes, Gonzales [/bib_ref] A recommended outline for discussing the management of acute bronchitis with patients includes the following steps. 1. Provide realistic expectations for the duration of the patient' s cough, which will typically last 10 to 14 days after the office visit. 2. Refer to the cough illness as a "chest cold" rather than bronchitis. [bib_ref] What's in a name? Public knowledge, attitudes, and experiences with antibiotic use..., Gonzales [/bib_ref] In a study of members of a commercial managed care organization' s health plan, use of the term "chest cold" was associated with much less frequent belief that antibiotic therapy was necessary to get better. 3. Personalize the risk of unnecessary antibiotic use. Inform patients that previous antibiotic use increases their likelihood of carriage of and infection with antibioticresistant bacteria, that antibiotics commonly have side effects (gastrointestinal symptoms or alterations in taste, for example), and that rare but serious adverse reactions may occur, such as anaphylaxis. 4. Explain to patients why we need to be more selective in treating only those conditions for which a major clinical benefit of antibiotics has been proven-tell them that the current epidemic in antibiotic resistance among community bacterial pathogens is a major public health concern. External review has included feedback from the Centers for Disease Control and Prevention; the American College of Physicians-American Society of Internal Medicine Clinical Efficacy Assessment Subcommittee; and representatives of the American Academy of Family Physicians, the American College of Emergency Physicians, and the Infectious Diseases Society of America. [fig] [: Gonzales R, Bartlett JG, Besser RE, Cooper RJ, Hickner JM, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background. Ann Emerg Med. June 2001;37:720-727.] [/fig] [table] Table: Randomized, placebo-controlled trials of antibiotic treatment in adults with acute bronchitis. * [/table]	None	http://www.annemergmed.com/article/S0196064401700911/pdf	Abstract The following principles of appropriate antibiotic use for adults with acute bronchitis apply to immunocompetent adults without complicating comorbid conditions, such as chronic lung or heart disease. 1. The evaluation of adults with an acute cough illness or a presumptive diagnosis of uncomplicated acute bronchitis should focus on ruling out serious illness, particularly pneumonia. In healthy, nonelderly adults, pneumonia is uncommon in the absence of vital sign abnormalities or asymmetrical lung sounds, and chest radiography is usually not indicated. In patients with cough lasting 3 weeks or longer, chest radiography may be warranted in the absence of other known causes. 2. Routine antibiotic treatment of uncomplicated acute bronchitis is not recommended, regardless of duration of cough. If pertussis infection is suspected (an unusual circumstance), a diagnostic test should be performed and antimicrobial therapy initiated. 3. Patient satisfaction with care for acute bronchitis depends most on physician–patient communication rather than on antibiotic treatment. [Gonzales R, Bartlett JG, Besser RE, Cooper RJ, Hickner JM, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background. Ann Emerg Med. June 2001;37:720-727.]
16b45ab6590d5321c7df28b62988a71f1cb3c95b	pubmed	Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines	Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines [table] Table S1: Studies using TMS in patients with implanted stimulating/recording electrodes. [/table] [table] Table S2: Randomized controlled multicenter trials investigating safety of rTMS in psychiatric disorders.Legend: MDD=major depressive disorder, # in the majority of studies sham TMS, serious adverse events (SAE), DLPFC = dorsolateral prefrontal cortex, NR = not reported. [/table] [table] Table S3: Safety table for QPS parameters. [/table] [table] Table S4: QPS studies.Total pulse number duration side effectsNo Table S5. TBS studies. [/table]	None	None	None
b86612d88eaf1a4fbcaf23ee0a9df2985240ce61	pubmed	ACVIM consensus statement: Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats	ACVIM consensus statement: Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats Consensus Statements of the American College of Veterinary Internal Medicine (ACVIM) provide the veterinary community with up-to-date information on the pathophysiology, diagnosis, and treatment of clinically important animal diseases. The ACVIM Board of Regents oversees selection of relevant topics, identification of panel members with the expertise to draft the statements, and other aspects of assuring the integrity of the process. The statements are derived from evidence-based medicine whenever possible and the panel offers interpretive comments when such evidence is inadequate or contradictory. A draft is prepared by the panel, followed by solicitation of input by the ACVIM membership which may be incorporated into the statement. It is then submitted to the Journal of Veterinary Internal Medicine, where it is edited before publication. The authors are solely responsible for the content of the statements. based on the latest available research, will assist practitioners in the development of a rational approach to the diagnosis and treatment of hypertension in companion animals. ## \| bp measurement Diagnosing and treating hypertension in the clinical patient necessitate accurate measurement of the patient's BP. Direct BP determination entails catheterization of a suitable artery and assessing arterial pressure using an electronic transducer. [bib_ref] Doppler ultrasonographic, oscillometric sphygmomanometric, and photoplethysmographic techniques for noninvasive blood pressure measurement..., Binns [/bib_ref] [bib_ref] New implanted chronic catheter device for determining blood pressure and cardiac output..., Garner [/bib_ref] [bib_ref] A method of measuring direct arterial blood pressure, Scully [/bib_ref] Although this is the gold standard, it is not practical for hypertension screening and treatment. Clinically, noninvasive indirect estimations of BP such as Doppler and oscillometric devices are commonly used. [bib_ref] Hypertension in cats with chronic renal failure or hyperthyroidism, Kobayashi [/bib_ref] [bib_ref] Comparative diagnostic test characteristics of oscillometric and Doppler ultrasonographic methods in the..., Stepien [/bib_ref] [bib_ref] Blood pressures obtained by indirect measurement in conscious dogs, Coulter [/bib_ref] Ideally, BP should be measured using devices that have been validated in the species of interest and under the circumstances in which the patient is being tested. Standards for the validation of indirect BP measuring devices in people are well established, 7 but no device has met these criteria in conscious dogs or cats. For this reason, a set of standards for validating indirect BP devices in awake dogs and cats has been proposed and accepted. [bib_ref] Guidelines for the identification, evaluation, and management of systemic hypertension in dogs..., Brown [/bib_ref] Although many studies have attempted to validate indirect BP devices in anesthetized patients, only a few have been performed in conscious animals. [bib_ref] Evaluation of oscillometric and Doppler ultrasonic devices for blood pressure measurements in..., Vachon [/bib_ref] [bib_ref] Comparison of high-definition oscillometry-a non-invasive technology for arterial blood pressure measurement-with a..., Martel [/bib_ref] [bib_ref] Comparison of ultrasonic Doppler flow monitor, oscillometric, and direct arterial blood pressure..., Bosiack [/bib_ref] [bib_ref] Evaluation of oscillometric and Doppler ultrasonic methods of indirect blood pressure estimation..., Haberman [/bib_ref] In the devices studied to date in awake animals, either a different validation standard was used [bib_ref] Evaluation of oscillometric and Doppler ultrasonic devices for blood pressure measurements in..., Vachon [/bib_ref] [bib_ref] Comparison of ultrasonic Doppler flow monitor, oscillometric, and direct arterial blood pressure..., Bosiack [/bib_ref] [bib_ref] Evaluation of oscillometric and Doppler ultrasonic methods of indirect blood pressure estimation..., Haberman [/bib_ref] or the device failed to meet the previously established criteria. [bib_ref] Comparison of high-definition oscillometry-a non-invasive technology for arterial blood pressure measurement-with a..., Martel [/bib_ref] Until devices that can meet the guidelines for measuring BP in conscious animals have been validated, it is our recommendation that currently available devices be used with a degree of caution. Because estimates of BP obtained using an indirect device can only be interpreted in light of results of appropriate validation testing in conscious animals, devices that have not been subjected to appropriate testing in conscious animals should not be used. Nonetheless, studies that have relied upon indirect estimation of BP using available devices have identified adverse effects of increased BP and benefits of intervention, indicating that some of these devices can provide clinically useful information. [bib_ref] Effect of control of systolic blood pressure on survival in cats with..., Jepson [/bib_ref] [bib_ref] Association between initial systolic blood pressure and risk of developing a uremic..., Jacob [/bib_ref] Therefore, we recommend that, once commercially available, only devices that meet the established validation standards in conscious cats and dogs be used. To obtain reliable results in the measurement of BP, it is important to follow a standard protocol . The individual taking the measurements should be skilled and experienced in the handling of animals and the equipment. Studies have shown that operator experience can have a significant impact on BP measurements. [bib_ref] Doppler ultrasonographic, oscillometric sphygmomanometric, and photoplethysmographic techniques for noninvasive blood pressure measurement..., Binns [/bib_ref] [bib_ref] Influence of the observer's level of experience on systolic and diastolic arterial..., Gouni [/bib_ref] Often the most skilled individual is a well-trained technician and not a veterinarian. Anxiety-or excitement-induced situational hypertension can be marked, [bib_ref] Evaluation of the white-coat effect in cats, Belew [/bib_ref] [bib_ref] White-coat effect on systemic blood pressure in retired racing greyhounds, Marino [/bib_ref] but can be minimized by measuring BP in a quiet area, away from other animals, before other procedures and only after the patients have been acclimated to their surroundings for 5-10 minutes. Whenever possible, the owner should be present and restraint should be kept to a minimum. The selection of a correctly sized cuff is critical in obtaining accurate measurements. [bib_ref] Doppler ultrasonographic, oscillometric sphygmomanometric, and photoplethysmographic techniques for noninvasive blood pressure measurement..., Binns [/bib_ref] Some veterinary-specific oscillometric devices have specially designed cuffs and these should always be used. When using Doppler and many oscillometric units, the width of the cuff should be 30%-40% of the circumference of the extremity at the site of cuff placement. The first measurement should be discarded and the average of 5-7 consecutive consistent indirect measurements should be obtained. If there is substantial variation, the readings should be discarded and the process repeated. In some patients, BP trends downward as the measurement process continues. In these animals, measurements should continue until a plateau is reached and then 5-7 consecutive consistent values should be recorded. Conversely in some patients, measurement of systolic blood pressure (SBP) may result in a progressive increase in readings. When this occurs, results must be interpreted in the clinical context of the individual patient. The animal's position and attitude, cuff size and site, cuff site circumference (cm), and name of the individual making the measurements should be carefully recorded and used for future pressure measurements. Individual patients may be noise-sensitive, but, in general, use of headphones by the measurer does not result in lower BP measurements. ## \| normal values for canine and feline bp Various studies have reported values for BP in normal dogs and cats. These values vary, reflecting differences in subject Protocol for accurate blood pressure (BP) measurement - Calibration of the BP device should be tested semiannually either by the user, when self-test modes are included in the device, or by the manufacturer. - The procedure must be standardized. - The environment should be isolated, quiet, and away from other animals. Generally, the owner should be present. The patient should not be sedated and should be allowed to acclimate to the measurement room for 5-10 minutes before BP measurement is attempted. - The animal should be gently restrained in a comfortable position, ideally in ventral or lateral recumbency to limit the vertical distance from the heart base to the cuff (if more than 10 cm, a correction factor of +0.8 mm Hg/cm below or above the heart base can be applied). - The cuff width should be approximately 30%-40% of circumference of the cuff site. - The cuff may be placed on a limb or the tail, taking into account animal conformation and tolerance, and user preference. - The same individual should perform all BP measurements following a standard protocol. Training of this individual is essential. - The measurements should be taken only when the patient is calm and motionless. - The first measurement should be discarded. A total of 5-7 consecutive consistent values should be recorded. In some patients, measured BP trends downward as the process continues. In these animals, measurements should continue until the decrease plateaus and then 5-7 consecutive consistent values should be recorded. evident in this species. [bib_ref] Epidemiological study of blood pressure in domestic cats, Bodey [/bib_ref] [bib_ref] Non-invasive blood pressure measurements in cats: clinical significance of hypertension associated with..., Mishina [/bib_ref] In a recent large study, males had higher BP than females and neutered cats had higher BP than intact animals, but the differences were very small. [bib_ref] Blood pressure measurements in 780 apparently healthy cats, Payne [/bib_ref] There are substantial interbreed differences in canine BP, most notably for hounds (eg, Greyhounds, Deerhounds) in which BP is higher than in mongrels 31 by approximately 10-20 mm Hg. [bib_ref] Epidemiological study of blood pressure in domestic dogs, Bodey [/bib_ref] [bib_ref] Arterial blood pressure, proteinuria, and renal histopathology in clinically healthy retired racing..., Surman [/bib_ref] [bib_ref] Comparative observations of the hearts of mongrel and greyhound dogs, Schneider [/bib_ref] [bib_ref] Comparison of arterial hemodynamics in the mongrel dog and the racing greyhound, Cox [/bib_ref] The BP among other breeds varies by 7-10 mm Hg 20,33 perhaps based on temperament. [bib_ref] Effect of long-term adaptation on indirect measurements of systolic blood pressure in..., Schellenberg [/bib_ref] [bib_ref] Comparison of Doppler ultrasonography and high-definition oscillometry for blood pressure measurements in..., Chetboul [/bib_ref] [bib_ref] Blood pressure, heart rate, and urinary catecholamines in healthy dogs subjected to..., Hoglund [/bib_ref] The panel recognizes the need for breedspecific BP ranges to be developed. In cats, no effect of breed has been observed on BP. [bib_ref] Epidemiological study of blood pressure in domestic cats, Bodey [/bib_ref] [bib_ref] Blood pressure measurements in 780 apparently healthy cats, Payne [/bib_ref] Obesity is associated with increases in BP in several species. [bib_ref] Obesity in dogs: effects on renal function, blood pressure, and renal disease, Joles [/bib_ref] [bib_ref] Hypertension and insulin resistance are not directly related in obese dogs, Rocchini [/bib_ref] [bib_ref] Obesity and hypertension: two epidemics or one?, Davy [/bib_ref] [bib_ref] Distribution of renal medullary hyaluronan in lean and obese rabbits, Dwyer [/bib_ref] [bib_ref] Hypertension in obese Zucker rats. Role of angiotensin II and adrenergic activity, Alonso-Galicia [/bib_ref] [bib_ref] Hypertension: a risk factor associated with weight status in dogs, Montoya [/bib_ref] This effect has been studied experimentally in dogs. [bib_ref] Obesity in dogs: effects on renal function, blood pressure, and renal disease, Joles [/bib_ref] [bib_ref] Does systemic hypertension damage the canine kidney?, Brown [/bib_ref] A small (<5 mm Hg) increase in BP was noted in obese dogs by oscillometry 20 but not by Doppler sphygmomanometry. [bib_ref] Variance of indirect blood pressure measurements and prevalence of hypertension in clinically..., Remillard [/bib_ref] The relationship between obesity and higher BP in dogs may be related to the prevalence of underlying disease. [bib_ref] Obesity-hypertension and its relation to other diseases in dogs, Perez-Sanchez [/bib_ref] In cats, no effect of obesity on BP was observed by oscillometry, [bib_ref] Epidemiological study of blood pressure in domestic cats, Bodey [/bib_ref] but cats that were underweight had slightly lower BP when measured with Doppler than those that were of ideal body weight or obese. [bib_ref] Blood pressure measurements in 780 apparently healthy cats, Payne [/bib_ref] Recent studies suggested no association among body condition score, body weight, and SBP measurements in dogs or cats, but muscle condition score and sarcopenia have been reported to affect radial but not coccygeal BP measurements in the cat. [bib_ref] Effects of various factors on Doppler ultrasonographic measurements of radial and coccygeal..., Whittemore [/bib_ref] [bib_ref] Effects of various factors on Doppler flow ultrasonic radial and coccygeal artery..., Mooney [/bib_ref] Blood pressure measurement results in normal animals are highly variable based on breed, temperament, patient position, measurement method, operator experience, and intrapatient variability, [bib_ref] Influence of the observer's level of experience on systolic and diastolic arterial..., Gouni [/bib_ref] [bib_ref] White-coat effect on systemic blood pressure in retired racing greyhounds, Marino [/bib_ref] [bib_ref] Arterial blood pressure, proteinuria, and renal histopathology in clinically healthy retired racing..., Surman [/bib_ref] [bib_ref] Effect of body position on indirect measurement of systolic arterial blood pressure..., Rondeau [/bib_ref] [bib_ref] Comparison of forelimb and hindlimb systolic blood pressures and proteinuria in healthy..., Scansen [/bib_ref] and it is difficult to determine a single value and range that might be applicable to all dogs or cats. Ranges of expected values in many studies of normal dogs and cats using various measurement techniques are presented in. In disease-free patient populations, in which the BP values typically are expected to be distributed normally, expected normal values are presented as mean AE SD, but in hypertensive patients, the frequency distribution of BP measurements tends to be skewed with fewer patients having very high measurements. [bib_ref] Prevalence of systolic hypertension in cats with chronic renal failure at initial..., Syme [/bib_ref] For this reason, the panel recommends that data from future studies of abnormal populations be presented as median and interquartile range. ## \| hypertension definitions The term systemic hypertension is applied to sustained increases in SBP, and generally can be categorized into 1 of 3 types. It may be caused by environmental or situational stressors, it may occur in association with other disease processes that increase BP (ie, secondary hypertension), or it may occur in the absence of other potentially causative disease processes (ie, idiopathic hypertension). Accordingly, we suggest the definitions and criteria described below. ## \| situational hypertension Increases in BP that occur as a consequence of the in-clinic measurement process in an otherwise normotensive animal are termed situational hypertension. Situational hypertension is caused by autonomic nervous system alterations that arise from the effects of excitement or anxiety on higher centers of the central nervous system. This type of hypertension resolves under conditions that decrease or eliminate the physiologic stimulus (eg, altering measurement conditions to decrease the animal's anxiety and measuring BP in the animal's home environment). In people, there is question as to whether the so-called "white coat hypertension" actually represents a risk factor for subsequent hypertensive damage, with some evidence suggesting increased long-term cardiovascular risk in these, as compared to normotensive, patients. [bib_ref] White-coat hypertension, Martin [/bib_ref] [bib_ref] White coat hypertension: to treat or not to treat?, Cuspidi [/bib_ref] There presently is no justification to treat situational hypertension in dogs or cats. More importantly, anxiety-or excitement-induced increases in BP can lead to an erroneous diagnosis of true pathologic systemic hypertension. [bib_ref] Variance of indirect blood pressure measurements and prevalence of hypertension in clinically..., Remillard [/bib_ref] [bib_ref] Comparison of blood pressure measurements obtained in dogs by use of indirect..., Kallet [/bib_ref] Unfortunately, the effects of anxiety on BP are not predictable, and some animals exhibit a marked increase in BP whereas others do not. Some animals even may exhibit a decrease in BP as a result of the measurement process. [bib_ref] Evaluation of the white-coat effect in cats, Belew [/bib_ref] In human patients, awareness of the phenomena of "white coat" hypertension and of "masked hypertension" (the latter term applied to cases in which in-clinic BP measurements are normal for a patient who is hypertensive in the nonmedical environment) has encouraged the evaluation of ambulatory or at-home BP as a complement to conventional in-clinic BP measurements. [bib_ref] ESH/ESC guidelines for the management of arterial hypertension: the task force for..., Mancia [/bib_ref] [bib_ref] Masked hypertension: understanding its complexity, Franklin [/bib_ref] Whether masked hypertension is important in veterinary species is unclear, and the use of ambulatory BP monitoring has not been systematically evaluated in veterinary medicine. ## \| secondary hypertension Secondary hypertension represents persistent, pathologically increased BP concurrent with a disease or condition known to cause hypertension, or hypertension associated with the administration of a therapeutic agent or ingestion of a toxic substance known to cause an increase in BP [fig_ref] TABLE 4: Therapeutic agents and intoxicants associated with secondary hypertension in dogs and cats... [/fig_ref]. Hypertension may persist despite effective treatment of the primary condition [bib_ref] Investigation of the role of aldosterone in hypertension associated with spontaneous pituitary-dependent..., Goy-Thollot [/bib_ref] [bib_ref] Systemic arterial blood pressure and urine protein/creatinine ratio in dogs with hyperadrenocorticism, Ortega [/bib_ref] [bib_ref] Prevalence of hypertension in hyperthyroid cats at diagnosis and following treatment, Syme [/bib_ref] and BP may increase after treatment is initiated. [bib_ref] Prevalence of hypertension in hyperthyroid cats at diagnosis and following treatment, Syme [/bib_ref] The presence of a condition known to cause secondary hypertension, even if effectively resolved by therapeutic intervention, should prompt serial follow-up evaluations. ## \| idiopathic hypertension The term "primary" or "essential" hypertension often is used in people to describe persistent pathological hypertension in the absence of any identifiable underlying cause and represents a complex multifactorial disorder involving genetic, lifestyle, and environmental factors. Essential hypertension has been reported in dogs. [bib_ref] Essential hereditary hypertension in dogs: a new animal model, Bovee [/bib_ref] Although secondary hypertension is most common in dogs and cats, idiopathic hypertension is more common than previously recognized, accounting for approximately 13%-20% of cases in cats. [bib_ref] Effect of control of systolic blood pressure on survival in cats with..., Jepson [/bib_ref] [bib_ref] Ocular lesions associated with systemic hypertension in cats: 69 cases (1985-1998), Maggio [/bib_ref] [bib_ref] Feline hypertension: clinical findings and response to antihypertensive treatment in 30 cases, Elliott [/bib_ref] Approximately 12% of nonazotemic nonhyperthyroid cats were hypertensive at baseline in one report, [bib_ref] Evaluation of predictors of the development of azotemia in cats, Jepson [/bib_ref] and in a more recent study of 133 apparently healthy initially normotensive cats aged ≥9 years, 7% developed idiopathic hypertension over the study's follow-up period. [bib_ref] Changes in systolic blood pressure over time in healthy cats and cats..., Bijsmans [/bib_ref] ## \| target organ damage (tod) Systemic hypertension is problematic only because chronically sustained increases in BP cause injury to tissues; the rationale for treatment of hypertension is prevention of this injury. Damage that results from the presence of sustained high BP is commonly referred to as end organ or TOD [fig_ref] TABLE 5: Evidence of target organ damage [/fig_ref] and the presence of TOD generally is a strong indication for antihypertensive treatment. Hypertension has been associated with proteinuria and histological renal injury in both experimental studies and in naturally occurring disease, an effect that has been identified in several species including humans, [bib_ref] Microalbuminuria: what is it? Why is it important? What should be done..., Bakris [/bib_ref] What remains unproven, at least in dogs and cats, is whether or not this decrease in proteinuria with antihypertensive drug treatment mitigates renal injury, or is simply a surrogate for improved renal outcomes, such as rate of decrease in GFR (usually assessed by measurement of serum creatinine concentration) or renal-related mortality. [bib_ref] Effect of control of systolic blood pressure on survival in cats with..., Jepson [/bib_ref] [bib_ref] Benazepril in Renal Insufficiency in Cats Study Group. Tolerability and efficacy of..., King [/bib_ref] Although the benefit is unproven, hypertension-induced or hypertension-exacerbated proteinuria currently remains an attractive target for treatment in veterinary patients. Several epidemiological studies have associated hypertension with proteinuria (and in some studies specifically albuminuria) in cats with naturally occurring diseases. [bib_ref] Survival of cats with naturally occurring chronic renal failure is related to..., Syme [/bib_ref] [bib_ref] Benazepril in Renal Insufficiency in Cats Study Group. Tolerability and efficacy of..., King [/bib_ref] [bib_ref] Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease, Chakrabarti [/bib_ref] In addition, albuminuria has been related to an increase in BP in experimental studies of induced renal disease in cats. [bib_ref] Effects of the calcium channel antagonist amlodipine in cats with surgically induced..., Mathur [/bib_ref] A recent study of cats found that even with anti-hypertensive treatment, higher time-averaged SBP was associated with glomerulosclerosis and hyperplastic arteriolosclerosis Chronic, high-dose sodium chloride - BP in normal cats and dogs appears to be relatively salt-insensitive. [bib_ref] Effects of dietary salt intake on renal function: a 2-year study in..., Reynolds [/bib_ref] [bib_ref] Dietary NaCl does not affect blood pressure in healthy cats, Luckschander [/bib_ref] [bib_ref] Effects of sodium chloride on selected parameters in cats, Kirk [/bib_ref] [bib_ref] Immune response after neonatal transfer of a human factor IX-expressing retroviral vector..., Xu [/bib_ref] - High-sodium diets do not appear to promote HT in cats with reduced renal function, [bib_ref] Effects of dietary sodium chloride intake on renal function and blood pressure..., Buranakarl [/bib_ref] [bib_ref] Effects of sodium chloride on selected parameters in cats, Kirk [/bib_ref] and salt-induced HT in the dog seems to be limited to experimental models that also involve nephrectomy [bib_ref] Effect of changes in salt intake on Aterial pressure and renal function..., Langston [/bib_ref] [bib_ref] Hypertension caused by salt loading in dog. 3. Onset transients of cardiac..., Coleman [/bib_ref] or mineralocorticoid administration. [bib_ref] Renal hemodynamics and vascular reactivity in canine DOCA-salt hypertension, Goering [/bib_ref] - BP effects of high-sodium intake in cats and dogs with pre-existing naturally occurring systemic HT, have not been systematically evaluated. Intoxicants with which systemic hypertension has been reported/associated: [formula] Cocaine 270,271 Dog [/formula] Methamphetamine/amphetamine 272-274 Dog ## 5-hydroxytryptophan 275 dog Agents associated with systemic hypertension in people, but whose BP effects have not been well characterized in dogs and cats: guarana (caffeine), ma huang (ephedrine), tacrolimus, licorice, and bitter orange. [bib_ref] The seventh report of the joint National Committee on prevention, detection, evaluation,..., Chobanian [/bib_ref] [bib_ref] Dietary supplements and hypertension: potential benefits and precautions, Rasmussen [/bib_ref] lesions after the patient's death. [bib_ref] Histomorphometry of feline chronic kidney disease and correlation with markers of renal..., Chakrabarti [/bib_ref] However, this effect was not replicated in a second, smaller, study. [bib_ref] A comparison of biochemical and histopathologic staging in cats with chronic kidney..., Mcleland [/bib_ref] In dogs with azotemic CKD, magnitude of BP has been associated with proteinuria, and this has been associated with shortened survival times. [bib_ref] Association between initial systolic blood pressure and risk of developing a uremic..., Jacob [/bib_ref] [bib_ref] Associations between proteinuria, systemic hypertension and glomerular filtration rate in dogs with..., Wehner [/bib_ref] Hypertension also was associated with shorter renal survival, but only if proteinuria was excluded from the analysis. 14 Proteinuria was directly related to the extent of increase in BP and to the rate of decrease in GFR in an experimental study in dogs. [bib_ref] Association of systemic hypertension with renal injury in dogs with induced renal..., Finco [/bib_ref] Dogs with leishmaniasis frequently have proteinuria and systemic hypertension, even when nonazotemic, although in this setting the proteinuria is thought to relate mainly to immune-mediated glomerular lesions, rather than occurring as a consequence of the hypertension. [bib_ref] Systemic hypertension in dogs with leishmaniasis: prevalence and clinical consequences, Cortadellas [/bib_ref] [bib_ref] Hypertension and its correlation with renal lesions in dogs with leishmaniosis, Braga [/bib_ref] Hypertensive greyhounds have an increased prevalence of microalbuminuria, although most dogs do not have histological evidence of renal injury. [bib_ref] Arterial blood pressure, proteinuria, and renal histopathology in clinically healthy retired racing..., Surman [/bib_ref] Hypertension may be present in any stage of CKD, and serum creatinine concentration is not directly related to BP. [bib_ref] Hypertension in cats with chronic renal failure or hyperthyroidism, Kobayashi [/bib_ref] [bib_ref] Absence of hypertension in dogs with renal insufficiency, Michell [/bib_ref] Hypertensive cats and dogs often have minimal or no azotemia. [bib_ref] Systemic hypertension in dogs with leishmaniasis: prevalence and clinical consequences, Cortadellas [/bib_ref] Ocular lesions are observed in many cats with hypertension and although prevalence rates for ocular injury vary, the frequency of ocular lesions has been reported to be as high as 100%. [bib_ref] Spontaneous systemic hypertension in dogs: five cases (1981-1983), Littman [/bib_ref] which occur with chronic hypertension in people, [bib_ref] Hypertension and cognitive function: pathophysiologic effects of hypertension on the brain, Manolio [/bib_ref] also are observed in dogs and cats. [bib_ref] Concurrent medical conditions and long-term outcome in dogs with nontraumatic intracranial hemorrhage, Lowrie [/bib_ref] A recent study described lesions on magnetic resonance imaging consistent with vasogenic edema in the occipital and parietal lobes of the brain in affected cats and dogs with neurologic signs. [bib_ref] Clinicopathologic and MRI characteristics of presumptive hypertensive encephalopathy in two cats and..., O'neill [/bib_ref] Hypertension appears to be a risk factor for ischemic myelopathy of the cranial cervical spinal cord, resulting in ambulatory tetraparesis or tetraplegia with intact nociception in old cats. [bib_ref] Feline ischaemic myelopathy with a predilection for the cranial cervical spinal cord..., Simpson [/bib_ref] Cardiac abnormalities are common in hypertensive cats 63,64,82 and dogs. [bib_ref] Echocardiographic and tissue Doppler imaging alterations associated with spontaneous canine systemic hypertension, Misbach [/bib_ref] When affected, the heart is a target organ and increased cardiac output is rarely the cause of hypertension in animals. [bib_ref] Ocular lesions associated with systemic hypertension in cats: 69 cases (1985-1998), Maggio [/bib_ref] [bib_ref] White-coat effect on systemic blood pressure in retired racing greyhounds, Marino [/bib_ref] Nevertheless, a risk of TOD has been proposed for these dogs when in-hospital SBP is >180 mm Hg.These guidelines likely will be refined as additional breed-specific information becomes available. In people, decreasing BP in hypertensive people lowers the risk of should be adjusted on re-evaluation if SBP is ≥160 mm Hg, with a minimal goal of treatment being to achieve a decrease in SBP to ≤160 mm Hg. Blood pressure <120 mm Hg, combined with clinical findings of weakness, syncope, or tachycardia, indicates systemic hypotension and treatment should be adjusted accordingly . Although frequently recommended as an initial step in the pharmacological management of high BP , dietary salt restriction is controversial, [bib_ref] Idiopathic hypertension in a cat with secondary hypertensive retinopathy associated with a..., Turner [/bib_ref] [bib_ref] Effects of dietary sodium intake on blood pressure measurements in partially nephrectomized..., Greco [/bib_ref] [bib_ref] Effects of dietary sodium chloride intake on renal function and blood pressure..., Buranakarl [/bib_ref] and available evidence suggests that substantial sodium restriction alone generally does not decrease BP. [bib_ref] Effects of dietary sodium intake on blood pressure measurements in partially nephrectomized..., Greco [/bib_ref] [bib_ref] Effects of dietary sodium chloride intake on renal function and blood pressure..., Buranakarl [/bib_ref] [bib_ref] Clinical and metabolic findings in dogs with chronic renal failure fed two..., Hansen [/bib_ref] Although sodium restriction activates the renin-angiotensin-aldosterone system (RAAS) axis [bib_ref] Essential hypertension in a dog, Bovee [/bib_ref] [bib_ref] Long-term regulation of arterial pressure, glomerular filtration and renal sodium reabsorption by..., Hall [/bib_ref] generally are not salt-sensitive, high salt intake may produce adverse consequences in some settings, [bib_ref] Salt restriction reduces hyperfiltration, renal enlargement, and albminuria in experimental diabetes, Allen [/bib_ref] [bib_ref] Hypertension caused by salt loading in the dog. 3. Onset transients of..., Coleman [/bib_ref] including animals with CKD. [bib_ref] Idiopathic hypertension in a cat with secondary hypertensive retinopathy associated with a..., Turner [/bib_ref] The panel therefore recommends avoiding high dietary sodium chloride intake. However, the selection of appropriate diet should include other patient-specific factors, such as underlying or concurrent diseases and palatability. If an antihypertensive regimen is ineffective, the usual decision is to increase the dosage of currently used agents or to add an alternative agent. A variety of other agents have BP-lowering efficacy [fig_ref] TABLE 7: Oral antihypertensive agents [/fig_ref] and these may be used as appropriate in patients for which risk reduction is not adequate with ACEi or CCB or a combination of Severely hypertensive (high TOD risk) SBP ≥180 mm Hg these drugs . Although diuretics are frequently administered to hypertensive people, these agents are not first-choice drugs for veterinary patients, particularly given the prevalence of CKD in hypertensive dogs and the adverse consequences of diuretic-induced dehydration and volume depletion in this setting. However, diuretics can be considered in the small subset of hypertensive animals in which volume expansion is clinically apparent (eg, those with edema). ## \| management of hypertension in dogs Antihypertensive agents in general, and RAAS inhibitors in particular, should be used with caution in dehydrated dogs in which GFR may decrease precipitously with their use. Unless severe hypertension with rapidly progressive TOD is present, these patients should be carefully rehydrated and then re-evaluated before instituting antihypertensive treatment. ## \| management of hypertension in cats Despite the potential role of either the systemic or intrarenal RAAS axis in the pathogenesis or maintenance of hypertension, [bib_ref] Non-invasive blood pressure measurements in cats: clinical significance of hypertension associated with..., Mishina [/bib_ref] [bib_ref] Factors influencing the relationship between the dose of amlodipine required for blood..., Bijsmans [/bib_ref] Although transdermal application has been explored, efficacy of this route of administration has not been established and PO administration is therefore the preferred route of administration. [bib_ref] Treatment of feline hypertension with transdermal amlodipine: a pilot study, Helms [/bib_ref] [bib_ref] Transdermal amlodipine besylate in lipoderm for the treatment of feline hypertension: a..., Mixon [/bib_ref] Adverse effects of amlodipine, including peripheral edema and gingival hyperplasia, are rarely reported in the dog and are also uncommon in cats. Although gingival hyperplasia has been reported in licensing studies during administration to young healthy cats, this seems to be relatively rare in clinical practice. [bib_ref] Generalised peripheral oedema associated with amlodipine therapy in two dogs, Creevy [/bib_ref] [bib_ref] Amlodipine induced gingival hyperplasia in a Great Dane, Pariser [/bib_ref] Despite dramatic antihypertensive efficacy, longitudinal control of SBP with amlodipine besylate has not been shown to increase survival time in hypertensive cats, [bib_ref] Feline hypertension: clinical findings and response to antihypertensive treatment in 30 cases, Elliott [/bib_ref] [bib_ref] Effect of control of systolic blood pressure on survival in cats with..., Jepson [/bib_ref] and its use may activate the systemic or intrarenal RAAS. [bib_ref] Plasma renin activity and aldosterone concentrations in hypertensive cats with and without..., Jepson [/bib_ref] A key predictive factor in the survival of hypertensive cats is proteinuria. A significant decrease in proteinuria has been identified in cats that are initially either borderline proteinuric or proteinuric when treated with CCB. [bib_ref] Effect of control of systolic blood pressure on survival in cats with..., Jepson [/bib_ref] However, although the combined use of amlodipine and an ACEi or amlodipine and an ARB is reportedly well tolerated, [bib_ref] Comparison of efficacy of long-term oral treatment with telmisartan and benazepril in..., Sent [/bib_ref] [bib_ref] Effect of concomitant amlodipine and benazepril therapy in the management of feline..., Elliott [/bib_ref] studies exploring any additional survival benefit of add-on antiproteinuric agents in hypertensive cats that remain proteinuric after BP control with amlodipine besylate are lacking. Nevertheless, based on the potential for proteinuria to contribute to the development and progression of renal disease in cats and its association with survival of cats with CKD, [bib_ref] Evaluation of predictors of the development of azotemia in cats, Jepson [/bib_ref] [bib_ref] Survival of cats with naturally occurring chronic renal failure is related to..., Syme [/bib_ref] [bib_ref] Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease, Chakrabarti [/bib_ref] antiproteinuric treatment should be considered in this situation. [bib_ref] Proteinuria in cats, Syme [/bib_ref] [bib_ref] Management of proteinuria in dogs and cats with chronic kidney disease, Vaden [/bib_ref] Telmisartan is an ARB currently licensed in Europe for the treatment of feline proteinuria due to CKD. [bib_ref] Comparison of efficacy of long-term oral treatment with telmisartan and benazepril in..., Sent [/bib_ref] Initial studies in healthy anesthetized cats undergoing radiotelemetric BP monitoring, telmisartan, but not losartan, significantly attenuated the pressor response to angiotensin I. [bib_ref] Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers..., Jenkins [/bib_ref] Attenuation of the SBP rise was significantly higher than for benazepril when telmisartan was administered at a higher than currently licensed dosage (3 mg/kg PO q24h). [bib_ref] Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers..., Jenkins [/bib_ref] [bib_ref] Safety of benazepril in 400 azotemic and 110 non-azotemic client-owned cats, Lavallee [/bib_ref] Deterioration in renal function tests and uremic crisis also was reported as an adverse event in 2/112 cats and 1/112 cats receiving telmisartan, respectively, although the initial stage of CKD in these cats is uncertain from data provided. [bib_ref] Comparison of efficacy of long-term oral treatment with telmisartan and benazepril in..., Sent [/bib_ref] In contrast, no alteration in serum creatinine concentration would be anticipated with introduction of a CCB such as amlodipine besylate. [bib_ref] Feline hypertension: clinical findings and response to antihypertensive treatment in 30 cases, Elliott [/bib_ref] Clinicians should be aware of the potential for acute exacerbation of azotemia with concurrent ACEi and ARB, and careful monitoring is recommended. [bib_ref] Benazepril in Renal Insufficiency in Cats Study Group. Tolerability and efficacy of..., King [/bib_ref] [bib_ref] Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced..., Brown [/bib_ref] [bib_ref] Controlled clinical evaluation of enalapril in dogs with heart failure: results of..., Group [/bib_ref] [bib_ref] Effects of enalapril maleate on survival of dogs with naturally acquired heart..., Ettinger [/bib_ref] Angiotensin converting enzyme inhibitors and ARB should not be started in dehydrated cats in which GFR may decrease precipitously. These patients should be carefully rehydrated and then re-evaluated before instituting ACEi or ARB treatment. Although several other antihypertensive agents ( Pheochromocytoma has been reported rarely in the cat. [bib_ref] Adrenal pheochromocytoma with contralateral adrenocortical adenoma in a cat, Calsyn [/bib_ref] [bib_ref] Adrenal pheochromocytoma in a cat, Henry [/bib_ref] [bib_ref] Plasma free metanephrines in healthy cats, cats with non-adrenal disease and a..., Wimpole [/bib_ref] [bib_ref] Apocrine gland adenocarcinoma and pheochromocytoma in a cat, Chun [/bib_ref] Combination treatment with phenoxybenzamine, an α 1 -and α 2adrenergic blocker, and amlodipine besylate, may be required to adequately control BP in affected cats. [bib_ref] Plasma free metanephrines in healthy cats, cats with non-adrenal disease and a..., Wimpole [/bib_ref] For cats in which tachyarrhythmias are of concern, beta-adrenergic blocker (eg, atenolol) treatment may be considered, but it should only be added after α-adrenergic blockade. For cats undergoing adrenalectomy, careful BP monitoring is required in the postoperative period, as persistent hypertension or hypotension may occur. repeated to a total dosage of 3.75 mg/kg, followed by a CRI of 25 μg/ kg/min), hydralazine (loading dosage of 0.1 mg/kg IV over 2 minutes, followed by a CRI of 1.5-5.0 μg/kg/min) or nitroprusside (0.5-3.5 μg/ kg/min IV CRI), although none of these medications has the advantage of renal vasodilatation. Phentolamine, a short-acting competitive α-adrenergic blocking drug anecdotally has been used successfully to manage intraoperative hypertension that may occur during removal of pheochromocytomas (loading dose, 0.1 mg/kg IV; CRI, 1 to 2 μg/kg/ min). [bib_ref] Surgical management of adrenal gland tumors with and without associated tumor thrombi..., Kyles [/bib_ref] In cats, even anecdotal information regarding the use of parenterally administered vasodilators is sparse. Subcutaneous administration of hydralazine (1.0-2.5 mg per cat SC) has been used to treat acute hypertension in postoperative feline renal transplant patients. [bib_ref] Management of hypertension controls postoperative neurologic disorders after renal transplantation in cats, Kyles [/bib_ref] In all cases of parenteral vasodilator administration, continuous or fre- To bridge these gaps, we recommend large multicenter clinical studies aimed at refining our understanding of normal BP and how it is best assessed. In addition, long-term studies are necessary to determine the best approach to hypertension treatment, and how these treatments will affect patient quality of life and life expectancy of our patients. We hope this document will be updated periodically to reflect advances in the field of veterinary medicine. ## \| hypertensive emergencies # Acknowledgments [fig] 7 \|: DIAGNOSIS OF HYPERTENSION The diagnosis of hypertension always should be based on reliable BP measurements, and therapeutic decisions in cats and dogs typically are based on SBP results (Figure 1). The presence of TOD (eg, retinopathy and CKD) justifies initiating treatment after a single measurement session, but in most cases, results should be confirmed by measurements repeated on multiple (>2) occasions. In cases of prehypertension (140-159 mm Hg) or hypertension at moderate risk of TOD (160-179 mm Hg), these measurement sessions can occur over 4-8 weeks. With more severe hypertension (≥180 mm Hg), however, the risk of TOD dictates that the measurement sessions be completed in 1-2 weeks. Once increases in BP are determined to be persistent, and not associated with measurement error or situational hypertension, the search for conditions associated with secondary hypertension ( [/fig] [fig] FIGURE 1: The recommended approach to the evaluation of a possibly hypertensive patient involves reliable measurements of blood pressure as well as the identification of possible target organ damage. Once a diagnosis of hypertension is established, a search for a compatible underlying condition and appropriate treatment should commence8.1 \| General treatment guidelinesBecause hypertension in dogs and cats often is secondary (≥80% of cases), antihypertensive drug treatment should be initiated along with treatment for any underlying or associated condition. Initial considerations (Figure 2) always should include identification and management of conditions likely to be causing secondary hypertension and identification and treatment of TOD. If possible, these considerations should be addressed with specific targeted diagnostic and therapeutic regimens. Effective management of a condition causing secondary hypertension may lead to complete or partial resolution of the high BP in some, but not all, cases.4,14,55 Decisions to use antihypertensive drugs should be based on the integration of all clinically available information, and a decision to treat (which may effectively mandate lifelong drug treatment) warrants periodic re-evaluation.Treatment for hypertension must be individualized to the patient and take into account concurrent conditions. Once daily treatment is ideal; fewer treatments always are preferred. A gradual persistent decrease in BP is the therapeutic goal. Acute marked decrease in BP should be avoided. If the chosen antihypertensive agent is only partially effective, the usual approach is to consider increasing the dosage or adding an additional drug. Management of highly resistant hypertension in people often requires multiagent (≥2) protocols; a similar situation often occurs in dogs, although this appears to be relatively rare in cats. It is often helpful to discuss with the owner the interindividual variability of response to antihypertensive medications when the first medication is prescribed, and the need for frequent monitoring until a therapeutic goal is reached.The goal of antihypertensive treatment is to decrease the likelihood and severity of TOD. Hypertension generally is not an emergency, and rapid decreases in BP usually should not be sought aggressively. Studies in people indicate that reduction of risk for TOD by antihypertensive treatment is a continuum and that the lower the BP, the lower the risk for TOD. Results of a recent laboratory study in dogs78 suggest that BP is a continuous risk marker for progression of kidney disease and may justify a similar treatment approach in veterinary patients. The panel feels that regardless of the initial magnitude of BP, the goal of treatment should be to maximally decrease the risk of TOD (SBP < 140 mm Hg) and that antihypertensive treatment [/fig] [table] TABLE 4: Therapeutic agents and intoxicants associated with secondary hypertension in dogs and cats DOC) is associated with statistically significant increases in BP,245,246 most especially when combined with unilateral nephrectomy or high dietary sodium intake.247,248 • Desoxycorticosterone pivalate (DOCP), administered at clinically relevant dosage rate (2.2 mg/kg IM q 30 days) to dogs with naturally occurring hypoadrenocorticism was not associated with significant increase in BP.249 Worsening or onset of systemic HT is common in animals with CKD related anemia when treated with recombinant human erythropoietin,250 recombinant canine or feline erythropoietin, 251,252 or darbepoetin alfa. 253,254 • 96% of dogs administered darbepoetin alfa experienced an increase in BP 253 • 37% of previously normotensive cats developed HT during darbepoetin alfa treatment 254 • HT noted in 40% and 50% of dogs and cats, respectively, treated with rhEPO 250 • It is difficult to know to what degree disease progression alone contributes to observed BP increases. Persistent HT is uncommon when administered long-term at recommended dosage (1.5 mg/kg PO q8h) in incontinent dogs. 256,257 • At high doses, acute intoxication may cause severe systemic HT. 258,259 Phenylephrine hydrochloride Dog Systemic HT reported in normal dogs, 260 and those scheduled for cataract surgery, 261 administered topical ocular phenylephrine hydrochloride. Ephedrine Dog Significant increases in direct BP were noted in normal dogs administered ephedrine (1.5 mg/kg PO q12h). 262 Pseudoephedrine Dog • At high doses, acute intoxication may cause systemic HT. 263 • When administered for long term to dogs with urinary incontinence, significant increases in indirect BP were not noted. 257 Toceranib phosphate Dog Systemic HT documented in 28% of previously normotensive dogs treated for various neoplastic diseases for 14 days. 264 [/table] [table] TABLE 5: Evidence of target organ damage (TOD) There are 2 clear indications for evaluating BP in a patient for which systemic hypertension may be a concern. First, BP should be measured in patients with clinical abnormalities consistent with hyperten-fore, it may be prudent to screen older animals for these conditions.The prevalence of hypertension in dogs and cats is not known. Surfalse diagnosis is likely to be high with widespread screening. Therefore, the panel does not recommend routine screening of all dogs and cats for the presence of systemic hypertension. Some conditions (eg, hyperthyroidism, hyperadrenocorticism, and CKD) that result in secondary hypertension are more prevalent in older animals, yet may be occult. Thus, it is reasonable to institute annual screening of cats and dogs ≥9 years of age. Still, high BP in otherwise healthy, particularly young, animals should be assumed to represent situational hypertension until proven otherwise with confirmatory measurements on multiple occasions. [/table] [table] Table 3: should begin. [/table] [table] TABLE 7: Oral antihypertensive agents [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/jvim.15331	An update to the 2007 American College of Veterinary Internal Medicine (ACVIM) consensus statement on the identification, evaluation, and management of systemic hypertension in dogs and cats was presented at the 2017 ACVIM Forum in National Harbor, MD. The updated consensus statement is presented here. The consensus statement aims to provide guidance on appropriate diagnosis and treatment of hypertension in dogs and cats.
506b7ee37b20b588ddf5dccec6d9f2311af0720c	pubmed	Development of a Rating System for Digestive System Impairments: Korean Academy of Medical Sciences Guideline	Development of a Rating System for Digestive System Impairments: Korean Academy of Medical Sciences Guideline A systematic and effective welfare system for people with digestive system impairments is required. In Korea, an objective and scientific rating guideline does not exist to judge the digestive system impairments. Whether the impairments exist or not and the degree of it need to be examined. Thus, with these considerations we need a scientific rating guideline for digestive system impairments to fit our cultural and social background. In 2007, a research team, for the development of rating impairment guidelines, was organized under the supervision of Korean Academy of Medical Sciences. The rating guidelines for digestive system impairments was classified into upper and lower gastrointestinal tracts impairments and liver impairment. We developed objective rating guidelines for the upper gastrointestinal tract, the impairment generated after surgery for the stomach, duodenum, esophagus, and for the lower gastrointestinal tract, the impairment generated after construction and surgery for colon, rectum, anus, and intestinal stomas. We tried to make the rating impairment guidelines to include science, objectivity, convenience, rationality, and actuality. We especially emphasized objectivity as the most important value. We worked to make it easy and convenient to use for both the subjects who received the impairment ratings and the doctors who will give the ratings. # Introduction The standard of living is continually improving with the increase of national wealth. Accordingly, interest in the lives and welfare of the disabled is also improving which requires execution of a systematic and effective policy for the disabled. In order to operate it, guidelines to rate the impairments objectively and scientifically is required [bib_ref] Review of Korean disability evaluation systems and suggestions for the improvement direction, Li [/bib_ref] [bib_ref] A comparative study on evaluation methods of permanent impairment in Korea, Rhee [/bib_ref]. The impairment rating guidelines currently used in Korea causes distrust and complaints. This is due to diagnostic errors, bogus disabled, and the fact that guidelines for the impairment of the digestive system does not even exist [bib_ref] The present condition and problems of guidelines for disability evaluation in Korea, Cho [/bib_ref]. There are many people unable to carry on normal lives due to serious digestive system diseases, and yet no help is given from the nation and society due to lack of proper guidelines. The United States has already a scientific impairment rating guideline prepared by the American Medical Association (AMA). Therefore, we have decided to develop our own scientific and objective diges-tive system impairment rating guidelines fitting the given conditions of Korea based on social and cultural realities. # Materials and methods The research committee was organized by specialists who have knowledge and experience in rating digestive system impairments under the supervision of the Korean Academy of Medical Sciences (KAMS). The committee consists of the medical doctors of internal medicine, general surgery, family medicine, and medical law and ethics. The committee members received education on the background and purpose, basic concept, rating methods, and principles of impairment of the rating impairment guidelines. The members analyzed the systems of European union, U.S.A. and many countries in Asia including the digestive system impairment rating. Especially AMA Guidesthat was reformed and put into prac-tice from the year 2000 was heavily referred. We used these guidelines positively in a way by making them satisfy the conditions of Korea, and then developed the digestive system impairment evaluation guidelines under the management of KAMS. In this evaluation guideline of the digestive system was divided into three parts: the upper and lower gastrointestinal tracts and the liver. We examined the lives of people with digestive diseases to see whether or not they could carry on with normal activities. We evaluated the loss of function in the digestive system as 100% impairment due to the possibility of death from function loss. We fixed the impairment rate in proportion to the impairment state with the relative rate to the loss before proper functioning. # Results ## General principles We paid careful attention to the KAMS Guidelines to satisfy the requirements of science, objectivity, convenience, rationality, and actuality. We placed objectivity as the most important value. Impairment evaluation should be conducted when the symptoms are in a fixed state, but if there is an expected change of symptoms, then another evaluation should be made two years later. In principle, the subject of impairment for medical evaluation should be as fixed symptoms that are left without recovery upon completion of treatment. The source of impairment does not have to result from traumas, but may also come from congenital diseases and just as a disease itself. The impairment should be evaluated by specialists of the appropriate fields of which it belongs to. We evaluated the loss of function in the digestive system as 100% impairment due to the possibility death from the loss of functions. We fixed the impairment rate in proportion to the impairment state with the relative rate to the loss before functioning. ## Evaluation guidelines for the upper gastrointestinal tract impairments The upper digestive tract includes the esophagus, stomach, duodenum, small intestine, and pancreas. Useful objective methods for confirming upper gastrointestinal tract impairments are: 1) fluoroscopy, contrast media using radiological tests and imaging studies such as a computed tomography (CT) or an magnetic resonance imaging (MRI), 2) cytology test or endoscopy including a biopsy, 3) esophageal manometry, 4) gastric acid secretory studies, 5) absorption abnormality test, 6) stool studies, and 7) Helicobacter pylori urea breath test. Also, fat content in the stool and intestinal malabsorption may be examined. The impairment rate, as signified in percentage, reflects the anatomical, physiological, and functional abnormality occurring in an organ or system and the ability to perform daily activities. Patients belong to the normal scope of gastrointestinal impairments if patients are able to perform daily Above 75% 1. In the case where it is impossible to carry on with daily life due to continual pain, bleeding, perforation of the intestine, duodenum diseases or damages requiring treatment in the hospital or surgical treatment is impossible due to other accompanying diseases 2. In the case of over 30% weight loss due to gastrointestinal or duodenum diseases or damages 50-74% 1. In the case where it is impossible to carry on with daily life due to continual pain, bleeding, perforation of the intestine, duodenum diseases or damages requiring treatment in the hospital and surgical treatment is possible. Reevaluation is required one year after evaluation 2. In case of 20-30% weight loss due to gastrointestinal or duodenum diseases or damages 30-49% 1. In the case of considerable disorder in daily life due to continual pain, bleeding, perforation of the intestine, duodenum diseases or damages requiring intermittent treatment in the hospital 2. In the case of 10-19% weight loss due to gastrointestinal or duodenum diseases or damages 3. In the case that the patient underwent more than once surgical operation due to gastrointestinal or duodenum diseases or damages, and in patients with dumping syndrome, reflux esophagitis, malabsorption, etc. Reevaluation after one year is required 20-29% 1. In the case of intermittent treatment in the hospital is required due to continual pain, bleeding, perforation of the intestine, duodenum diseases or damages 2. In case of 0-9% weight loss due to gastrointestinal or duodenum diseases or damages 3. In the case that the patient underwent more than once surgical operation due to gastrointestinal or duodenum diseases or damages so continual care is needed. Reevaluation after one year is required 10-19% 1. In the case that the symptoms caused by gastrointestinal, duodenum diseases or damages were eased due to treatment but continual care is needed 0-9% 1. In the case of occurring lasting pain, bleeding, perforation due to gastrointestinal or duodenum diseases or damages but recovered with surgery ## Evaluation guidelines for the lower gastrointestinal tract impairments The lower gastrointestinal tract impairments include the colon, the rectum, and the anus. The signs and symptoms of the lower gastrointestinal tract impairment are: abdominal pain, pelvic pain, perineal pain, difficulty of defecation, tenesmus, stool incontinence, hematochezia, abscess, fissure, and fistula. In general findings, fever, weight loss, weakness, anemia, etc. may indicate lower gastrointestinal tract impairment. Useful objective methods to confirm colon, rectum, and anus impairment are the following tests such as: 1) digital rectal examination, proctoscopy, sigmoidoscopy, colonoscopy, 2) biopsy, 3) microscopic examination of the stool and cultivation, 4) fluoroscopy and radiological test using contrast media, and 5) CT and MRI examinations. The impairment rate, as signified in percentage, reflects the anatomical, physiological, and functional abnormality occurring in an organ or system and the ability to perform daily activities. Patients belong to the normal scope of gastrointestinal impairments if patients are able to perform daily activities; show regular and intermittent gastrointestinal mani- ## Rate of physical impairment (%) Above 75% 1. With the symptoms of gastroesophageal reflux disease (GERD), dysphasia, dynophagia due to disease in the esophagus and damage which prevents daily life in that the patient requires treatment in a hospital with an endoscopy, an esophagography, or an esophageal manometry, and significant anatomical, functional damage in the esophagus was found. Surgical treatment is impossible due to other accompanying diseases 2. Above 30% weight loss due to diseases or damages in the esophagus 50-74% 1. With the symptoms of gastroesophageal reflux disease (GERD), dysphasia, dynophagia due to esophageal disease and damage which prevents daily life in that the patient requires treatment in a hospital with an endoscopy, an esophagography, or an esophageal manometry, and significant anatomical, functional damage in the esophagus was found. Surgical treatment is possible and reevaluation after a year is required 2. 20-29% weight loss due to the diseases or damages in the esophagus 25-49% 1. With the symptoms or stigma of continual gastroesophageal reflux disease (GERD), dysphasia, dynophagia due to diseases or damages in the esophagus from the results of an endoscopy, an esophagography, or an esophageal manometry, and significant anatomical and functional damage in the esophagus was found, and medical care is needed 2. 10-19% weight loss due to diseases or damages in the esophagus 1. In the case of surgery of the upper digestive tract (esophagus, stomach, duodenum, small intestine, pancreas, gallbladder, bile duct) was performed requiring treatment in the hospital for continual parenteral nutrition to control symptoms and complications or malnutrition and weight loss of over 30% occurred after becoming ill An evaluation 6 months after surgery and reevaluation after a year is required 50-74% 1. In the case of surgery of the upper digestive tract (esophagus, stomach, duodenum, small intestine, pancreas, gallbladder, bile duct) was performed requiring parenteral nutrition to control symptoms and complications or malnutrition and weight loss over 20-29% occurred after becoming ill An evaluation 6 months after surgery and reevaluation after a year is required 25-49% 1. In the case of surgery of the upper digestive tract (esophagus, stomach, duodenum, small intestine, pancreas, gallbladder, bile duct) was executed requiring parenteral nutrition to control symptoms and complications and malnutrition and weight loss of over 20% occurred after becoming ill An evaluation 6 months after surgery and reevaluation after a year is required 10-24% 1. In the case of surgery for upper digestive tract (esophagus, stomach, duodenum, small intestine, pancreas, gallbladder, bile duct) was executed requiring intermittent treatment at a hospital to control symptoms, signs and weight loss of less than 9% occurred after becoming ill An evaluation 6 months after surgery and reevaluation after a year is required 0-9% 1. In the case of surgery of the upper digestive tract (esophagus, stomach, duodenum, small intestine, pancreas, gallbladder, bile duct) was performed, but follow-up was not needed An evaluation 6 months after surgery and reevaluation after a year is required festations without need of specific dietary treatment or medications; and are able to keep normal weight with necessary nutrition. We divided the lower gastrointestinal impairments evaluation into the colon, rectum, anus, intestinal stomas and after surgery of the lower gastrointestinal tract [fig_ref] Table 4: Evaluation guidelines for colon and rectum impairment [/fig_ref]. ## Evaluation guidelines for liver impairment The symptoms of hepatic bile impairment are pain, nausea, vomiting, anorexia, general weakness, fever, jaundice, and itching. The symptoms of progressive liver disease com-plications are edema, ascites, esophageal varix, portal hypertension which generates bleeding, hepatic encephalopathy, metabolic impairment, and the loss of kidney function. Useful objective methods to confirm liver impairments are 1) an abdominal sonogram, 2) radiological examination such as percutaneous and endoscopic cholangiography, 3) CT and MRI, 4) liver isotope studies, 5) liver biopsy & fine needle aspiration biopsy, and 6) a laboratory test for diagnosis of bile duct and other liver functions. The determination of impairment degree occurred by liver diseases is executed by specialists noting the clinical symptoms, results of the liver function test, and the results of the image test. The evaluation ## Rate of physical impairment Above 75% In the case of impossible daily life due to continuous diarrhea and bleeding by chronic Inflammatory Bowel Disease (IBD) and requiring treatment in a hospital and yet surgical treatment is impossible due to other accompanying diseases and over 30% weight loss due to chronic IBD 50-74% In the case of impossible daily life due to continuous diarrhea and bleeding by chronic Inflammatory Bowel Disease (IBD) requiring treatment in a hospital and surgical treatment is possible. Reevaluation after a year is required and 20-29% weight loss due to chronic IBD ## 35-49% In the case where intermittent treatment in a hospital is required due to continuous diarrhea and bleeding, and complications generated from IBD and when medications do not work and in the case of an enterocutaneous fistula generated from chronic IBD and 10-19% weight loss due to chronic IBD 20-35% In the case of a surgical operation for chronic IBD more than once and lasting care is required and less than 10% weight loss due to chronic IBD ## 10-19% In the case of symptoms of chronic IBD being eased intermittently by treatment, but continual care is still required 0-9% In case of the existence of chronic IBD symptoms, but performance of normal daily life is possible In the case of continual incontinence of a formed stool due to considerable loss of anal sphincter muscles generated from diseases or damages and has been confirmed by a manometry ## 35-19% A state of chronic anal fistula generation due to diseases or damages, and recovery was not possible even with surgery, and intermittent fecal incontinence of a formed stool which requires continual treatment 10-19% Intermittent gas or liquid stool incontinence 0-9% In the case of periodic colonic irrigation or enema due to severe constipation, and in the case of continuous pain in the anus or constipation which has been diagnosed as perineal descent syndrome In the case of incontinence, if recovery after treatment is expected, then reevaluation is performed after a year In the case of possessing more than two intestinal stomas in the state that the intestinal contents keep draining through holes other than the intestinal stomas which show impossibility of a cure even with surgery and more than one of them are accompanied by complications 40-49% In the case of possessing more than two intestinal stomas and in the case of possessing an ileostomy, transverse colostomy, or urostomy in the state that the intestinal contents continually drains through holes other than the intestinal stomas which show impossibility of a cure even with surgery and more than one of them are accompanied by complications 15-39% Patients with an ileostomy or transverse colostomy and in the case of possessing a sigmoid colostomy in the state that the intestinal contents continually drains through holes other than the intestinal stomas which show impossibility of a cure or accompanied by complications -14% Patients with a transverse or sigmoid colostomy . Evaluation guidelines of impairment after an ostomy criterion of liver impairment is summarized in [fig_ref] Table 8: Evaluation guidelines for liver impairment [/fig_ref]. # Discussion We developed an evaluation guidelines for digestive system impairments under the supervision of KAMS suitable to the conditions of Korea by referring to the AMA Guides. The disabled people in Korea, social environment, and hospital environment were taken into consideration while drawing up the guidelines. We worked to make it easy and convenient to use for both the subjects who receive the impairment evaluation and the doctors who give the evaluation. The guidelines of the impairment rating are the synthesis of science and public opinion. The rating of digestive system impairments of KAMS are the clinically evaluated ratings of physical impairments. The physical impairment of AMA Guides are also the ratings of physical impairments. In order to satisfy the scientific characteristics, we referred to the AMA Guides as our model. The impairment rate of AMA has scientific characteristics and public trust to be used as a ''global standard'' [bib_ref] Assessment of physical impairment and disability evaluation, Lee [/bib_ref]. To satisfy objectivity we considered the patient's signs but did not consider the patient's symptoms as much. For this we rated the impairment according to the objective signs and the results of examinations. Using this score we developed a method of evaluating the degree of impairment. We avoided excessively detailed evaluation for convenience, introducing a comprehensive evaluation method so that the evaluation of overall functions will be achieved. We made a sum total of the varied impairments of a specific area not to be greater than the total functional loss of the appropriate organ. This impairment evaluation is divided into the upper and lower gastrointestinal tracts and liver. In regarding the upper gastrointestinal tract of the stomach, duodenum, and esophagus, we also determined the impairment rate after surgery for the upper gastrointestinal tract, unlike the AMA Guides. The decision to include the impairment rate after surgery is because many people, who undertook surgical operation for the upper gastrointestinal tract, complain of the difficulty in performing daily life tasks, but no objective evaluation guidelines had existed in the U.S.A. as well as in Korea for this situation. Accordingly, the impairment evaluation after surgery for the digestive system would be useful. Regarding the lower gastrointestinal tract, we made consensus on the evaluation guidelines for impairment of constructed intestinal stomas. This new consensus was a modification of previously used guideline in Korea. The guidelines Development of a Rating System for Digestive System Impairments S275 Rate of physical impairment 0-19% In the case of an ulcer and inflammation around the anus due to frequent defecation after rectal cancer or rectal trauma An evaluation 6 months after surgery and reevaluation after a year is required were converted into an impairment rating scale. The impairment evaluation of anal disease was determined objectively. Stool incontinence generated from anal sphincter impairment was given special consideration. In choosing evaluation guidelines for the upper gastrointestinal tract, we considered weight loss. If the organ is unable to absorb nutrition, it causes weight loss. The measurement of weight loss is economical and easy in that both patients and doctors would agree objectively and it would be a useful evaluation guideline for upper gastrointestinal tract impairment. If the impairment can be cured with surgical treatment, the patient is to be reexamined after a year to receive an objective and rational evaluation. The same goes for lower gastrointestinal tract impairments. The Child-Pugh classification should be followed objectively in the case of liver impairment, with leftover function of the liver. Complications such as ascites, spontaneous bacterial peritonitis, hepatic encephalopathy should be regarded, and then we made the entire impairment guidelines of liver disease objectively and easily. These impairment guidelines are developed after Korean environment for disabled people and hospitals. Considering the reality, the present impairment guidelines needs supplementary and periodic improvements. With respect to the hospital environment, close examination might be needed for improved scientific evaluation. Not all hospitals possess very expensive and rare equipment. Therefore, doctors should be able to rate impairments objectively with general equipment. In some patients that need more attention, referral system to a hospital with special equipment is needed. The evaluation of digestive system impairment is applied to a medically permanent impairment, a fixed physical state but not a temporary state of impairment. Permanent impairment means a fixed impairment which has not changed a year after evaluation [bib_ref] Review of the disability grade documents with central nervous system impairment by..., Lee [/bib_ref]. A certain time interval was set up for evaluation of the digestive system impairment after it is fixed. The fixation of symptoms is generally judged after completion of treatment, but it is not always the case. If it does not get worse or there is no possibility of getting better, it could be considered as a fixed symptom, even during treatment. If the symptom or impairment gets worse, another team of interval could be set up the patient. Regarding the symptom without an objective evaluation tool with which most people would agree, such as pain, the committee agreed to defer the impairment evaluation until a useful evaluation tool is developed [bib_ref] Merits and shortcomings of the American Medical Association guides to the evaluation..., Rondinelli [/bib_ref]. [table] Table 1: Evaluation guidelines for stomach or duodenum impairment [/table] [table] Table 2: Evaluation guidelines for esophagus impairmentRate of physical impairment (%) [/table] [table] Table 3: Evaluation guidelines of impairment after an operation of the upper digestive tract [/table] [table] Table 4: Evaluation guidelines for colon and rectum impairment [/table] [table] Table 5: Evaluation guidelines for anal impairment [/table] [table] Table 7: Evaluation guidelines of impairment after an operation of the lower digestive tract Child Pugh grades B, C) of lasting liver disease with one of the following in a mixed state occurring 2 times a year: 1) Hepatic encephalopathy 2) Sontaneous bacterial peritonitis 3) Esophagus or stomach, varix bleeding10-34%With objective proof of (Child-Pugh grades B, C) of lasting liver disease with one of the following in the patient's past history: Chronic liver disease (such as liver cirrhosis) or underwent liver transplantation due to hepatocellular carcinoma [/table] [table] Table 8: Evaluation guidelines for liver impairment [/table]	None	http://synapse.koreamed.org/Synapse/Data/PDFData/0063JKMS/jkms-24-S271.pdf	A systematic and effective welfare system for people with digestive system impairments is required. In Korea, an objective and scientific rating guideline does not exist to judge the digestive system impairments. Whether the impairments exist or not and the degree of it need to be examined. Thus, with these considerations we need a scientific rating guideline for digestive system impairments to fit our cultural and social background. In 2007, a research team, for the development of rating impairment guidelines, was organized under the supervision of Korean Academy of Medical Sciences. The rating guidelines for digestive system impairments was classified into upper and lower gastrointestinal tracts impairments and liver impairment. We developed objective rating guidelines for the upper gastrointestinal tract, the impairment generated after surgery for the stomach, duodenum, esophagus, and for the lower gastrointestinal tract, the impairment generated after construction and surgery for colon, rectum, anus, and intestinal stomas. We tried to make the rating impairment guidelines to include science, objectivity, convenience, rationality, and actuality. We especially emphasized objectivity as the most important value. We worked to make it easy and convenient to use for both the subjects who received the impairment ratings and the doctors who will give the ratings.
15b6eeb56111436c4bb3767f679f16f0c0e26915	pubmed	Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2	Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2 # Introduction other fields. The definitions of the recommendation grades used in these guidelines are provided in. A Working Group was established in November 2015. After a consensus meeting in October 2016, external opinions (from 23 academic societies and 6 patient associations) were summarized. After an external assessment based on Appraisal of Guidelines for Research & Evaluation (AGREE) II by the Cancer Therapy Guideline Appraisal Committee, the final manuscript was prepared in June 2017. The Working Group comprised specialists in the 8 target areas covered by this guideline-female reproductive system, mammary glands, urinary tract system, pediatric patients, hematopoietic system, bone and soft tissues, brain, and digestive system-and specialists in fertility, nursing, and pharmacology. Moreover, for the preparation of this guideline, support was obtained from the 2016 project entitled "Establishment of Integrated Platform for Drastic Advancement in Fertility Preservation Cancer Therapy (representative investigator: Yutaka Osuga) performed by the Japan Agency for Medical Research and Development. ## Chapter 1: gynecologic cancers ## General remarks Typical cancers of the female genital organs include uterine cervical cancer, endometrial cancer, and ovarian tumor. Of these, cervical cancer most often affects women under 40 years of age, although in recent years, endometrial cancer and ovarian tumor have become more prevalent among younger adults. Because cancers of the female genital organs affect the main organs involved in fertility, treatments for these cancers are likely to lead directly to the loss of fertility. Therefore, measures to preserve fertility in patients with these types of cancers are particularly important. ## Clinical question 1 Which patients with cervical cancer are eligible for conservative surgery (trachelectomy)? In recent years, the number of young women with cervical cancer in whom fertility preservation should be considered has been increasing because the age of onset of cervical cancer has been decreasing and the tendency to marry and have a child at a later age has been increasing. According to the Patient Annual Report for Fiscal Year 2010 issued by the Japan Society of Obstetrics and Gynecology (JSOG) Gynecological Oncology Committee, the number of patients with stage IA1 to IB1 cervical cancer who were younger than 40 years of age was estimated to be 1105, and these patients were estimated to account for 33% of all patients with cervical cancer at these stages. To answer this clinical question (CQ), we discussed which patients with cervical cancer are eligible for conservative surgery (trachelectomy) on the assumption that the pathological diagnosis and staging of the malignancy are accurate. The clinical stages referred to in this CQ were assigned according to the JSOG 2011/International Federation of Gynecology and Obstetrics (FIGO) 2008 cervical cancer staging criteria, which are presented in Japanese in the General Rules for Clinical and Pathological Management of Uterine Cervical Cancer, 3rd edition. Recommendation 1 1-1. Patients with squamous cell carcinoma or adenocarcinoma may be considered as primary candidates for conservative surgery (trachelectomy). (Recommendation Grade C1). 1-2. Conservative surgery (trachelectomy) may be considered for tumors with a diameter equal to or less than 2 cm that are localized in the uterine cervix. (Recommendation Grade C1). ## Clinical question 2 Which surgical procedures are recommended to preserve fertility in patients with cervical cancer ? When considering this CQ, we discussed the optimal surgical procedures for preserving fertility in patients with cervical cancer by stage and by histological type of the disease. Recommendation 2 2-1. Disease at stage IA1 or less that is confirmed at conization to have no vessel invasion, negative cone margins bilaterally, and negative histology of endocervical curettage may require no further interventions. (Recommendation Grade C1). Based on scientific evidence, the approach is recommended C1 Despite the presence of limited scientific evidence, the approach is recommended C2 Because of the paucity of scientific evidence, the approach is not recommended D Based on scientific evidence for its non-efficacy or harm(s), the approach is not recommended 2-2. Semi-radical trachelectomy plus pelvic lymph node dissection or radical trachelectomy may be considered depending on the tumor interstitial invasion depth, presence or absence of vessel invasion, and tumor diameter. (Recommendation Grade C1). ## Clinical question 3 Which patients with endometrial cancer are eligible for fertility preservation (high-dose progesterone therapy) [fig_ref] Recommendation 2: Different fertility preservation options are indicated for prepubertal versus postpubertal patients and... [/fig_ref] ? In Japan, patients with endometrial cancer under 40 years of age account for 5.1% of all patients with this malignancy, but the percentage has been increasing steadily in association with a considerable increase in the number of patients with endometrial cancer. The standard therapy for endometrial cancer is hysterectomy, and an increasing number of patients undergo fertility preservation. Hence, we conducted a survey to ascertain the current consensus on the indications for such therapy. ## Recommendation 3 Fertility preservation may be considered for highly differentiated endometrioid carcinoma (Grade 1) or atypical endometrial hyperplasia that is probably localized within the endometrium. (Recommendation Grade C1). ## Clinical question 4 Which patients with malignant ovarian tumors are eligible for fertility preservation [fig_ref] Figure 3: Algorithm [/fig_ref] ? In Japan, the number of patients with newly diagnosed malignant ovarian tumors has been increasing and is expected to exceed 10,000 per year in the near future. At the same time, the tendency for women to marry later has also been increasing, leading to more pregnancies at higher ages. Therefore, an increasing number of patients with malignant ovarian tumors will be interested in fertility preservation. To answer this CQ, we discussed the indications for fertility preservation in women with malignant ovarian tumors. ## Clinical question 5 Which surgical procedures are recommended to preserve fertility in patients with malignant ovarian tumors [fig_ref] Figure 3: Algorithm [/fig_ref] ? We discussed this CQ to determine the optimal surgical procedures to preserve fertility in patients with malignant ovarian tumors. Recommendation 5 5-1. For epithelial malignant ovarian tumors, adnexectomy of the affected side plus omentectomy, intraperitoneal cytology, and pelvic/paraaortic lymph node dissection (biopsy) with or without contralateral ovarian biopsy and with or without biopsy of intraperitoneal lesions may be considered. (Recommendation Grade C1). 5-2. For borderline epithelial ovarian tumors, adnexectomy of the affected side plus omentectomy, intraperitoneal cytology, and intraperitoneal observation may be considered. (Recommendation Grade C1). 5-3. For ovarian germ cell tumors, adnexectomy of the affected side plus omentectomy, intraperitoneal cytology, and intraperitoneal observation is recommended. (Recommendation Grade B). . For ovarian stromal cell tumors, adnexectomy of the affected side plus omentectomy, intraperitoneal cytology, and intraperitoneal observation may be considered. (Recommendation Grade C1). ## Clinical question 6 What reproductive support should be provided to patients with gynecologic malignancy who have undergone fertility preservation? Fertility preservation for gynecologic malignancy can be surgical or medical. Because gynecologic malignancy affects the organs involved in fertility, a number of points had to be considered in addressing this CQ. For example, questions arose such as whether patients undergoing surgery for cervical cancer require any assisted reproductive technology (ART) intervention because of the altered structure of their uterus or whether patients receiving medical therapy for endometrial cancer require any ART intervention to enable early pregnancy. If these questions were left unanswered, the significance of fertility preservation per se might be doubted. The term reproductive support used in the recommendations below means a broad concept that involves a wide range of attempts to become pregnant, ranging from the pre-interventional stage (e.g., selftiming) to simpler and more advanced infertility interventions. Recommendation 6 6-1. Artificial insemination or ex vivo fertilization may be considered as reproductive support for patients with cervical cancer who have undergone radical trachelectomy as fertility preservation surgery. (Recommendation Grade C1). 6-2. Artificial insemination or ex vivo fertilization may be considered as reproductive support for patients with endometrial cancer to enable early pregnancy. (Recommendation Grade C1). 6-3. Ex vivo fertilization may be considered as reproductive support for patients with ovarian cancer who have been fully informed about the risk of malignant dissemination or metastasis associated with oocyte harvesting. (Recommendation Grade C1). ## Chapter 2: breast cancer ## General remarks At the time of diagnosis of breast cancer, young female patients express an interest in having a child, partially because of the tendency for women to become pregnant at a later age. The probability of long-term survival of breast cancer patients after treatment has increased with improved early detection of the disease and outcomes of medical therapy. However, the hormone-dependent nature of breast cancer, chemotherapy-induced impairment of ovarian function, and increasing age during long-term endocrine therapy are the main obstacles to conception and parturition in women with breast cancer. When considering the CQs, we reviewed the important points for oncologists and reproductive specialists to consider in discussing conception and fertility preservation with women with breast cancer . ## Clinical question 1 Which patients with breast cancer are eligible for fertility preservation? Treatments for breast cancer should not be uniform but should be individualized by assessing the recurrence risk estimated from the clinical stage and subtype of the cancer, expected response to treatment (responsiveness to drugs), and potential adverse reactions to treatments. Because about 70% of primary breast cancers are estrogen receptor-positive, hormone-sensitive tumors, posttreatment changes in the hormonal environment associated with conception or fertility preservation or both may have negative impacts on the prognosis of breast cancer. To answer this CQ, we reviewed the possibility of pregnancy after breast cancer treatment and the indications for fertility preservation among women with breast cancer from the viewpoint of the impact of treatment and fertility preservation on the prognosis of this malignancy. Our aim was to prevent suboptimal reproductive counselling that might unnecessarily discourage patients from becoming pregnant or make them have excessive expectations about any future pregnancy. Recommendation 1 1-1. Fertility preservation may be considered in patients with stage 0 to III breast cancer who are to receive standard treatment and likely to survive for a long time after treatment. (Recommendation Grade C1). 1-2. Patients with stage IV breast cancer with distant metastasis or recurrent breast cancer are not eligible for fertility preservation. (Recommendation Grade D). ## Clinical question 2 Is delayed initiation of chemotherapy permitted in patients with breast cancer who are interested in fertility preservation? When patients with breast cancer receive any ART fertility preservation intervention, initiation of chemotherapy may need to be delayed to enable oocyte retrieval after ovarian stimulation. Hence, we discussed how long chemotherapy can be delayed for fertility preservation. Recommendation 2 2-1. For fertility preservation, initiation of adjuvant chemotherapy may be delayed until 12 weeks postoperatively. However, some studies have suggested that delaying chemotherapy by more than 5 weeks has a negative impact on the prognosis of breast cancer. Therefore, any fertility preservation intervention before postoperative chemotherapy should be performed as quickly as possible. (Recommendation Grade C1). 2-2. Delaying initiation of neoadjuvant chemotherapy for fertility preservation is not permitted, because its safety has not been established. Any fertility preservation intervention before neoadjuvant chemotherapy should be performed as quickly as possible to avoid delays in initiating the planned chemotherapy. (Recommendation Grade C2). ## Clinical question 3 From the aspect of the prognosis of malignancy, when can a woman with stage I-III breast cancer who is interested in becoming pregnant consider pregnancy after completing cancer-directed therapy? We considered both (1) the effect of conception on the prognosis (e.g., recurrence risk) of breast cancer and (2) the embryofetal toxicity (e.g., teratogenicity) of the cancer-directed therapy. In the recommendation below, we address this question from the former aspect; the latter aspect is addressed in the subsequent CQ. ## 3 Because a woman with breast cancer becomes older while receiving long-term endocrine therapy, she may have a reduced possibility of becoming pregnant if she waits until completion of endocrine therapy. Hence, we also addressed the question whether a woman with breast cancer can interrupt endocrine therapy to attempt to become pregnant. ## Recommendation 3 Women with breast cancer who have completed standard treatment comprising surgery, radiotherapy, chemotherapy, and/or endocrine therapy may consider becoming pregnant, because their pregnancy will have little adverse effect on the prognosis of their breast cancer. The acceptable timing for initiating attempts to become pregnant may be individualized according to the subtype and recurrence risk of breast cancer. (Recommendation Grade C1). When top priority is given to reducing the recurrence risk and breast cancer mortality, it is recommended to administer adjuvant hormone therapy or oral tamoxifen for 5 years or longer. With regard to the recurrence risk if oral medication is suspended in women who wish to have a baby, the results of an ongoing prospective, global study (POSITIVE study) by the International Breast Cancer Study Group (IBCSG) are awaited [bib_ref] Pregnancy after breast cancer: are young patients willing to participate in clinical..., Pagani [/bib_ref]. ## Clinical question 4 From the aspect of embryofetal toxicity (e.g., teratogenicity) of medical treatment and radiotherapy for breast cancer, when can a woman with breast cancer who is interested in becoming pregnant consider pregnancy after completing cancer-directed therapy? In this CQ, we considered the question of the timing of pregnancy after cancer-directed therapy from the aspect of embryofetal toxicity (e.g., teratogenicity) of cancer treatment. ## Recommendation 4 After the end of cancer-directed therapy, a washout period or period of contraception of adequate duration should be adhered to, depending on the teratogenic potential of the drug(s) used. The acceptable timing of initiating attempts to become pregnant after undergoing radiotherapy may be determined on the basis of the estimated recurrence risk and the medical treatment plan. (Recommendation Grade C1). ## Clinical question 5 Which fertility preservation options can be offered to a woman with breast cancer who is interested in becoming pregnant? Anticancer drugs used to treat female cancers (e.g., alkylating agents) are known to be gonadotoxic and to reduce the ovarian reserve. The incidence of amenorrhea (anovulation) for 3 months or longer within 1 year after treatment for breast cancer varies across drugs and regimens used and ranges from 20 to 100% [bib_ref] Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer, Bines [/bib_ref]. The American Society of Clinical Oncology (ASCO) Clinical Practice Guideline Update on Fertility Preservation for Patients With Cancer states that 30-70% of women with breast cancer who are under 40 years of age develop chemotherapy-induced amenorrhea after receiving 4 cycles of doxorubicin plus cyclophosphamide combined with a taxane, a finding that classifies this chemotherapy regimen as having an intermediate infertility risk [bib_ref] of Clinical Oncology clinical practice guideline update, Loren [/bib_ref]. These data predict that young women with breast cancer will develop refractory infertility due to premature ovarian failure immediately after receiving treatment with this standard regimen. The time lag after the end of cancer treatment until permission can be given to attempt pregnancy or until attempting pregnancy is deemed socially acceptable carries the risk of a further reduction of fertility with aging [bib_ref] Controversies in preservation of ovary function and fertility in patients with breast..., Gerber [/bib_ref] [bib_ref] Guidelines for the ethical conduct of studies to evaluate drugs in pediatric..., Wallace [/bib_ref]. Taking all these risks into account, it seems very important to educate women with breast cancer who are interested in having a child about the possibility of reduced fertility resulting from cancer treatment and to counsel them regarding fertility preservation options. When considering this CQ, we intended to assist health care providers in providing women with breast cancer with the most current information on embryo (fertilized oocyte) cryopreservation, unfertilized oocyte cryopreservation, ovarian tissue cryopreservation, and ovarian suppression with a gonadotropin-releasing hormone (GnRH) agonist as fertility preservation options that can be used before initiation of breast cancer treatment. Recommendation 5 5-1. Embryo (fertilized oocyte) cryopreservation is recommended for female patients who have a male partner. (Recommendation Grade B). 5-2. Unfertilized oocyte cryopreservation may be considered for female patients who do not have a male partner. (Recommendation Grade C1). 5-3. Ovarian tissue cryopreservation, although it remains experimental, may be considered in centers with the necessary expertise for female patients who do or do not have a male partner if there is a need for urgent cancer-directed therapy that may limit the time available for embryo (fertilized oocyte) or unfertilized oocyte cryopreservation or if induction of ovulation for oocyte harvesting is difficult (e.g., in prepubertal females). (Recommendation Grade C1). 5-4. Use of GnRH agonists for the purpose of fertility preservation is not recommended. (Recommendation Grade C2). ## 3 ## Chapter 3: urologic cancers ## General remarks Typical malignancies that affect the urological system or male genital organs include renal cancer, urothelial cancer, prostate cancer, and testicular tumor. Of these malignancies, testicular tumor frequently affects men aged 20-49 years, i.e., men in whom fertility preservation is most relevant. Renal, urothelial, and prostate cancers have higher incidence rates than testicular tumor but generally affect individuals aged 60 years and above. Of note, even middle-aged or older male patients may have an interest in having a child, and such patients should be counselled regarding fertility preservation. Renal and urothelial cancers less frequently affect women aged 20-49 years. To answer the following CQs, we reviewed the epidemiology, methods of treatment, and prognosis of individual types of urological malignancies [fig_ref] Figure 5: Algorithm [/fig_ref]. ## Clinical question 1 Which patients with urological malignancy should be counselled regarding fertility preservation interventions? The therapeutic outcome for urological malignancies in young adults has been improving with the advancement of treatment options. In particular, in many patients, testicular tumors have become curable with chemotherapy and surgery. This development has increased the importance of fertility preservation to maintain the patient's quality of life (QOL) after cancer-directed therapy. Nevertheless, in practice, patients with testicular tumors appear not to be sufficiently counselled regarding fertility preservation or provided with optimal fertility preservation measures; this is even more the case in patients with renal and bladder cancers, which occur also at young ages. Of primary importance is that treating oncologists recognize which patients with urological malignancies are eligible for fertility preservation and counsel these patients regarding this issue. Of importance is also to establish a nationwide system that enables fertility preservation interventions, including sperm cryopreservation, to be implemented without the need to delay initiation of cancer-directed therapy. To answer this CQ, we considered which patients with urological malignancies are eligible for fertility preservation. ## Recommendation 1 If a patient scheduled to receive a treatment that is likely to cause infertility is interested in fertility preservation, it is recommended to counsel the patient regarding fertility preservation interventions before initiation of cancer-directed therapy. (Recommendation Grade B). ## Clinical question 2 Is delayed initiation of cancer-director therapy permitted in patients with urological malignancies who are interested in fertility preservation to afford them the opportunity to receive a fertility preservation intervention before starting cancer treatment? Testicular tumor frequently affects young and middleaged men, and in many patients even advanced disease is curable with chemotherapy and surgery. Patients with testicular tumor often have impaired spermatogenesis before initiation of treatment, and cisplatin impairs sperm production in a dose-dependent manner. To respond to this CQ, we addressed the optimal timing of sperm cryopreservation and the acceptability of delayed initiation of cancer treatment and thereby focused on testicular tumor. ## Recommendation 2 The delay in initiating cancer-directed therapy to enable provision of a fertility preservation intervention should be minimized. Because some advanced testicular tumors require urgent medical therapy, the accept- ## Class effect and effect by dose Patient is interested in preserving fertility? ## Cq2, cq4 Acceptable timing to consider conception after completion of treatment ability of delaying initiation of treatment may be determined on a case-by-case basis. (Recommendation Grade C1). ## Clinical question 3 When can a patient with a urological malignancy who is interested in having a child consider pregnancy after completing cancer-directed therapy? The earlier diagnosis and advancement of therapy have led to improved therapeutic outcomes for urological malignancies. In particular, in many patients, testicular tumor has become curable with chemotherapy and surgery. Consequently, to improve patients' QOL, it is important to provide appropriate information to patients with urological malignancies who hope to have a child after completing cancer treatment. We addressed this issue in this CQ. ## Clinical question 4 Which fertility preservation options are recommended for patients with urological malignancy who are interested in having a child? The advancement of multi-modality therapy for urological malignancies has led to an increased probability of cure in patients at reproductive age and increased the needs for preserving patient fertility as one of the measures for improving QOL. In this CQ, we considered the current options for fertility preservation in patients with urological malignancy who are at reproductive age. ## Chapter 4: pediatric cancers ## General remarks Therapeutic outcomes for pediatric cancers have improved considerably over the past several decades. However, longterm complications such as reduced fertility have raised significant concerns for patients cured of pediatric cancer. This chapter first explains the ethical considerations that must specifically be taken into account in treating pediatric patients [fig_ref] Figure 6: Algorithm for fertility preservation in pediatric cancer patients [/fig_ref]. When considering the subsequent CQs, we aimed to provide recommendations that enable oncologists caring for pediatric cancer patients to properly assess the risk of reduced fertility after cancer treatment within the short time from the diagnosis until the initiation of treatment and to implement a fertility preservation intervention in cooperation with reproductive medicine specialists. ## Ethical considerations specific for pediatric patients When counselling pediatric patients regarding fertility preservation and/or providing them with a fertility preservation intervention, health care providers must consider ethical considerations that are specific to this population. Because there is currently no guidance on informed consent/assent in pediatric practice in Japan, below we discuss the ethical considerations specific for pediatric patients that must be taken into account in dealing with fertility preservation issues in pediatric cancer patients by referring to the American Academy of Pediatrics (AAP) Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations [8], the Guidance on Clinical Investigation of Medicinal Products in the Pediatric Population, and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Assent, a concept advocated by the AAP in 1995, means active agreement to undergo any medical intervention by a minor who is informed to the fullest extent that their age permits . The assent process consists of the following 4 steps: (1) the patient's understanding of his/her condition to the fullest extent that his/her age permits; (2) explanation to the patient about expected outcomes of the diagnostic or therapeutic intervention proposed and their significance; (3) assessment of the level of the patient's understanding of his/her condition and exploration of factors that affect the patient's decision making; and iv) expression of the patient's will whether or not to agree to undergo the medical intervention proposed. Thus, the assent process does not merely aim to receive agreement from a pediatric patient but, more importantly, to receive agreement from a pediatric patient that is given from his/her own will after being informed to the fullest extent that his/her age permits and understanding the information. Through these steps, pediatric patients develop an ability to understand their conditions and to make decisions by themselves by considering their conditions. The AAP recommends that for decision making in pediatric practice, assent should be received from pediatric patients who have reached an intellectual age of 7 years or above. The APP also recommends that before giving any intervention to adolescents who have sufficient ability to understand, their informed consent should be obtained in addition to their parents' consent. The Guidance on Clinical Investigation of Medicinal Products in the Pediatric Populationrecommends that written assent to participate in a clinical study should be received from pediatric patients aged 12 years or older. Regarding the ages of pediatric patients in whom assent generally applies, the Guidance also recommends that all study participants should be informed to the fullest extent possible about the study in language and terms that they are able to understand. In the Questions and Answers on this Guidance, the Evaluation and Licensing Division of the Pharmaceutical and Medical Safety Bureau of the Ministry of Health, Labour and Welfare expresses its opinion that those aged 7 years or above are able to understand a simple explanation. In Japan, the Ethical Guidelines for Medical and Health Research Involving Human Subjectsalso make recommendations on informed consent and assent from minors. According to the recommendations, minors who have completed compulsory education or are aged 16 years or above should be regarded as having sufficient ability to decide whether or not to participate in research and as qualified to give informed consent and the best effort must be made to receive assent from minors who have not completed compulsory education and are aged under 16 years. Based on these guidance/guideline recommendations, before providing any fertility preservation intervention to pediatric patients, it is desirable to (1) obtain informed consent from the patients and their parents if the patients have completed compulsory education or are aged 16 years or above and are considered to have sufficient ability to make decisions and (2) inform the patients in an age-specific manner and to receive their assent, in addition to their parents' informed consent, if the patients have not completed compulsory education and are aged under 16 years. ## Clinical question 1 Which pediatric cancer patients are eligible for fertility preservation? To answer this question, we also considered the aspect of the level of understanding of the patient and of the patient's parents, as well as the ethical background of fertility preservation in pediatric patients. For this purpose, we first considered the infertility problems encountered by survivors of pediatric cancers [bib_ref] of Clinical Oncology clinical practice guideline update, Loren [/bib_ref]. Here, we discussed the indications for fertility preservation in pediatric cancer patients by considering their ages and whether (1) planned chemo-or radiotherapy would impair or completely abolish gonadal function, (2) survival is highly probable after cancer treatment, (3) the patients have enough time and physical strength to receive any fertility preservation intervention, and (4) the patient and/or the patient's parents can fully understand that ovarian tissue cryopreservation remains experimental. The solid tumors we reviewed included brain tumors (e.g., medulloblastoma and germ cell tumor), neuroblastoma, noncentral nervous system germ cell tumor, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, retinoblastoma, and nonrhabdomyosarcoma soft tissue tumor. Fertility preservation is indicated for patients who require a treatment approach for these types of pediatric cancers that is likely to cause infertility, under consideration of the reported outcomes and probability of survival after treatment, and who have enough time and physical strength to undergo a fertility preservation intervention before initiation of the treatment. Standard chemotherapy for pediatric hematologic malignancies (e.g., leukemias and lymphomas) reduces fertility in less than 20% of patients. However, fertility preservation is indicated for pediatric patients who are to receive any procarbazine-containing chemotherapy regimen for Hodgkin's disease or to undergo radiotherapy directed toward the gonadal system or pelvis or hematopoietic cell transplant (HCT). Patients undergoing HCT frequently experience an irreversible reduction of fertility, although the risk of infertility varies across the conditioning regimens performed before HCT. Therefore, postpubertal pediatric cancer patients and their parents should be counselled to inform them about the concept of fertility preservation. We also specifically reviewed fertility preservation options for female and male pediatric cancer patients. In prepubertal female patients, ovarian tissue cryopreservation may be considered and should be proposed, even though this technique remains experimental. The Edinburgh criteria [bib_ref] Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer, Bines [/bib_ref] should be followed to determine which female patients are eligible for this fertility preservation option. Ovarian tissue cryopreservation is also an option for postpubertal female patients if cancer treatment needs to be initiated quickly, and it may be chosen after full counselling of the patients and their family. Another option for postpubertal female patients is unfertilized oocyte cryopreservation. In male pediatric cancer patients, no technically established fertility preservation options are available for prepubertal patients. However, all postpubertal patients who are interested in having a child should preferably be offered counselling on fertility preservation, more concretely, on sperm cryopreservation before initiation of cancer treatment. ## Recommendation 1 Regardless of the type of cancer, pediatric cancer patients scheduled to receive any treatment that is likely to cause infertility should be considered eligible for fertility preservation, whereby the treatment regimen used and the probability of survival after cancer treatment should also be taken into account. (Recommendation Grade B). ## Clinical question 2 Which fertility preservation options can be offered to pediatric cancer patients? The therapeutic outcomes for pediatric cancers have been improving such that the 5-year survival rate is reported to have reached 80% in all pediatric cancer patients. This higher survival rate has increased the importance of reducing the risk of long-term complications of cancer treatment and helping survivors achieve better QOL. Fertility preservation is an important challenge, among others. In this CQ, we conducted an evidence-based assessment and review of fertility preservation options that can be offered to pediatric cancer patients. ## Recommendation 2 In pediatric cancer, different fertility preservation options are indicated in prepubertal ver-sus postpubertal patients and male versus female patients. Therefore, the recommendation is subdivided according to the individual populations. 2-1. Unfertilized oocyte cryopreservation may be considered in postpubertal female patients. (Recommendation Grade C1). 2-2. Ovarian tissue cryopreservation is the only fertility preservation option for prepubertal female patients. It may also be considered for postpubertal female patients if there is a need for urgent cancer treatment. This technique still remains experimental, but it may be performed in the context of clinical trials in centers with the necessary expertise. ## Clinical question 3 Can treatment of pediatric cancers be delayed to allow fertility preservation? Pediatric cancer patients can receive a fertility preservation intervention only if the intervention will have no adverse effect on the prognosis of the cancer. However, the intervention may require the initiation of cancer-directed therapy to be delayed. Because pediatric cancer is generally a rapidly progressing disease, it is desirable to initiate treatment quickly after diagnosis. Hence, when considering this CQ, we discussed whether treatment of pediatric cancer can be delayed to enable fertility preservation. ## Recommendation 3 Delaying cancer-directed therapy may be considered only if the delay will have no adverse effect on the prognosis of the cancer. (Recommendation Grade C1). ## Clinical question 4 How should pediatric cancer patients be counseled regarding pregnancy and parturition after completion of treatment? With the improvement of therapeutic outcomes, some pediatric cancer patients have achieved long-term survival, and survivors of pediatric cancer may become able to have a child. Both patients and health care providers have become more aware of the risks of infertility and premature ovarian failure associated with cancer treatment and of the maternal and offspring health status among cancer survivors who maintain fertility. Evidence shows that cancer treatment is unlikely to cause an increased frequency of congenital anomalies in offspring, but there are some reports of an increased risk of premature parturition if the mother has previously received cancer treatment. We discussed the risks for pregnancy and parturition in survivors of pediatric cancers by considering the results of large overseas cohort studies. ## Chapter 5: hematologic cancers ## General remarks The hematologic malignancies that rarely occur in young individuals are referred to only in Part 1 of this guideline [bib_ref] Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation..., Miyuki [/bib_ref] and were not addressed in the following CQs. Instead, in Clinical Questions 1 through 5, we considered the common effects on fertility of treatments for hematologic malignancies (chemotherapy, radiotherapy, molecular targeting therapy, and HCT) and the fertility preservation methods available for patients with these malignancies. In Clinical Question 6, we reviewed whether fertility preservation in a patient with a hematologic malignancy can have any adverse effects on offspring if the patient or the patient's partner becomes pregnant after cancer treatment [fig_ref] Figure 7: Algorithm for fertility preservation in patients with hematologic malignancy [/fig_ref]. ## Clinical question 1 Which patients with hematologic malignancies are eligible for fertility preservation? Treatments for hematologic malignancies include chemotherapy, radiotherapy, molecular targeting therapy, and HCT. These treatments can affect spermatogenesis and menstruation. Standard chemotherapy regimens for acute leukemia, non-Hodgkin's lymphoma, and Hodgkin's disease have a low risk for infertility, whereas procarbazine-containing chemotherapy regimens for Hodgkin's disease, gonadal/pelvic irradiation, and HCT conditioning considerably reduce fertility in both male and female patients. Thus, a hematologic malignancy may progress to a stage that requires treatment that will have a marked effect on fertility. Hence, we discussed which patients with hematologic malignancies are eligible for fertility preservation. Recommendation 1 1-1. Regardless of the type of hematologic malignancy, whenever possible fertility preservation should be considered before initiation of cancer-directed therapy. (Recommendation Grade C1). 1-2. If fertility preservation is not feasible before initiation of cancer treatment, it may be considered again when any change is made to the treatment strategy. (Recommendation Grade C1). ## Acute leukemia (cq3) Other hematologic malignancies (refer to Part 1 of these guidelines) ## Hematopoietic cell transplant anticipated (cq2, cq5) Pregnancy and parturition after fertility preservation (CQ6) ## Malignant lymphoma (cq4) Sperm cryopreservation Embryo (fertilized oocyte) cryopreservation, (unfertilized) oocyte cryopreservation, or ovarian tissue cryopreservation ## Ovarian shielding ## Clinical question 2 How should patients with hematologic malignancies be counselled regarding the impact of HCT on their fertility? HCT conditioning with high-dose chemotherapy and/ or total body irradiation has a greater impact on fertility than other cancer treatments. With the improved outcomes of HCT, the number of long-term survivors of hematologic malignancies has been increasing. Because loss of fertility would markedly impair survivors' QOL, we discussed how patients with hematologic malignancies should be counselled regarding the impact of HCT on their fertility. 2-2. Patients may be informed that it is uncertain whether their fertility can be better preserved with reduced intensity conditioning before HCT. (Recommendation Grade C1). ## Clinical question 3 Which fertility preservation methods can be recommended for patients with acute leukemia who are interested in having a child? Acute leukemia frequently affects young individuals. The first treatment goal is to achieve complete remission, which requires urgent intensive combination chemotherapy with cytotoxic agents. Female patients in particular have no time to spare for a fertility preservation intervention before initiation of cancer treatment. We discussed which fertility preservation methods can be recommended for patients with acute leukemia who will potentially receive treatment that is likely to reduce their fertility. Recommendation 3 3-1. Although initial standard chemotherapies for hematologic malignancies are usually not highly gonadotoxic, in centers where they are available reproductive specialists should be consulted promptly. (Recommendation Grade B). ## 3-2. embryo (fertilized oocyte) cryopreservation is recommended for female patients who have a male partner. (recommendation grade b). 3-3. Unfertilized oocyte cryopreservation may be considered for female patients who do not have a male partner. (Recommendation Grade C1). 3-4. In general, ovarian tissue cryopreservation is not recommended for female patients who do or do not have a male partner because of the risk of leukemic cells contaminating tissue; however, this technique is currently performed in some centers in an experimental manner with the expectation that future developments may make it a feasible procedure. (Recommendation Grade C2). 3-5. Use of GnRH agonists may be considered for the purpose of controlling menstruation but is not recommended for the purpose of fertility preservation. (Recommendation Grade C2). 3-6. Sperm cryopreservation is recommended for postpubertal male patients and, whenever possible, should be performed before initiation of treatment. (Recommendation Grade B). ## Clinical question 4 Which fertility preservation methods can be recommended for patients with other hematologic malignancies who are interested in having a child? In this CQ, we focused on lymphoma and chronic myeloid leukemia, which-like acute leukemia-often affect individuals at reproductive age. Other hematologic malignancies typically occur at older ages, and little information is available on the impacts on fertility of the malignancies and the associated treatments. Therefore, these malignancies were not addressed in this CQ, but they are briefly reviewed in Part 1 of this guideline. Patients scheduled to receive lymphoma treatments, which have a low risk for infertility (refer to Chapter 5, CQ1), are likely to maintain fertility after treatment and should not unnecessarily delay initiation of cancer treatment. However, lymphoma may potentially progress to a stage that requires treatment with a high risk for infertility (e.g., alkylating agent-based regimens and HCT). Imatinib, a drug used to treat chronic myeloid leukemia, has been shown to be teratogenic, but there is no definitive evidence for the teratogenicity of second-or later generation tyrosine kinase inhibitors or for their impacts on fertility. Because in the future, an increasing number of newer molecular targeting agents will be introduced into the market for the treatment of chronic myeloid leukemia, attention should be paid to the individual teratogenicity and impacts on fertility of these agents. Considering these circumstances, we discussed which fertility preservation methods can be recommended for patients with lymphoma and chronic myeloid leukemia. ## Clinical question 5 Which fertility preservation methods can be recommended for patients undergoing HCT who are interested in having a child? HCT is likely to cause patients to lose fertility. When undergoing HCT, patients with hematologic malignancies may have already lost fertility because of the effects of the underlying malignancy or prior cancer treatments. Even patients who have not lost fertility often lose it after undergoing HCT. Some patients with acute leukemia become eligible for HCT after failure of initial induction chemotherapy. Therefore, patients with hematologic malignancies should be counselled regarding fertility preservation before initiation of treatment. In this CQ, we discussed which fertility preservation methods can be recommended for patients undergoing HCT, regardless of the type of cancer. Recommendation 5 5-1. Embryo (fertilized oocyte) cryopreservation is recommended as long as this intervention does not compromise cancer treatment outcomes. (Recommendation Grade B). 5-2. Unfertilized oocyte cryopreservation may be considered as long as this intervention does not compromise cancer treatment outcomes. (Recommendation Grade C1). 5-3. Use of GnRH agonists may be considered for the purpose of controlling menstruation but is not recommended for the purpose of fertility preservation. (Recommendation Grade C2). 5-4. Sperm cryopreservation is recommended for male patients and, whenever possible, should be performed before initiation of treatment. . 5-5. Testicular shielding is not recommended. (Recommendation Grade C2). ## Clinical question 6 How should patients with hematologic malignancies be counselled regarding posttreatment pregnancy and parturition? Recent improvements in cancer treatments and technological advancements in reproductive medicine have enabled an increasing number of patients with hematologic malignancies to conceive and give birth to a child after completing cancer treatment. However, because the anti-cancer agents used and the duration of their use, as well as recurrence risk, vary across the different types of malignancy, the question when pregnancy may be considered after completion of cancer treatment should be discussed from the aspects of both the impacts of conception on the prognosis (e.g., recurrence) of malignancy and the embryofetal toxicity of cancer treatment. In this CQ, we discussed how patients with hematologic malignancies should be counselled regarding pregnancy and parturition after completion of cancer treatment. Recommendation 6 6-1. Patients should be informed that it is difficult to apply uniform criteria to determine the acceptable timing for considering pregnancy after completion of cancer treatment. (Recommendation Grade B). 6-2. Patients with hematologic malignancies should be informed that if they or their partners have become pregnant after cancer treatment it is uncertain whether the risk of congenital anomalies in their children is higher than in children of parents who did not previously receive cancer treatment. (Recommendation Grade B). 6-3. Female patients who have undergone abdominal/ pelvic irradiation should be closely monitored during pregnancy until parturition to prevent spontaneous abortions and premature deliveries. (Recommendation Grade B). ## 3 ## Chapter 6: bone and soft tissue tumors ## General remarks Bone and soft tissue tumors are of mesenchymal origin, and the majority of malignant bone and soft tissue tumors are sarcomas. Because bone and soft tissue sarcomas often affect children, adolescents, and young adults (aged 15-39 years), many patients with this malignancy are eligible for fertility preservation [fig_ref] Figure 3: Algorithm [/fig_ref]. Sarcomas can develop in any part of the body, but many of them occur in the pelvis and can thus affect the patient's ability to become pregnant and give birth (Clinical Question 4). Surgical resection is the mainstay treatment for bone and soft tissue sarcomas, and chemo-and radiotherapy are also used in the adjuvant setting [fig_ref] Figure 3: Algorithm [/fig_ref]. Multi-modality therapy has considerably improved the prognosis of bone and soft tissue sarcomas and increased the number of long-term survivors of these malignancies. In treating bone and soft tissue sarcomas, it is important to enable these survivors to have the opportunity to preserve their fertility [fig_ref] Figure 8: Algorithm [/fig_ref]. ## Clinical question 1 Which patients with malignant bone and soft tissue tumors are eligible for fertility preservation? Multi-modality therapy for malignant bone and soft tissue tumors has improved patients' therapeutic outcomes and raised the expectations for maintaining fertility after cancer treatment. In this CQ, we discussed which patients with malignant bone and soft tissue tumors are eligible for fertility preservation. ## Recommendation 1 Patients with malignant bone and soft tissue tumors who will be at high risk for infertility, including those requiring chemotherapy and those with tumors of pelvic or retroperitoneal origin, should be considered eligible for fertility preservation, whereby the treatment regimens used and the probability of survival should be taken into account. . ## Clinical question 2 Which fertility preservation options can be offered to patients with malignant bone and soft tissue tumors? Recent advancements in multi-modality therapy for malignant bone and soft tissue tumors have led to improved therapeutic outcomes in CAYA patients, but concerns remain about the impacts of treatments on patients' gonadal function. We discussed which fertility preservation methods can be recommended for patients with malignant bone and soft tissue tumors who are interested in having a child after cancer treatment. ## Clinical question 3 When can a patient with malignant bone and soft tissue tumors who is interested in having a child consider pregnancy after completing cancer-directed therapy? We performed a literature review to gather information on patients with high-grade bone and soft tissue tumors who became pregnant and gave birth to a child after completing chemotherapy and discussed the acceptable timing for patients with such tumors to consider conception. Recommendation 3 3-1. If any teratogenic anti-cancer drug is used, contraception may be considered until the drug and its metabolite(s) are no longer detectable in the body or until they can assume to no longer be present on the basis of the drug half-life. (Recommendation Grade C1). 3-2. In male patients, sperm cryopreservation before medical cancer treatment or total body irradiation can enable later intracytoplasmic sperm injection at any time. (Recommendation Grade B). 3-3. During the first 2 years after completion of treatment, pregnancy may be considered if patients are made fully aware of the high risk of cancer recurrence and metastasis during this time. (Recommendation Grade C1). ## Clinical question 4 Are patients who are treated for malignant bone and soft tissue tumors arising from the pelvis able to become pregnant and give birth to a child? Multi-modality therapy for malignant bone and soft tissue tumors has improved the therapeutic outcomes of these tumors so that young female survivors of these tumors more often have the opportunity to become pregnant and give birth to a child. Hence, we discussed whether female patients with malignant bone and soft tissue tumors arising from the pelvis can become pregnant and give birth to a child after cancer treatment. ## Recommendation 4 Despite the presence of various risks, female patients with pelvic malignant bone and soft tissue tumors may become pregnant and deliver babies (transvaginally) after cancer treatment. (Recommendation Grade C1). ## Chapter 7: brain cancers ## General remarks Pediatric brain tumors for which chemo-and radiotherapy can compromise fertility preservation are medulloblastoma, pineoblastoma, and ependymoma. The pediatric brain tumors that can cause hypothalamic/pituitary dysfunction or require chemo-and radiotherapy and thus compromise fertility preservation are central nervous system germ cell tumor, optic pathway/hypothalamic pilocytic astrocytoma, and other types of astrocytoma. Craniopharyngiomas can cause hypothalamic/pituitary dysfunction or require radiotherapy that can compromise fertility preservation. Because of the prognosis, careful counselling regarding fertility preservation is needed in patients with diffuse intrinsic pontine glioma, thalamic astrocytoma, and some embryonic tumors (embryonal tumor with multilayered rosettes, embryonal tumor with abundant neuropil and true rosettes, atypical teratoid rhabdoid tumor, and choroid plexus carcinoma). Unlike pediatric patients, adolescent and young adult patients (aged 15-39 years) with brain tumors are likely to have a heterosexual partner at the time of diagnosis. Glioma is more common in adolescent and young adult patients than in pediatric patients and is often treated with temozolomide; before starting radiotherapy or chemotherapy with temozolomide, fertility preservation should be considered [fig_ref] Figure 9: Algorithm [/fig_ref]. ## Clinical question 1 Which fertility preservation methods can be offered to patients with brain tumors? Compared with other malignancies, brain tumors more often affect CAYA populations. Surgery-, radiotherapy-or chemotherapy-induced impairment of hypothalamic, pituitary, and gonadal functions can cause sexual dysfunction and/ or reduced fertility after treatment. These problems are more serious in younger patients and may only become apparent a long time after complete cure of the underlying malignancy. Therefore, it is important to fully assess the impacts of cancer treatment on reproductive function and to discuss fertility preservation methods before initiation of treatment. In this CQ, we reviewed optimal fertility preservation methods for patients with brain tumors if i) surgery-and brain irradiation-induced hypothalamic/pituitary dysfunction is expected to cause reproductive dysfunction or ii) chemotherapy or spinal irradiation may directly impair gonadal function. Recommendation 1 Different fertility preservation options are indicated for prepubertal versus postpubertal patients and male versus female patients with brain tumors. Therefore, the recommendation is subdivided according to the individual populations. 1-1. Full pretreatment counselling, posttreatment monitoring of ovarian function, and appropriate estrogen/progestin replacement therapy are recommended for patients who are likely to become infertile only because of hypothalamic/pituitary hypofunction resulting from disease involvement or cancer treatment (e.g., surgery and chemoand radiotherapy ## Clinical question 2 Is delayed initiation of cancer-director therapy permitted in patients with brain tumors who are interested in fertility preservation to afford them the opportunity to receive a fertility preservation intervention before the start of cancer treatment? An increasing number of patients with brain tumors achieve remission and consider pregnancy after completing cancer treatment. An increasing number of patients are also interested in fertility preservation before the start of cancer treatment. There are about 150 types of brain tumors, and these tumors are treated in various ways for various durations with treatments that impair fertility to various degrees. Hence, we discussed how long initiation of brain tumor treatment can be delayed if patients request fertility preservation. ## Recommendation 2 It is desirable to initiate cancer treatment as quickly as possible by taking the optimal timing of treatment of the underlying malignancy and the patient's status into account. (Recommendation Grade C1). ## Clinical question 3 When can a patient with a brain tumor who is interested in having a child consider pregnancy after completing cancerdirected therapy? With the recent improvement in therapeutic outcomes of brain tumors, an increasing number of young patients with brain tumors are considering pregnancy and are interested in having a child after completing cancer treatment. This question is particularly relevant in patients who are in sustained remission and who have been permitted by their physicians to consider pregnancy. Patients diagnosed with brain tumors, while considering pregnancy may also think about the acceptable timing of pregnancy in relation to cancer treatment. Because patients with brain tumors may have disease-or treatment-related complications, such as hypothalamic/pituitary dysfunction, neurocognitive disorders, and epilepsy, careful counselling is needed for those who are considering pregnancy. Hence, we discussed the acceptable timing for patients with brain tumors to initiate pregnancy attempts. Recommendation 3 3-1. If any teratogenic anti-cancer drug is used, contraception may be considered until the drug and its metabolite(s) are no longer detectable in the body or until the time of corresponding duration has elapsed. (Recommendation Grade C1). 3-2. To determine whether to permit patients with brain tumors to consider pregnancy, a comprehensive evaluation by specialists in related fields may be considered. (Recommendation Grade C1). ## Chapter 8: digestive system cancers ## General remarks Digestive system cancers include cancers of the esophagus, stomach, colon, liver, biliary tract, and pancreas. All these cancers frequently affect elderly individuals, and many juvenile-onset cancers of digestive organs are hereditary (Clinical Question 2). If diagnosed at early stages, most digestive system cancers are curable with endoscopic intervention or surgical resection. In patients with advanced disease, health care providers should consider the potential impacts on fertility of intrapelvic surgery or perioperative adjuvant chemo-or chemoradiotherapy (Clinical Questions 1 & 2). In patients with digestive system cancers that are directly invading or metastatic to genital organs (e.g., ovaries) or are unresectable or recurrent, the feasibility of fertility preservation should be carefully assessed by considering the prognosis of the disease (Clinical Questions 1 & 2). In general, only a few of the anticancer drugs frequently used to treat digestive system cancers are highly gonadotoxic, but health care providers should be aware that all such drugs have teratogenicity. Little evidence is available on fertility in patients with digestive system cancers; the fertility preservation methods available for digestive system cancer patients (Clinical Question 3) and the acceptable timing for those patients to consider pregnancy after cancer treatment (Clinical Question 4) are the same as those recommended for patients with cancers of other organs. ## Clinical question 1 Which patients with digestive system cancers are eligible for fertility preservation? Until recently, there have been few active discussions about fertility preservation in patients with digestive system cancers because these cancers more frequently affect elderly individuals and are often refractory to treatment. However, recent improvements in therapeutic outcomes with the advancement of multi-modality therapy and diagnostic procedures has raised public awareness of the importance of fertility preservation in patients with these cancers. However, uncertainties remain about the disadvantages of interventions to preserve fertility in patients with digestive system cancers, and the optimal timing and method for such interventions remain to be established. For patients with digestive system cancers, chemoradiotherapy for rectal cancer has a high risk for infertility in female patients, whereas most standard chemotherapy regimens have an intermediate-to-low risk (ASCO 2013 Clinical Practice Guideline Update). The ASCO Clinical Practice Guideline Update on Fertility Preservation for Patients With Cancer recommends that health care providers caring for patients with cancer should address the possibility of infertility as early as possible before treatment starts. Hence, we extensively reviewed the risk of reduced fertility resulting from treatments for digestive system cancers and the potential disadvantages of fertility preservation methods and thereby focused on colorectal cancer, because it is the cancer where this issue has been addressed most frequently. ## Recommendation 1 Fertility preservation may be considered in patients scheduled to receive any treatment that is likely to cause infertility, whereby the treatment regimens used and the probability of survival should be taken into account. (Recommendation Grade C1). ## Clinical question 2 How should patients with digestive system cancers be counselled regarding fertility preservation? We performed a literature review to identify the pathological conditions and treatments related to digestive system cancers that require counselling about fertility preservation. Recommendation 2 2-1. Patients diagnosed with hereditary cancer should be counselled about genetic testing and screening for potential synchronous or asynchronous multiple cancers of genital organs and associated fertility problems. (Recommendation Grade B). 2-2. Patients with curable cancers may be educated about the possibility of reduced fertility resulting from operative complications, perioperative adjuvant radiotherapy, and perioperative adjuvant chemotherapy. (Recommendation Grade C1). 2-3. Patients with advanced digestive system cancers that are directly invading or metastatic to genital organs may be counselled regarding the proposed treatments directed toward the genital organs from the aspects of both the expected course and the prognosis of the malignancy and fertility preservation. (Recommendation Grade C1). ## Clinical question 3 Which fertility preservation options can be offered to patients with digestive system cancers? Various fertility preservation options can be offered to CAYA cancer patients, although the level of recommendation varies. Because fertility preservation techniques and options are reviewed in detail in Part 1 of this guideline, in this CQ, we reviewed whether any specific techniques or options can be offered to patients with digestive system cancers. ## Recommendation 3 In principle, no specific fertility preservation methods are available for patients with digestive system cancers, but this patient population can be offered the same methods as are used in patients with other malignancies (refer to Part 1 of this guideline for further details). The techniques described below may be considered, provided that their indications are carefully assessed and they are used in a safe manner. 3-1. Embryo (unfertilized oocyte) cryopreservation is recommended for female patients who have a male partner. (Recommendation Grade B). 3-2. Unfertilized oocyte cryopreservation may be considered for female patients who do not have a male partner. (Recommendation Grade C1). 3-3. Ovarian tissue cryopreservation, although it remains experimental, may be considered in centers with the necessary expertise for female patients who do or do not have a male partner if there is a need for urgent cancer-directed therapy such that there may be limited time for embryo (fertilized oocyte) or unfertilized oocyte cryopreservation or if ovulation induction is difficult for oocyte harvesting (e.g., in prepubertal females). (Recommendation Grade C1). ## 3-4. Ovarian transposition (oophoropexy) may be considered in female patients when radiotherapy is performed for rectal cancer. (Recommendation Grade C1). 3-5. Sperm cryopreservation is recommended for male patients. . 3-6. Nerve-sparing surgery is recommended if surgery is likely to cause erectile/ejaculatory dysfunction. (Recommendation Grade B). ## Clinical question 4 When can a patient with digestive system cancer who is interested in having a child consider pregnancy after completing cancer-directed therapy? Multi-modality therapy, which primarily comprises surgery, chemotherapy, and radiotherapy, is used to treat digestive system cancers, and its impacts on subsequent conception and pregnancy remain to be determined. For patients interested in having a child after completing cancer-directed therapy, the question when they are permitted to consider pregnancy after completion of cancer treatment is particularly important. ## Recommendation 4 If any anti-cancer drug used is teratogenic, contraception may be considered until the drug and its metabolite(s) are no longer detectable in the body or until they can assume to no longer be present on the basis of the drug halflife. (Recommendation Grade C1). Guideline Review Committee ## Supplementary information The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s10147-021-02076-7. 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://creativecommons.org/licenses/by/4.0/. [fig] Figure 3: Algorithm [/fig] [fig] Figure 5: Algorithm [/fig] [fig] Recommendation 3 3 - 1: In male patients, sperm cryopreservation before initiation of cancer treatment can enable later intracytoplasmic sperm injection at any time. (Recommendation Grade B).3-2. Contraception for an appropriate period of time may be considered in patients who have used any drug that is teratogenic or does not have an established embryofetal safety. (Recommendation Grade C1). [/fig] [fig] Figure 6: Algorithm for fertility preservation in pediatric cancer patients (Chapter 4, Clinical Questions 1-4). TESE testicular sperm extraction Educate patients about the possibility of reduced fertility resulting from cancer-directed therapy (CQ1)Counsel patients regarding fertility preservation options (CQ2) Discuss whether fertility preservation is compatible with cancer-directed therapy (CQ3) [/fig] [fig] .: Ovarian transposition (oophoropexy) is recommended in both prepubertal and postpubertal female patients if pelvic irradiation is performed (Recommendation Grade B) 2-4 Sperm cryopreservation is recommended in postpubertal male patients (Recommendation Grade B) 2-5 No fertility preservation options are currently indicated for prepubertal male patients (No Recommendation Grade) [/fig] [fig] Recommendation 4 4 - 1: Survivors of pediatric cancers should be informed that there is no direct evidence for a significant increase in the risk of congenital anomalies in children born to parents who have previously received cancer treatment. (Recommendation Grade B). 4-2. Female survivors of pediatric cancers should be informed that risks during pregnancy and at parturition are different across different types of cancer, ages at treatment, and treatment regimens used. (Recommendation Grade B). 4-3. Female patients who have undergone abdominal/ pelvic irradiation should be informed that they have to be closely monitored during pregnancy until parturition to prevent spontaneous abortions and premature deliveries. (Recommendation Grade B). [/fig] [fig] Figure 7: Algorithm for fertility preservation in patients with hematologic malignancy (Chapter 5, Clinical Questions 1-6) Patients with hematologic malignancy who may be interested in having a child Yes Educate patients about the possibility of reduced fertility resulting from cancer-directed therapy (CQ1) Patient is interested in having a [/fig] [fig] Recommendation 2 2 - 1: Both male and female patients should be informed that HCT often leads to irreversible impairment of fertility. (Recommendation Grade B). [/fig] [fig] Recommendation 2: Different fertility preservation options are indicated for prepubertal versus postpubertal patients and male versus female patients with malignant bone and soft tissue tumors. Therefore, the recommendation is subdivided according to the individual populations. 2-1. Embryo (fertilized oocyte) cryopreservation is recommended for female patients who have a male partner if they can wait for 2 weeks or more to initiate cancer chemotherapy. (Recommendation Grade B). 2-2. Unfertilized oocyte cryopreservation may be considered for postpubertal female patients who do not have a male partner. (Recommendation Grade C1). [/fig] [fig] Figure 8: Algorithm [/fig] [fig] Figure 9: Algorithm [/fig]	None	https://link.springer.com/content/pdf/10.1007/s10147-021-02076-7.pdf	None
83957bc9edd154d79e04a769cbe53b5bcaa72d7c	pubmed	Management of Diabetes in Long-term Care and Skilled Nursing Facilities: A Position Statement of the American Diabetes Association	Management of Diabetes in Long-term Care and Skilled Nursing Facilities: A Position Statement of the American Diabetes Association Diabetes is more common in older adults, has a high prevalence in long-term care (LTC) facilities, and is associated with significant disease burden and higher cost. The heterogeneity of this population with regard to comorbidities and overall health status is critical to establishing personalized goals and treatments for diabetes. The risk of hypoglycemia is the most important factor in determining glycemic goals due to the catastrophic consequences in this population. Simplified treatment regimens are preferred, and the sole use of sliding scale insulin (SSI) should be avoided. This position statement provides a classification system for older adults in LTC settings, describes how diabetes goals and management should be tailored based on comorbidities, delineates key issues to consider when using glucose-lowering agents in this population, and provides recommendations on how to replace SSI in LTC facilities. As these patients transition from one setting to another, or from one provider to another, their risk for adverse events increases. Strategies are presented to reduce these risks and ensure safe transitions. This article addresses diabetes management at end of life and in those receiving palliative and hospice care. The integration of diabetes management into LTC facilities is important and requires an interprofessional team approach. To facilitate this approach, acceptance by administrative personnel is needed, as are protocols and possibly system changes. It is important for clinicians to understand the characteristics, challenges, and barriers related to the older population living in LTC facilities as well as the proper functioning of the facilities themselves. Once these challenges are identified, individualized approaches can be designed to improve diabetes management while lowering the risk of hypoglycemia and ultimately improving quality of life.The epidemic growth of type 2 diabetes in the U.S. has disproportionately affected the elderly. In 2012, the prevalence of diabetes among people aged $65 (25.9%) was more than six times that of people aged 20-24 years (4.1%) (1). In the long-term care (LTC) population, the prevalence of diabetes ranges from 25% to 34% across multiple studies (2-4). The high prevalence of diabetes among older adults has contributed to the unsustainable growth of health care costs in the U.S. The estimated total cost of diabetes in 2012 was $245 billion. Average medical expenditures for people with diagnosed diabetes were 2.3 times higher than among people without diabetes. LTC costs for people with diabetes were estimated at $19.6 billion in 2012(5).The high prevalence of diabetes in older adults is due to age-related physiological changes, such as increased abdominal fat, sarcopenia, and chronic low-grade inflammation, that lead to increased insulin resistance in peripheral tissues and relatively impaired pancreatic islet function (6). Diabetes increases the risk of cardiovascular and microvascular complications but also increases the risk of common geriatric syndromes, including cognitive impairment, depression, falls, polypharmacy, persistent pain, and urinary incontinence. The older diabetes population is highly heterogeneous in terms of comorbid illnesses and functional impairments. These characteristics have frequently been used to exclude older individuals from randomized clinical trials. The heterogeneity of the population and the lack of clinical trial data represent challenges to determining standardized intervention strategies that can work for all older adults with diabetes. As the vast majority of the patients with diabetes in LTC facilities have type 2 diabetes, most recommendations in this position statement are directed toward that population. However, we have suggested specific recommendations for patients with type 1 diabetes when appropriate. ## General approach to care Recommendations c Management of diabetes among older adults residing in LTC facilities is challenging due to heterogeneity in this population. Careful evaluation of comorbidities and overall health is needed before developing goals and treatment strategies for diabetes management. E c Diabetes management in LTC patients (residents) requires different approaches because of unique challenges faced by this population and the workings of LTC facilities. E ## Need for different approaches for ltc population The challenge of caring for older adults with diabetes arises not only from their clinical heterogeneity but also from their considerable variability in living arrangements and social support, which significantly impacts diabetes management. Some older adults live independently, some in assisted care facilities that provide partial support with medical management, and some in fully supervised LTC facilities. As the challenges and self-care responsibilities change in these different environments, different recommendations are needed for each setting on how to manage diabetes in individual patients [fig_ref] Table 1 -: Characteristics of older adults and their diabetes management based on living situation... [/fig_ref]. The management strategies for community-dwelling and hospitalized patients with diabetes have been previously described by the American Diabetes Association (ADA). ## Current literature in management of diabetes in ltc patients Several organizations have developed diabetes guidelines for patients living in LTC settings. Almost all of these guidelines emphasize the need to individualize care goals and treatments related to diabetes, the need to avoid sliding scale insulin (SSI) as a primary means of regulating blood glucose, and the importance of providing adequate training and protocols to LTC staff who may be operating without the presence of a practitioner for prolonged periods. ## The american medical directors association guidelines The most extensive guideline available was developed by the American Medical Directors Association (AMDA) (11). These guidelines include a 12-step program for LTC staff that comprises all phases of diabetes care from diabetes detection to institutional quality assessment. The glucoselowering steps advocated by the AMDA are consistent with those published in the ADA position statement on patientcentered individualized approaches to glucose lowering in adults with diabetes [bib_ref] Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update..., Inzucchi [/bib_ref]. In terms of A1C goals, the AMDA guidelines are also consistent with those recommended in the 2012 ADA consensus report [bib_ref] Diabetes in older adults, Kirkman [/bib_ref]. To achieve goals, it is acknowledged that the notion of a "diabetic diet" is outdated and that a more liberal diet may be appropriate among LTC patients. The guidelines are fairly nonspecific with regard to choice of glucoselowering agents but advise practitioners to avoid the use of SSI and to transition to scheduled basal insulin (and prandial as required) shortly after admission. Beyond these long-term goals of care, the AMDA guidelines provide recommendations to LTC staff regarding when to call a practitioner (11). The guidelines recommend that LTC facilities develop their own facility-specific policies and procedures for hypoglycemia treatment. These guidelines emphasize that frail patients with cognitive impairment may present with atypical symptoms, mainly neuroglycopenic or behavioral in nature. The unique needs of patients with diabetes who are terminally ill or have limited life expectancy are also discussed. ## Other guidelines Along with the AMDA guidelines, guidelines from the ADA, the International Association of Gerontology and Geriatrics (IAGG), and the European Diabetes Working Party for Older People (EDWPOP) have provided selective guidance for LTC populations. The ADA consensus panel identified the challenges of caring for patients in LTC facilities, such as irregular and unpredictable meal consumption, inadequate staffing, and frequent transitions in care [bib_ref] Diabetes in older adults, Kirkman [/bib_ref]. Additionally, the IAGG and EDWPOP have called to reduce the prevalence and burden of pressure ulcers [bib_ref] Diabetes mellitus in older people: position statement on behalf of the International..., Sinclair [/bib_ref]. Building on a core set of principles from these guidelines, this position statement elaborates on unique features of diabetes management in patients in LTC facilities and provides practical strategies to the clinical staff caring for them. ## Goals and strategies Recommendations c Hypoglycemia risk is the most important factor in determining glycemic goals due to the catastrophic consequences in this population. B c Simplified treatment regimens are preferred and better tolerated. E c Sole use of SSI should be avoided. C c Liberal diet plans have been associated with improvement in food and beverage intake in this population. To avoid dehydration and unintentional weight loss, restrictive therapeutic diets should be minimized. B c Physical activity and exercise are important in all patients and should depend on the current level of the patient's functional abilities. C Establishing the goals of care and management strategies for an individual in the LTC setting requires an acknowledgment of heterogeneity in terms of stage of disease, complications, comorbidities, self-care ability, life expectancy, and risk of adverse drug events [bib_ref] Prevalence of diabetes and the burden of comorbid conditions among elderly nursing..., Dybicz [/bib_ref]. The most important aspects of developing goals and strategies for a patient residing in LTC are described below. ## Hypoglycemia Care goals should be established at the time of admission to the LTC facility for all chronic conditions. Glycemic goals in particular are dependent on the patient's risk of hypoglycemia. Hypoglycemia is the leading limiting factor in the glycemic management of type 1 and insulin-treated type 2 diabetes [bib_ref] Rates of complications and mortality in older patients with diabetes mellitus: the..., Huang [/bib_ref] [bib_ref] Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2..., Donnelly [/bib_ref] [bib_ref] Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment..., Uk Hypoglycaemia Study [/bib_ref]. Multiple factors increase the risk of hypoglycemia in older adults, including impaired renal function, slowed hormonal regulation and counterregulation, variable appetite and nutritional intake, polypharmacy, and slowed intestinal absorption [bib_ref] Update on diabetes in the elderly and in nursing home residents, Migdal [/bib_ref]. The strongest predictors of severe hypoglycemia have been found to be advanced age, recent hospitalization, and polypharmacy [bib_ref] Incidence and risk factors for serious hypoglycemia in older persons using insulin..., Shorr [/bib_ref] [bib_ref] National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare..., Lipska [/bib_ref] , all of which are common in the LTC population. Advanced age is associated with higher rates of cognitive dysfunction, causing difficulty in carrying out complex care activities such as glucose monitoring and adjustment of insulin doses. Impaired renal function and reduced hepatic enzyme activity may interfere with the metabolism of sulfonylureas and insulin, thereby potentiating their hypoglycemic effects. Age-related decrease in b-adrenergic receptor function and defective glucose counterregulatory hormone responses increase the vulnerability of older adults to severe hypoglycemia [bib_ref] Diabetes and altered glucose metabolism with aging, Kalyani [/bib_ref]. The presenting symptoms of hypoglycemia in older adults can be primarily neuroglycopenic (confusion, delirium, dizziness) rather than adrenergic (palpitation, sweating, tremors) [bib_ref] Lack of knowledge of symptoms of hypoglycaemia by elderly diabetic patients, Thomson [/bib_ref]. The presence of cognitive impairment coupled with hypoglycemia unawareness puts some older adults with diabetes in LTC facilities at increased risk because they may not recognize and/or fail to communicate hypoglycemia to their caregivers. Additionally, caregivers may not recognize that symptoms such as confusion, delirium, and dizziness may be related to hypoglycemia. ## Hyperglycemia Although much attention is rightly focused on hypoglycemia, persistent hyperglycemia increases the risk of dehydration, electrolyte abnormalities, urinary incontinence, dizziness, falls, and hyperglycemic hyperosmolar syndrome. The 2012 ADA consensus report states that goals that minimize severe hyperglycemia are indicated for all patients [bib_ref] Diabetes in older adults, Kirkman [/bib_ref]. Thus, glycemic goals for patients in LTC are guided by preventing hypoglycemia while avoiding extreme hyperglycemia. [fig_ref] Table 2 -: Framework for considering diabetes management goalsFrailty, fear of falls, inadequate staff supervision,... [/fig_ref] provides a framework for considering treatment goals for patients living in different settings, facing distinct clinical circumstances. ## Strategies to improve diabetes management The clinical complexity and functional and psychosocial heterogeneity of the older population in LTC facilities require innovative thinking and individualized strategies to care for them [bib_ref] The effect of comorbid illness and functional status on the expected benefits..., Huang [/bib_ref] [bib_ref] Polypharmacy in the elderly: a literature review, Fulton [/bib_ref] [bib_ref] Study of Osteoporotic Fractures Research Group. Diabetes and incidence of functional disability..., Gregg [/bib_ref] [bib_ref] Diabetes mellitus is associated with an increased risk of falls in elderly..., Maurer [/bib_ref]. Certain conditions such as cognitive dysfunction, depression, physical disabilities, eating problems, and repeated infections are commonly found in the LTC population. Moreover, patients in LTC are now more likely to undergo invasive interventions and treatments such as gastrostomies for enteral feeding, hemodialysis, prolonged courses of intravenous antibiotics, advanced wound care treatments, and even chronic ventilator management. Possible strategies to manage diabetes in some of these clinical presentations are described in [fig_ref] Table 3 -: Commonly found comorbidities in LTC and strategies to improve diabetes care Clinical... [/fig_ref]. ## Medication management Glucose-lowering medications also require attention to comorbid conditions and other medications to avoid side effects and drug interactions. Unlike in older adults living in the community, insulin injections for individuals in LTC are usually given by the facility staff. However, risk of hypoglycemia remains high with insulin in this population, especially due to irregular eating patterns, evolving health status, and the inappropriate use of SSI. Many other glucose-lowering agents are now available; [fig_ref] Table 4 -: Advantages, disadvantages, and caveats in using glucose-lowering agents in LTC population [/fig_ref] outlines the advantages, disadvantages, and caveats in using common glucose-lowering agents in the LTC population. ## Ssi Across existing guidelines, one consistent recommendation is to avoid the sole use of SSI, which was recently added to the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Unfortunately, it is customary in most facilities to check premeal and bedtime blood glucose levels and to rely on the sole use of SSI or either oral agents or basal insulin accompanied by SSI as the primary means to control blood glucose. Persistent SSI use leads to wide blood glucose excursions. It is also a burden for patients and requires significant nursing time and resources [bib_ref] The prevalence and persistence of sliding scale insulin use among newly admitted..., Pandya [/bib_ref]. However, there is no clearly defined practical guide to switch patients who are admitted to LTC from SSI to basal-bolus insulin. [fig_ref] Table 5 -: Strategies to replace SSI in LTCSSI is used in short term due... [/fig_ref] provides strategies to convert insulin treatment from an SSI-based regimen to scheduled insulin therapy. ## Improving nutrition health Historically, therapeutic "diabetic" diets have been prescribed to older adults in the LTC setting. There is growing evidence that such therapeutic diets may inadvertently lead to decreased food intake, unintentional weight loss, and undernutrition, which is the opposite of the desired outcome. In response, LTC facilities have shifted away from therapeutic diets, offering a wider variety of food choices, addressing personal food preferences, and providing dining options in regard to time and type of meals. Liberal diets have been associated with improvement in food and beverage intake in the LTC population to better meet caloric and nutrient requirements. While carbohydrate intake should be taken into consideration, "no concentrated sweets" or "no sugar" diet orders are ineffective for glycemic management and should not be recommended. Instead, a consistent carbohydrate meal plan that allows for a wide variety of food choices (e.g., general diet) may be more beneficial for both nutritional needs and glycemic control in patients with type 1 diabetes or type 2 diabetes on mealtime insulin. ## Enteral nutrition support Diabetes-specific enteral nutrition formulas (DSFs) (e.g., Glucerna, Glytrol, Diabetisource AC) are available to help to manage glycemic excursions during tube feedings. These formulas generally have lower carbohydrate and higher monounsaturated fat content compared with standard formulas (SFs). Randomized controlled trials have found DSFs favorable to SFs for blood glucose management. However, even greater [bib_ref] American College of Clinical Pharmacy. Improving care transitions: current practice and future..., Hume [/bib_ref] [bib_ref] Preventing medication errors in transitions of care: a patient case approach, Johnson [/bib_ref]. Transitional care is defined as "actions that ensure coordination and continuity of care and are based on a comprehensive care plan". Poorly executed transitional care can result in significant financial burdens for patients, payers, facilities, and the U.S. health care system as a whole. Preventable costs occur because of unnecessary rehospitalizations, inconsistent patient monitoring, duplicative tests, medication errors, delays in diagnosis, and lack of follow-through on referrals [bib_ref] American College of Emergency Physicians, and Society for Academic Emergency Medicine, Snow [/bib_ref]. Transitions in care indicate that a patient is undergoing changes in health status, which may include physical and/or cognitive function, changes in dietary patterns, and ability to perform diabetes selfcare behaviors. For example, an older adult on insulin may experience delirium as a common complication during and after hospitalization or may require a change in insulin dose when recuperating from acute illness and as nutritional intake improves. Inadequate communication between inpatient and outpatient providers and a lack of an effective communication infrastructure contribute to poor patient outcomes [bib_ref] Deficits in communication and information transfer between hospital-based and primary care physicians:..., Kripalani [/bib_ref] [bib_ref] Problems after discharge and understanding of communication with their primary care physicians..., Arora [/bib_ref]. ## Challenges in transition care To date, there is no standard transition of care document with all the needed information for diabetes management that accompanies a patient from one setting to another [bib_ref] American College of Clinical Pharmacy. Improving care transitions: current practice and future..., Hume [/bib_ref]. Discharge summaries often lack crucial information such as diagnostic test results, treatment or hospital course, discharge medications, test results pending at discharge, patient or family education, and follow-up plans [bib_ref] Posthospital medication discrepancies: prevalence and contributing factors, Coleman [/bib_ref]. Therefore, the need to restart oral therapies (e.g., metformin), typically discontinued in the inpatient setting, can be overlooked. Additionally, pending results, such as those regarding renal function after contrast dye studies are performed, may not be shared with the LTC facility, leading to test duplication. In addition, continuance of SSI after admission or transfer back to the LTC facility is a long-standing problem for patients with diabetes [bib_ref] The prevalence and persistence of sliding scale insulin use among newly admitted..., Pandya [/bib_ref]. Often neither the provider responsible for the patient's care nor the consulting pharmacists are present on-site at LTC facilities on a daily basis. Thus, the need to obtain further testing or outpatient follow-up may not be adequately communicated or coordinated by the LTC providers [bib_ref] Tying up loose ends: discharging patients with unresolved medical issues, Moore [/bib_ref]. Furthermore, the lack of a readily available complete interprofessional care team may present challenges for nursing staff providing daily care, especially when clarifying medication orders due to formulary conversions or trying to answer questions from patients or family members [bib_ref] American College of Clinical Pharmacy. Improving care transitions: current practice and future..., Hume [/bib_ref]. A pharmacist-provided medication regimen review may not be readily available in all assisted living facilities, which increases the risk of medication errors, unnecessary medications, and potential drug-drug interactions (e.g., sulfonylureas and antibiotics) (39). Another factor contributing to the challenges during care transitions is the lack of a single clinician taking responsibility for coordination across the continuum of the patient's overall health care, regardless of setting [bib_ref] Lost in transition: challenges and opportunities for improving the quality of transitional..., Coleman [/bib_ref]. High staff turnover is another issue that may affect the continuity of care of LTC patients [bib_ref] Nursing home staff turnover and retention: an analysis of national level data, Donoghue [/bib_ref]. Well-designed systems of care, thorough documentation, and appropriate communication can help to alleviate some of the problems associated with high staff turnover and meet the often complex care needs of patients with diabetes. Focused, interprofessional quality improvement initiatives have been shown to decrease hypoglycemia rates and improve processes of diabetes care in skilled nursing facilities [bib_ref] IDF Clinical Guidelines Task Force. Global guideline for type 2 diabetes: recommendations..., Boyle [/bib_ref]. ## Patient-level factors Barriers at the patient or family level may include limited disease state knowledge and erroneous or unrealistic expectations. For example, some patients or family members may not be aware of the chronic and progressive nature of type 2 diabetes or of the possible need to convert from oral therapies to insulin therapy despite appropriate dietary intake in patients with long-standing illness. Clear and direct communication of treatment plans and follow-up expectations with patients and/or caregivers by health care providers is critical to decrease patient/ family barriers. ## Strategies for successful transitions A successful transition is a process whereby senders and receivers validate the transfer, accept the information, clarify any discrepancies, and act on the information to ensure a smooth and safe transition of care. The AMDA clinical practice guidelines have identified a series of steps, potential barriers, and strategies for management at system and provider levels as well as the patient level Concerns about diabetes management at end of life have been reported by providers [bib_ref] Diabetes management in patients receiving palliative care, Quinn [/bib_ref] , but until fairly recently, no guidelines were available. Dunning et al. [bib_ref] Developing clinical guidelines for end-of-life care: blending evidence and consensus, Dunning [/bib_ref] proposed the development of one of the first clinical practice guidelines for diabetes and end-of-life care [bib_ref] Diabetes and end of life: ethical and methodological issues in gathering evidence..., Dunning [/bib_ref]. Early identification of patients who require end-oflife care is critical. Despite the reported increase in the rate of palliative care enrollment over the past 2 decades, about one-third of patients have been enrolled within last 2 weeks of their lives, preventing them from receiving the full benefits of palliative care services. One way to improve the timely identification of patients that might benefit from earlier enrollment in palliative care would be to use diabetes registries in collaboration with the palliative care team and primary care services. The therapeutic decisions for diabetes management at end of life should be made after consideration of 1) risk of hypoglycemia and hyperglycemia, 2)presence of geriatric syndromes and comorbidities, and 3) life expectancy. These patients tend to have compromised self-care due to end-stage disease itself in addition to fatigue and drowsiness from medicines. In addition, it is important to respect the patient's right to refuse treatment as well as to consider religion and cultural traditions, including the care of the body after death. Strategies for diabetes management may include relaxing glycemic targets, simplifying regimens, using low-risk glucose-lowering agents, providing education on recognition of hypoglycemia, and enhancing communication strategies. Several conditions may result in hypoglycemia (anorexia-cachexia syndrome from chemotherapy and opiate analgesics, malnourishment, swallowing disorders). Therefore, it is important to have timely discussions about nutritional support, advance directives, and ethical issues, involving the patient, family, and caregivers in the decision process. ## Glucose monitoring It is not always possible to decrease the frequency of capillary glucose monitoring in patients with type 1 diabetes. However, in most patients residing in LTC facilities with type 2 diabetes, a high frequency of capillary monitoring of blood glucose should only be considered under special circumstances (e.g., starting corticosteroids) and where the danger of hypoglycemia is particularly high (e.g., with significant nutritional problems). Capillary monitoring of blood glucose could vary from twice daily to once every 3 days depending on the patient's condition. Oral glucose-lowering agents are preferred, as are simplified insulin regimens with a low hypoglycemic risk and avoidance of complex regimens with higher treatment burden, to reduce the risk of adverse effects and medication errors [bib_ref] Evidence-informed guidelines for treating frail older adults with type 2 diabetes: from..., Mallery [/bib_ref]. [fig_ref] Table 4 -: Advantages, disadvantages, and caveats in using glucose-lowering agents in LTC population [/fig_ref] provide additional information on insulin therapy. In some patients, agents that might cause nausea, gastrointestinal disturbance, or excess weight loss (e.g., metformin or glucagon-like peptide 1 receptor agonist) may need to be discontinued, while in other patients it may be appropriate to withdraw therapy, including insulin, during the terminal stage. ## Management of comorbidities Comorbidities in patients with diabetes present challenges and special consideration when the patient has limited life expectancy. The International Diabetes Federation (IDF) guideline describes management of blood pressure, lipids, and foot care at end of life in patients with diabetes (http:// www.idf.org/sites/default/files/IDF-Guideline-for-older-people-T2D.pdf). Pain is an important component of end-of-life management. Pain could be related to diabetes complications and comorbidities, such as peripheral neuropathy, depression, falls, trauma, skin tears, and periodontal disease, and should be well managed. For those with evidence of cognitive dysfunction, end-of-life planning and a communication strategy should be undertaken while the individual can still make rational decisions. Meal plans that avoid weight loss, nonpharmacological options to prevent or manage behavioral problems, and timely identification and management of depression should be used to improve the quality of remaining life. Diabetes management in patients with advanced cancer presents unique challenges. Specific recommendations for management of hyperglycemia, hypoglycemia, corticosteroid use, and education for patients and families are well described in a recent guideline [bib_ref] Managing diabetes mellitus in patients with advanced cancer: a case note audit..., Mccoubrie [/bib_ref]. ## Treatment strategies Simplified treatment regimens are generally recommended. Common reasons for overly tight glycemic control in hospice patients were found to be 1) discomfort with discussions about reducing or stopping chronic medications, 2) concern about mild hyperglycemia especially by patients and caregivers, and 3) worry about not achieving quality indicators for glycemic control [bib_ref] Improving diabetes care for hospice patients, Lee [/bib_ref]. To address these issues, it is important to educate patients, families, and other providers about the fact that Healthcare Effectiveness Data and Information Set (HEDIS) measures do not apply to hospice patients and that it is acceptable to keep blood glucose levels between 200 and 300 mg/dL in hospice patients taking glucose-lowering medication. Similarly, Angelo et al. [bib_ref] Management of diabetes during the last days of life: attitudes of consultant..., Angelo [/bib_ref] questioned the benefit of tight glycemic control and raised the concern about potential harm in patients with diabetes approaching the end of life. They proposed three strata for management of patients with diabetes and advanced disease. These patients are inclined to simply continue with their previous regimen. Practitioners must use this stage to begin a dialogue with patients and caregivers about reducing the intensity of glycemic control. There is very little role for measuring A1C in these patients. Patients should be warned and educated about the signs of hypoglycemia and hypoglycemia unawareness. The acute risks of hyperglycemia as experienced in this stage center mainly on the risk of a hyperosmolar hyperglycemic state and associated complications, such as osmotic diuresis, recurrent infection, and poor wound healing. ## Patients with organ failure As patients move into this phase, the importance of glycemic control is less apparent and preventing hypoglycemia is of greater significance. Patient and caregiver education regarding the telltale signs of dehydration and hypoglycemia and an appropriate plan of action is of vital importance. The risk of renal or hepatic failure becomes more evident at this stage, and insulin or other glucoselowering medication dosages may need to be reduced in both patients with type 1 diabetes and patients with type 2 diabetes. ## Dying patient Most practitioners in this case would simply withdraw all oral hypoglycemic agents and stop insulin in most patients with type 2 diabetes. Ford-Dunn et al. (53) suggested that treatment and monitoring be stopped in patients with type 2 diabetes once they are in the terminal phase, but there was less consensus for the management of type 1 diabetes under similar scenarios. At this point, care is focused on patient comfort and preparatory bereavement counseling for caretakers and patients, where appropriate. Patients admitted to LTC facilities are typically seen by a medical provider at least once every 30 days for the first 90 days after admission and at least once every 60 days thereafter. In practice, patients are seen within the first week of admission and also when medically necessary (although this may be several days after an event or change of condition). This system means that patients may have uncontrolled blood glucose levels or wide excursions without the practitioner being notified. Adjustments to treatment regimens can be made by telephone, fax, or order entry into electronic health records. Standing orders for glucose monitoring and practitioner notification that are approved by the facility and the practitioner at the time of admission may be useful. [fig_ref] Table 6 -: Specific situations needing attention in patients with diabetes in LTC setting Recommendations... [/fig_ref] delineates the practical recommendations for the LTC staff in management of specific situations in patients with diabetes. ## Integration of diabetes management into ltc facilities ## Challenges for facilities and staffing Pandya and Patel (54) have described the challenges in managing diabetes in postacute and LTC settings. The challenges specific to patients include altered pharmacokinetics and pharmacodynamics of medications, increased risk of hypoglycemia, unpredictable meal consumption, comorbidities such as cognitive dysfunction and depression, psychological resistance to insulin, impaired vision and dexterity, and greater potential for adverse effects and drug interactions. Institutional-level challenges include staff turnover and lack of familiarity with patients, restrictive diet orders, inadequate review of glucose logs and trends, lack of facility-specific diabetes treatment algorithms for blood glucose Patient not eating, vomiting, or unable to take oral glucose-lowering medications c Call practitioner as soon as possible c Consider insulin therapy and adjust dose accordingly based on nutritional status It is more important to address persistently abnormal trends in blood glucose values rather than attempting to adjust the treatment regimen in response to a few isolated abnormal values. levels and provider notifications, and, often, lack of administrative buy-in to promote the roles of the medical director, the director of nursing, and the consultant pharmacist. Challenges specific to staff and practitioners include multiple changing treatment approaches, lack of team communication, excessive reliance on SSI, inappropriate dosing or timing of insulin, knowledge deficits, lack of comfort with new insulin and injectable agents, failure of timely stepwise advance in therapy, failure to individualize care, and therapeutic nihilism. It requires a dedicated interprofessional team composed of registered nurses, certified nursing assistants, diabetes educators, dietitians, food service managers, consultant pharmacists, physical therapists, social workers, and practitioners to manage older patients with diabetes in LTC facilities. ## Monitoring the facility's management of diabetes In order to assess and improve facilitywide management of diabetes directed by multiple practitioners, the facility leadership (e.g., the director of nursing, nurse managers, medical director, and consultant pharmacist) should collect data and trends and plan strategies to improve selected process or outcome indicators relevant to diabetes management. These could include sharing data with managerial staff, providing staff education, and planning a performance improvement project. In general, the facility medical leadership and nursing administration have the opportunity to develop and implement patient care policies that can facilitate optimal management of the older patient with diabetes and to coordinate efforts with the multidisciplinary team. Nursing leadership training programs for nurses working in LTC facilities that include skills in diabetes management can also help to improve quality of care offered to patients in these facilities [bib_ref] Enhancing nursing leadership in long-term care. A review of the literature, Harvath [/bib_ref] [bib_ref] Evaluation of a leadership development academy for RNs in long-term care, Vogelsmeier [/bib_ref]. Federal citation tags (F-tags) are federal regulations that are used by each state's Department of Health and Centers for Medicare and Medicaid Services to survey quality of care provided to patients in LTC facilities. F-tags can be given at an annual state licensing survey or in response to a complaint survey at any time of the year. LTC facilities that are noncompliant may be subject to financial penalties. Consequently, ensuring a high level of care for patients with diabetes in LTC facilities is also necessary for compliance with federal regulations. # Conclusions Diabetes is a common, morbid, and costly disease in older adults. This population is heterogeneous and presents unique challenges pertaining to diabetes management. It is important for clinicians to understand the characteristics, challenges, and barriers related to the older population living in LTC facilities. This understanding requires knowledge of the patient population as well as the functioning of the facilities. Once the challenges are identified, individualized approaches can be designed to improve diabetes management while lowering the risk of hypoglycemia and ultimately improving quality of life. [table] Table 1 -: Characteristics of older adults and their diabetes management based on living situation Frequent education and reeducation c Frequent education and reeducation c Education prior to discharge Excessive use of SSI ADL, activities of daily living (such as bathing, toileting, eating, dressing, transferring); IADL, instrumental activities of daily living (such as cooking, taking medications, traveling, using the telephone, shopping, managing finances, housework). [/table] [table] Table 2 -: Framework for considering diabetes management goalsFrailty, fear of falls, inadequate staff supervision, and lack of incentives act as barriers to regular physical activity for patients in the LTC facility. However, physical activity should be encouraged in all individuals to improve independence, functionality, and quality of life. The type of activity recommended should depend on the patient's current level of activity and ability. Programs to enhance mobility, endurance, gait, balance, and overall strength are important for all patients in LTC facilities.Transitions from the hospital or home to LTC, transitions across care settings in LTC facilities, changes in providers, and discharges to the community setting are high-risk times for patients with diabetes. For older adults with diabetes, especially those with complex comorbidities, limited health literacy, cognitive impairment, five or more prescribed medications, or end-of-life care, the risk for adverse outcomes during these care transitions is [/table] [table] Table 3 -: Commonly found comorbidities in LTC and strategies to improve diabetes care Clinical presentation that may interfere with diabetes management Possible strategies to manage diabetes Confusion, cognitive dysfunction, delirium c Irregular dietary intake or skipped meals c Refusal of blood glucose monitoring c Refusal of medications or injectionsc Offer a regular diet and preferred food items c Offer food substitutions if meal intake is ,75% c Administer prandial insulin immediately after meals to match carbohydrate intake to avoid hypoglycemia c Block testing (monitoring at different times of the day to identify patterns, e.g., checking fasting glucose on some days, prelunch or predinner on other days) to provide pattern without multiple daily checks c Increase glucose monitoring during acute mental status or behavior changes c Switch to a long-acting form of oral medications that can be given once daily or to crushed or liquid formulation c Switch to mixed insulin to decrease daily injections, although hypoglycemia risk will remain high High risk of deconditioning and pressure ulcers c Require assistance with food and fluid intake c High risk of functional disability c Encourage activity that patient can perform, e.g., exercise pedals for non-weight-bearing patients c Assessment for pressure ulcers c Encourage ADL independence Excessive skin problems, e.g., infections, ulcers, delayed wound healing Low vision has large impact on quality of life [/table] [table] Table 4 -: Advantages, disadvantages, and caveats in using glucose-lowering agents in LTC population [/table] [table] Table 5 -: Strategies to replace SSI in LTCSSI is used in short term due to irregular dietary intake or due to acute illness c Short-term use may be needed for acute illness and irregular dietary intake c As health and glucose levels stabilize, stop SSI and return to previous regimen as toleratedWide fluctuations in glucose levels in patients with cognitive decline and/or irregular dietary intake on a chronic basis [/table] [table] Recommendation c: Patients admitted to LTC facilities are not seen daily by a practitioner. Because of this reality, successful diabetes care needs to include a dedicated interprofessional team. This team may be composed of practitioners (physicians, nurse practitioners, and physician assistants), registered nurses, licensed practical/vocational nurses, certified nursing assistants, diabetes educators, dietitians, food service managers, consultant pharmacists, physical therapists, and/or social workers. E [/table] [table] Table 6 -: Specific situations needing attention in patients with diabetes in LTC setting Recommendations for LTC staff for diabetes management Glucose meter reading ,70 mg/dL and unresponsive c Treat hypoglycemia per protocol without any delay Consecutive glucose meter readings ,70 mg/dL c Call practitioner c Confirm low glucose value by laboratory test c Evaluate nutritional intake c Consider an increase in frequency of glucose monitoring for 24 h c Adjust diabetes regimen as needed Glucose meter readings .250 mg/dL two or more times within 24-h period accompanied by a new or change in medical or functional status c Call practitioner c Increase frequency of glucose monitoring Glucose meter readings .300 mg/dL during all or part of 2 consecutive days c Confirm high glucose value by laboratory test c Evaluate nutritional intake Any glucose reading too high to measure by glucose meter c Adjust diabetes regimen as needed c If glucose levels are persistently high after changes to the diabetes regimen, consider medical evaluation for other causes (i.e., infection) [/table]	None	https://care.diabetesjournals.org/content/diacare/39/2/308.full.pdf	Diabetes is more common in older adults, has a high prevalence in long-term care (LTC) facilities, and is associated with significant disease burden and higher cost. The heterogeneity of this population with regard to comorbidities and overall health status is critical to establishing personalized goals and treatments for diabetes. The risk of hypoglycemia is the most important factor in determining glycemic goals due to the catastrophic consequences in this population. Simplified treatment regimens are preferred, and the sole use of sliding scale insulin (SSI) should be avoided. This position statement provides a classification system for older adults in LTC settings, describes how diabetes goals and management should be tailored based on comorbidities, delineates key issues to consider when using glucose-lowering agents in this population, and provides recommendations on how to replace SSI in LTC facilities. As these patients transition from one setting to another, or from one provider to another, their risk for adverse events increases. Strategies are presented to reduce these risks and ensure safe transitions. This article addresses diabetes management at end of life and in those receiving palliative and hospice care. The integration of diabetes management into LTC facilities is important and requires an interprofessional team approach. To facilitate this approach, acceptance by administrative personnel is needed, as are protocols and possibly system changes. It is important for clinicians to understand the characteristics, challenges, and barriers related to the older population living in LTC facilities as well as the proper functioning of the facilities themselves. Once these challenges are identified, individualized approaches can be designed to improve diabetes management while lowering the risk of hypoglycemia and ultimately improving quality of life.
3ce65e6b091b2ffce9e2bad357949974304abc5d	pubmed	Impact of implant–abutment connection, positioning of the machined collar/microgap, and platform switching on crestal bone level changes. Camlog Foundation Consensus Report.	Impact of implant–abutment connection, positioning of the machined collar/microgap, and platform switching on crestal bone level changes. Camlog Foundation Consensus Report. Objectives: The aim of this consensus meeting was to assess the impact of implant-abutment connection, positioning of the machined collar/microgap, and platform switching on crestal bone level changes.Materials and methods: Two comprehensive systematic reviews were prepared in advance of the meeting. Consensus statements, practical recommendations, and implications for future research were based on within group as well as plenary scrutinization and discussions of these systematic reviews.Results: Placing the smooth part of the implant below the alveolar crest may lead to bone loss.Despite a more pronounced bone remodeling, the subcrestal positioning of the microgap may help to retain the bony coverage of the rough surface. Crestal bone remodeling has been observed for either internal and external, or conical and butt-joint connections. There was a trend favoring the platform switching concept to prevent or minimize peri-implant marginal bone loss.Conclusions: Future research should consider an uniform and comparable study design, either excluding or exactly documenting possible confounding factors. Remodeling of the crestal alveolar bone is considered to be a physiological process following implant placement. In previous years, numerous preclinical and clinical studies have identified potential confounding biological, technical, and biomechanical factors that may contribute to this unavoidable event. Subsequently, implant designs and surgical protocols were modified to help the clinician maintain marginal bone. The aim of the present consensus report was to critically address the available evidence reporting on the impact of implantabutment connection, positioning of the machined collar/microgap, and platform switching on crestal bone level changes. ## Group discussion and consensus To prepare group discussions, competent clinicians and researchers (referred to as "experts") from various countries with a focus on implant therapy were appointed and provided with two systematic reviews in advance of the consensus meeting: - Schwarz F, Hegewald A, Becker J. Impact of implant-abutment connection and positioning of the machined collar/microgap on crestal bone level changes [bib_ref] Impact of implant-abutment connection and positioning of the machined collar/ microgap on..., Schwarz [/bib_ref]. - Strietzel FP, Neumann K, Hertel M. Impact of platform switching on marginal peri-implant bone level changes [bib_ref] Impact of platform switching on marginal periimplant bone level changes, Strietzel [/bib_ref]. This International Expert Meeting took place in Rome, Italy in January (18th and 19th) 2013 and was organized and supported by the Camlog Foundation (Basel, Switzerland). At the beginning of the meeting, the authors presented both systematic reviews in detail (i.e., methodology, results, conclusions) to the experts. Subsequently, the participants were separated into two working groups [fig_ref] Figure 1: Members of working group [/fig_ref]. Discussions and the formulation of consensus statements within groups were each directed by one chairperson and one secretary. The statements, elaborated by the members of the working groups, were presented and discussed in plenary sessions and revised Impact of implant-abutment connection and positioning of the machined collar/microgap on crestal bone level changes. [bib_ref] Impact of implant-abutment connection and positioning of the machined collar/ microgap on..., Schwarz [/bib_ref] Focused question What is the impact of implant-abutment configuration and the positioning of the machined collar/microgap on crestal bone level changes? ## Major findings and conclusions A supracrestal positioning of the machined collar at both one-and two-piece implants was associated with less crestal bone level changes than a subcrestal positioning of the smooth-rough border. When evaluating the positioning of the microgap at two-piece implants relative to the alveolar crest, data synthesis has identified that a subcrestal position may be favored over an epicrestal insertion of the implant neck. At the time being, the impact of the implant-abutment connection lacks documentation. ## Consensus statements regarding positioning of the machined collar - Placing the smooth part of the implant below the alveolar crest may lead to bone loss. - The currently available evidence does not allow for any conclusive statements regarding the impact of potential confounding factors (e.g., clinical experience of the clinician; surgical and anatomical parameters, such as soft-tissue thickness and vascularization, disand reassembly of the abutment, interproximal bone height at neighboring teeth, bone quality, prosthetic concepts, and loading protocol) on bone remodeling. ## Clinical recommendations regarding positioning of the machined collar - Under the aspect of limiting peri-implant bone remodeling, the clinician is advised to avoid any subcrestalpositioningofsmoothimplantparts. - Accordingly, if existent, the smoothrough border should at best coincide with the adjacent alveolar bone and determine the insertion depth at both one-and twopiece implants. Consensus statements regarding positioning of the microgap - Placing the microgap of the evaluated two-part implants in a subcrestal position (at least 1 mm) may be associated with a higher amount of bone loss during the remodeling process than implants placed in an epi-or supracrestal position. - However, despite a more pronounced bone remodeling, the subcrestal positioning of the microgap may help to retain the bony coverage of the rough surface. - Under the consideration of the detrimental impact of a smooth neck on bone remodeling, a subcrestal positioning of the shoulder may be limited to entirely roughened two-part implants. ## Consensus statements regarding implantabutment connection - The impact of the implant-abutment connection lacks documentation and may not allow for any robust conclusions. - Crestal bone remodeling has been observed for either internal and external, or conical and butt-joint connections. - Some evidence suggests that microbial leakage may occur irrespective of the design of the implant-abutment connection. ## Clinical recommendations regarding implantabutment connection - The clinician is advised to choose a stable implant-abutment complex to minimize the potential impact of micromovement and microbial leakage on crestal bone remodeling. ## Implications for future research - There is a need for more well-designed, randomized, parallel-arm controlled clinical trials to further evaluate the impact of implant-abutment configuration and the positioning of the machined collar/microgap on crestal bone level changes in humans. - The potential influence of relevant confounding clinical factors should be carefully addressed. Impact of platform switching on marginal peri-implant bone level changes. [bib_ref] Impact of platform switching on marginal periimplant bone level changes, Strietzel [/bib_ref] ## Focused question Is there an impact of platform switching on marginal bone level changes around endosseous implants? ## Major findings and conclusions Due to heterogeneity of the included studies, their results should be interpreted cautiously. However, within the limits of the recently available publications on randomized controlled clinical trials and prospective clinical cohort studies, the tendency revealing from the studies' results favors the platform switching technique to prevent or minimize peri-implant marginal bone loss, compared with implants with platform matching abutments. Further investigations should consider a uniform and comparable study design, either excluding or exactly documenting possible confounding factors. ## Consensus statements regarding platform switching - Platform switching is one therapeutic concept that has been proposed to preserve crestal bone levels around dental implants. The biological bases of this concept are as follows: 1. The increase in distance between the implant-abutment interface (microgap) and the bone surface 2. The increase in horizontal soft-tissue dimension, which may protect the bone crest. - Although there is evidence to support these histological outcomes from experimental animal studies, the clinical outcomes evaluated in human studies have not clearly shown the beneficial effect of this concept. However, the trend is generally positive. - So far, no negative effects of platform switching have been published. There are some concerns about situations with a small volume of soft-tissue thickness as well as the limitations of two-dimensional radiological measurements provided in most studies. - There was a high degree of heterogeneity among the selected studies, because the factors that influence bone levels were not balanced between the groups. - Two concerns were expressed that the long-term effect of platform switching on soft-tissue health and the biomechanical stability of the implant-abutment connection are currently unknown. ## Clinical recommendations regarding platform switching - Considering the evidence available so far, clinical recommendations regarding indications for platform switching cannot be stated clearly. - Platform-switched restorations may be suitable for use in all indications where platform-matched restorations can be used at the clinician's discretion. ## Implications for future research - Further investigations should consider an uniform and comparable study design, either excluding or exactly documenting possible confounding factors (e.g., patient and site characteristics, implant/abutment geometry, dimension of the horizontal offset, surgical technique, prosthetic protocol, maintenance care). [fig] •: When attempting to retain crestal bone levels coronal to the implant shoulder, the clinician may favor a subcrestal over either an epi-or supracrestal positioning of the neck. [/fig] [fig] Figure 1: Members of working group. (a) Insertion depth/Implant-abutment connection. Chairperson: Gil Alcoforado. Secretaries: Katja Nelson, Alex Sch€ ar. Rapporteur: Frank Schwarz. Participants: Luis Aracil, Thomas Barth, Alfonso Baruffaldi, J€ urgen Becker, Stephan Beuer, Claudio Cacaci, Wong Chanchai, Luca Cordaro, Laszlo Csato, Ben Derksen, Rolf Ewers, Manuel G omez, Hans-J€ urgen Hartmann, Helfried Hulla, Peter Hunt, Gerhard Iglhaut, Attila K am an, Martin Keweloh, Alfons Kiener, Axel Kirsch, Henning Lehmann Bastian, Carlo Maiorana, Piotr Majewski, Ralf Masur, Timothy Patrick McVaney, Andreas Meschenmoser, Werner Millesi, Eric Normand, Toshiyuki Oshima, Frank Palm, Torsten E. Reichert, Lutz Ricken, Robert Sader, Jos e Vincente Sanz, Georg Christoph Scheiderbauer, Alexander Schramm, Vojtech Slezacek, Ralf Smeets, Andres Stricker, Hendrik Terheyden, Wilfried Wagner, Fumihiko Watanabe, Daniel Wismeijer, Manfred Wolf. (b) Platform switching. Chairperson: Thomas Taylor. Secretary: Florian Beuer. Rapporteur: Frank Peter Strietzel. Participants: Karl-Ludwig Ackermann, Rodrigo Andr es Garcia, Isaac Angel, Mario Beretta, Sven Marcus Beschnidt, Sergio de Paoli, Kerem Dedeoglu, Antoine Diss, Fernando Guerra, Christian Hamm€ acher, Arndt Happe, Frederic Hermann, Detlef Hildebrand, Andr as Husz ak, Matthias Kern, Gerald Krennmair, Yasemin Kulak Ozkan, Jan M€ arkle, Marc Mongeot, Gerhard Neuendorff, Selim Pamuk, Franc ßoise Peters, Mariano Sanz Alonso, Paul Sipos, Michael Stimmelmayr, Maciej Stupka, Peter Thoolen, Carsten Urbild, Pieter van Elsas, Stefan Wolfart. [/fig]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/clr.12269	Objectives The aim of this consensus meeting was to assess the impact of implant–abutment connection, positioning of the machined collar/microgap, and platform switching on crestal bone level changes. Materials and methods Two comprehensive systematic reviews were prepared in advance of the meeting. Consensus statements, practical recommendations, and implications for future research were based on within group as well as plenary scrutinization and discussions of these systematic reviews. Results Placing the smooth part of the implant below the alveolar crest may lead to bone loss. Despite a more pronounced bone remodeling, the subcrestal positioning of the microgap may help to retain the bony coverage of the rough surface. Crestal bone remodeling has been observed for either internal and external, or conical and butt–joint connections. There was a trend favoring the platform switching concept to prevent or minimize peri-implant marginal bone loss. Conclusions Future research should consider an uniform and comparable study design, either excluding or exactly documenting possible confounding factors.
2c833c93225fa3bf5c035022beb0567b34d1a1c0	pubmed	The Management of Acute Myocardial Infarction: Guidelines and Audit Standards	The Management of Acute Myocardial Infarction: Guidelines and Audit Standards Successful management of acute myocardial infarction depends in the first instance on the patient recognising the symptoms and seeking help as quickly as possible. Once in hospital, fast track admission procedures and protocols for pain relief, early thrombolysis and appropriate ancillary measures (eg aspirin, IV betablockers) should be promptly instituted. Specialist advice and, if necessary, transfer to specialist units should be considered if additional complications arise. Follow-up management after discharge from hospital requires cooperation between primary and secondary care to prolong survival by reducing risk factors, using aspirin, betablockers and angiotensin converting enzyme inhibitors and instituting a suitable rehabilitation programme. Audit measures are included in the report to help general practitioners and hospital doctors review their practice and assess it against the standards set.Prepared on behalf of the joint workshop by: # Introduction Acute myocardial infarction is a major cause of morbidity and mortality, and accounts for a substantial proportion of acute hospital admissions. This paper summarises the working papers presented and the ensuing discussion at a workshop held under the auspices of the Joint Audit Committee of the British Cardiac Society and the Royal College of Physicians in September 1993. Following a convention previously established in audit papers from the Royal College, potential audit points are identified in the text by , and points which are the subject of controversy, or require further research, by . For convenience, audit and research points are also summarised in the Appendix. Presentation, out of hospital care and admission to hospital Acute myocardial infarction characteristically presents with the acute onset of severe chest pain, although atypical presentations with different types of pain, or even its absence, are well documented. The population prevalence of ischaemic heart disease increases steeply with age, but the median age of patients admitted to hospital with myocardial infarction in a large UK survey was 64 years [bib_ref] Time delays in provision of thrombolytic treatment in six district general hospitals, Birkhead [/bib_ref]. Patients older than 65 years present more often with atypical features [bib_ref] Comparison of clinical presentation of acute myocardial infarction in patients older than..., Solomon [/bib_ref] ; they are more likely to die before hospital admission, and there may be bias against admitting them to hospital. Most patients experience the first symptoms of myocardial infarction at home rather than at a workplace. The first priorities in treating patients with suspected acute myocardial infarction are to bring them within reach of a defibrillator [bib_ref] Treatable arrhythmias in cardiac arrests seen outside hospital, Colquhoun [/bib_ref] , and to relieve pain and anxiety. The best ways of achieving these aims will vary with local conditions: in urban areas defibrillatorequipped ambulances may be able to respond within minutes, whilst in remote rural regions rapid response will largely depend on the general practitioner. Local plans need to be agreed between general practitioners, the ambulance service and hospitals. Patients often delay too long before seeking advice, even those who have previously experienced infarction. Fears that encouraging patients to summon help from emergency services by ringing 999 would lead to excessive and inappropriate self referral have not been realised [bib_ref] Early repeating of myocardial infarction: impact of an experiment in patient education, Rowley [/bib_ref]. There may be scope for further patient education, perhaps by means of information leaflets distributed with prescriptions for anti-anginal medication . Local guidelines for ensuring rapid and appropriate assistance for patients with possible myocardial infarction should be agreed between general practitioners, the ambulance service and hospital consultants . The guidelines should emphasise the need for prompt access to a defibrillator and personnel trained in its use. Education should be directed at patients with known ischaemic heart disease to encourage them to seek assistance early. In urban areas, there should be a response to 90% of calls within 20 minutes [A]. The management of acute myocardial infarction Diagnosis and treatment of acute myocardial infarction Diagnosis in the community The best guides to the diagnosis of acute coronary thrombosis in the community are the history and clinical examination . The electrocardiogram is specific, but of limited sensitivity, ie a normal electrocardiogram does not exclude an evolving coronary thrombosis. ## Diagnosis in hospital Once the patient has reached hospital the electrocardiogram is a useful guide to those patients who will benefit from thrombolytic therapy [fig_ref] Table 2: Relationship between ECG findings and mortality [/fig_ref]. Cardiac enzyme measurements, particularly of plasma creatine kinase, are helpful in assessing myocardial damage, but results are seldom available early enough to help with decisions about thrombolysis. This information is however important in making decisions about length of coronary care unit or hospital stay . Delays in diagnosis and treatment after hospital admission are common and need to be avoided or reduced by clear local guidelines on 'fast track' admission procedures and by delegating decisions about management to junior doctors working to carefully specified treatment protocols . ## Treatment Adequate pain relief with intravenous opiates and antiemetics is important. Specific treatment for myocardial infarction consists of the early administration of oral aspirin, thrombolytic agents and, in appropriate cases, intravenous betablockers [bib_ref] Late assessment of thrombolytic efficacy (LATE) study with alteplase 6-24 hours after..., Late Study Group [/bib_ref]. Whether (or not) thrombolytic therapy is administered in the community or after admission to hospital depends on local circumstances. Early thrombolysis is important for optimal results: at least 50% of eligible patients should receive thrombolytic therapy within 90 minutes of the onset of major symptoms [A]. Thrombolytic . Clinical features of acvute myocardial infarction Background: More common in men than women. Incidence increases with age. ## Symptoms: Severe pain, persisting at rest and despite nitrates; pain seldom described as stabbing. Nausea, vomiting are common. Signs: Signs of sympathetic activation (pallor, sweating)-Narrow pulse pressure. Occasionally: frequent extrasystoles, third heart sound, features of pulmonary oedema. ; age is not, in itself, a contraindication to thrombolysis. Streptokinase is the most widely used thrombolytic agent. It should be given with aspirin but there is no convincing evidence for any additional advantage in giving heparin as well, Streptokinase is antigenic and repeat use within at least one year should be avoided [bib_ref] Safety and efficacy of repeat thrombolytic therapy after acute myocardial infarction, White [/bib_ref]. Alteplase (tissue type plasminogen activator) when given as a front loaded infusion in combination with oral aspirin and intravenous heparin has shown, in one trial, better survival results than streptokinase (absolute survival improvement about 1 %), but it is more expensive, has a more complex administration schedule and is associated with a higher risk of cerebral haemorrhage, especially in patients over 65 with hypertension and/or body weight less than 65 kg [bib_ref] Individual risk assessment for intracranial haemorrhage during thrombolytic therapy, Simoons [/bib_ref]. Survival after receiving anistreplase is no better than with streptokinase but it has a simple administration schedule which can be useful in thrombolysis out of hospital. Apart from aspirin, the only additional therapy which has consistently improved outcome when administered acutely is intravenous betablockade. This should be used more widely, particularly for patients with hypertension and inappropriate tachycardia [A], Intravenous magnesium sulphate produced a significant improvement in survival in the LIMIT-2 study [bib_ref] A randomised trial of intravenous magnesium sulphate in suspected acute myocardial infarction:..., Woods [/bib_ref] , but this was not confirmed in the larger ISIS-4 trial (personal communication). Role of specialist units or tertiary care centres Most patients suffering myocardial infarction in the UK will be admitted to district general hospitals and managed by general physicians with an interest in cardiology. Specialist cardiological advice should be available for complications, and agreed criteria established for the transfer to tertiary centres of patients suffering from ventricular septal rupture, severe mitral regurgitation, persistent chest pain, recurrent ventricular arrhythmias, and patients who require permanent pacemaker implantation . The initial diagnosis of myocardial infarction, and hence the decision to transfer a patient to hospital, should be made on the basis of the clinical history and examination. The electrocardiogram is a useful guide to those patients who will benefit most from thrombolysis. Units should develop and review local policies to ensure that all eligible patients receive thrombolytic therapy and appropriate ancillary therapy promptly, and that the use of thrombolysis is audited. At least 50% of eligible patients should receive thrombolytic therapy within 90 minutes of the onset of major symptoms [A]. Intravenous streptokinase and oral aspirin remain the appropriate 'front line' thrombolytic regimen for patients not previously given streptokinase. ## Follow-up after myocardial infarction The aim of follow-up treatment after infarction should be to reduce long term mortality and to expedite rehabilitation. Aspirin, betablockers and angiotensin converting enzyme inhibitors (in patients who have shown evidence of mild heart failureall improve survival when administered as long term treatment after myocardial infarction. Although they are all presumed to act by different mechanisms, it is not known whether their effects are additive, and there is no clear evidence if or when they should be stopped ; nor is it known how survival with long term anticoagulation compares with aspirin; exceptions are patients with atrial fibrillation, or who have had extensive anterior infarction with aneurysm formation, in whom anticoagulation reduces the risk of thromboembolism [R]. Hypercholesterolemia is a marker for reduced long term survival and an increased risk of cardiac events in patients of all ages, including those over 65; there is evidence from meta-analysis, but not yet from individual trials, that this risk is reduced by lowering blood cholesterol [bib_ref] The value of lowering cholesterol after myocardial infarction, Rossouw [/bib_ref] [R]. Acute stress, such as infarction or unstable angina, causes a fall in cholesterol concentrations which may persist for six to eight weeks. Because of this, the incidence of hypercholesterolaemia in infarct patients will be underestimated unless cholesterol concentration is measured in blood taken immediately on admission. Analysis of a repeat sample two to three months after infarction is also helpful . Long term survival after infarction is progressively worse with increasing age, in those with large infarcts, and in those with severely impaired left ventricular function. It is best in younger patients with normal left ventricular function and good exercise tolerance [bib_ref] Age related increase in mortality among patients with first myocardial infarctions treated..., Maggioni [/bib_ref]. Routine exercise electrocardiography after infarction has been advocated as a strategy to detect patients with residual ischaemia who would be candidates for myocardial revascularisation [bib_ref] Prognostic value of exercise testing soon after myocardial infarction, Theroux [/bib_ref]. Patients with a good exercise capacity (> Stage 3 on the Bruce protocol) have a good prognosis, and the negative predictive power of exercise testing is good, but its positive predictive power is limited, ie only a proportion of those with a 'positive' test go on to reinfarction [bib_ref] Reassessment of treadmill stress testing for risk stratification in patients with acute..., Stevenson [/bib_ref] [bib_ref] Which patients should have exercise testing after myocardial infarction treated with thrombolysis?, Murray [/bib_ref]. The worst prognosis is in patients unable to exercise because of heart failure or chest pain, or whose blood pressure falls during exercise. It has been suggested that 'routine' exercise testing in patients aged 65 years or older adds little to the prediction of subsequent cardiac events within one year [bib_ref] First myocardial infarction in patients under 60 years old: the role of..., Cross [/bib_ref] ; conversely however, objective demonstration of good exercise tolerance is often of considerable value in rehabilitation. There is no convincing evidence to support a policy of routine coronary angiography after myocardial infarction, even in young patients [bib_ref] Are routine non-invasive tests useful in prediction of outcome after myocardial infarction..., Myers [/bib_ref]. Angiography may, however, be appropriate for patients with post infarct angina, or whose blood pressure falls on moderate exercise, and patients with persistent symptoms or multivessel coronary disease will benefit from revascularisation. Left main coronary artery stenosis is very uncommon in patients studied shortly after acute infarction, possibly because they have a high initial mortality rate [bib_ref] Segmental analysis of coronary arterial stenoses in patients presenting with angina or..., De Bono [/bib_ref]. Radionuclide ventriculography measures left ventricular ejection fraction, which is a good predictor of long term outcome. Echocardiography also provides information about ventricular function, and in addition is helpful in diagnosing ventricular septal defect, papillary muscle rupture, partial ventricular rupture and pericardial effusion. Echocardiography (preferably with colour-flow Doppler) is indicated in any patient who develops a new murmur after infarction, or in any patient who becomes haemodynamically acutely unstable. Echocardiography and radionuclide facilities should be used when clinically indicated. Units which do not have their own facilities for coronary angiography should have a suitable arrangement with a specialist unit providing this service, and defined referral criteria should be agreed as part of this arrange- [formula] ment [A]. [/formula] ## Post infarct rehabilitation Post infarct rehabilitation is a process of restoring physical and psychological fitness, and is also a vehicle for secondary prevention measures such as stopping smoking and controlling hyperlipidaemia. Many hospitals have rehabilitation programmes which are extremely popular with patients and their relatives. Individual trials have often been too small to show a significant effect on major outcome measures, but meta-analysis indicates a reduction of about 20% in total and cardiovascular mortality, though not in the risk of recurrent myocardial infarction [bib_ref] An overview of randomized trials of rehabilitation with exercise after myocardial infarction, O'connor [/bib_ref] [bib_ref] Working party report on cardiac rehabilitation, Horgan [/bib_ref]. For optimal results, follow-up and reinforcement may be needed for up to 12 months [bib_ref] Working party report on cardiac rehabilitation, Horgan [/bib_ref] , and this may only be realistic for community rather than hospital based projects , Communication between primary and secondary care There should be a clear understanding, based on agreed local protocols, for which aspects of post infarct follow-up and rehabilitation the hospital will take responsibility and which will be provided by general practitioners . Ideally, general practitioners should be warned in advance of the forthcoming discharge of a patient after myocardial infarction; in any event, the general practitioner should receive a discharge summary within seven days . It should give the diagnosis and the evidence on which that is based, record any post infarct complications such as cardiac arrest or heart failure, give an indication of risk stratification, and include a management plan, with details of any rehabilitation arrangements or follow-up appointments. Minimum data sets for recording information about patients with myocardial infarction Recording data for audit purposes is only worthwhile if they will actually be useful for recording and modifying practice. A number of excellent computer databases are available for CCU use, but information collected from other hospital areas may need to be more limited in scope. The following lists are neither exclusive nor intended to be used indiscriminately. Prehospital phase: time of receipt of call, time of attendance and time of hospital arrival (from ambulance logs or a special admission proforma); note of any difficulty or delay in securing hospital admission; prehospital complications such as cardiac arrest or arrhythmia; medication administered before admis- [table] Table 2: Relationship between ECG findings and mortality [/table] [table] sion: Early hospital phase: time of arrival, time to initial assessment, time of transfer to ward, time to throm-Is there a practice policy on advising patients what to do in the case of a suspected heart attack?Is there a practice policy on the management of suspected heart attack?Is a record kept of suspected heart attack and its outcome? Is there a policy for training staff and patients in basic or advanced life support? Is there a policy for the aftercare and rehabilitation of patients discharged from hospital after a heart attack? Primary care?'outcome' audit How many patients in the practice suffer actual or suspected myocardial infarction in a year? What proportion made a first call to the GP? What was the average response time? What proportion of patients with actual or suspected MI were admitted to hospital? What proportion suffered cardiac arrest or required medication? Secondary care?'process'audit Is there a policy, agreed with the ambulance service and GPs, on the process for rapid admission of suspected infarct patients? Journal of the Royal College of Physicians of London Vol. 28 No. 4 July/August 1994 D P de Bono and A Hopkins Are guidelines on the 'fast track' assessment of suspected infarct patients available on the admission ward or in the accident and emergency department, and are staff aware of them? Are times of arrival, assessment and treatment of infarct patients always documented? Secondary care?'outcome' measures ? Number of patients with suspected infarcts seen for assessment ? Number (proportion) with time of arrival and Number (proportion) receiving thrombolytic therapy within 90 minutes of onset of major symptoms Hospital admission to discharge Secondary care?'outcome' audit Number of patients admitted with suspected MI Number (proportion) of patients in whom MI was subsequently confirmed Number (proportion) receiving thrombolytic therapy; betablockade; aspirin; ACE inhibitor Hospital discharge and follow-up Primary and secondary care?'process' audit Is there an agreed policy between hospital and general practice for the rehabilitation and discharge of post infarct patients? Does it include specific provision for patient and family education and secondary prevention? Is there a policy for exercise testing and referral, if appropriate, for other investigations including angiography? Are appropriate facilities available for rehabilitation and education? 'Outcome' audit What proportion of MI patients are discharged alive? What proportion receive advice about lifestyle and rehabilitation? What proportion receive continuing hospital follow-up? What proportion return to work? What proportion achieve a significant modification of risk factors? What proportion are readmitted within one, six or 12 months? Participants in the joint workshop Dr R Balcon, Consultant Cardiologist, London Chest Hospital; Dr J S Birkhead, Consultant Physician, Northampton General Hospital; Dr N H Brooks, Consultant Cardiologist, Wythenshawe Hospital, Manchester; Dr D A Chamberlain, Consultant Cardiologist, Royal Sussex County Hospital; Professor S M Cobbe, Walton Professor of Medical Cardiology, University of Glasgow; Dr R Collins, BHF Senior Research Fellow, [/table]	None	None	Successful management of acute myocardial infarction depends in the first instance on the patient recognising the symptoms and seeking help as quickly as possible. Once in hospital, fast track admission procedures and protocols for pain relief, early thrombolysis and appropriate ancillary measures (eg aspirin, IV betablockers) should be promptly instituted. Specialist advice and, if necessary, transfer to specialist units should be considered if additional complications arise. Follow-up management after discharge from hospital requires cooperation between primary and secondary care to prolong survival by reducing risk factors, using aspirin, betablockers and angiotensin converting enzyme inhibitors and instituting a suitable rehabilitation programme. Audit measures are included in the report to help general practitioners and hospital doctors review their practice and assess it against the standards set.
e4a56dfcfcfb68a3e4840b1a1299b531358ce8ef	pubmed	Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force	Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force Therapeutic targets have been defined for axial and peripheral spondyloarthritis (SpA) in 2012, but the evidence for these recommendations was only of indirect nature. These recommendations were re-evaluated in light of new insights. Based on the results of a systematic literature review and expert opinion, a task force of rheumatologists, dermatologists, patients and a health professional developed an update of the 2012 recommendations. These underwent intensive discussions, on site voting and subsequent anonymous electronic voting on levels of agreement with each item. # Introduction Recommendations on general treatment targets in spondyloarthritis (SpA) and the strategy to treat SpA to these targets were developed in 2012 by an international task force. [bib_ref] Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of..., Smolen [/bib_ref] These recommendations are deliberately generic and intended to inform the optimal treatment approach rather than advise around a specific drug entity, since it was deemed important to develop and describe a conceptual framework independent of particular drug availability or preference. Other groups have focused on drug therapies in management recommendations for axial SpA and psoriatic arthritis (PsA) [bib_ref] European League against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis..., Gossec [/bib_ref] [bib_ref] Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment..., Coates [/bib_ref] [bib_ref] 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis, Van Der Heijde [/bib_ref] ; two of the three management recommendations adopted the treat-to-target (T2T) concept. This concept, originally developed for chronic diseases such as diabetes, [bib_ref] Glycosylated hemoglobin and the risk of retinopathy in insulin-dependent diabetes mellitus, Warram [/bib_ref] has already been successfully implemented for rheumatoid arthritis (RA). [bib_ref] Treating rheumatoid arthritis to target: 2014 update of the recommendations of an..., Smolen [/bib_ref] Systematic literature reviews (SLRs) underpinning the T2T recommendations for RA revealed data from several trials with efficacy of a target-driven therapeutic approach as superior to usual clinical care in RA for clinical, functional and structural outcomes. The 2012 task force applied this concept to SpA, despite the fact that the SLR on the original T2T recommendations for SpA revealed only indirect evidence favouring this approach, given the absence of data from strategic clinical trials. [bib_ref] Treating axial and peripheral spondyloarthritis, including psoriatic arthritis, to target: results of..., Schoels [/bib_ref] All recommendations developed in 2012 for SpA treatment to target were based on evidence levels of the lowest category 1 (category 5),which derives solely from expert opinion, even if they were based on several lines of indirect evidence. Therefore, an ambitious research agenda was then proposed to focus on improving the definition of treatment targets and validating respective instruments and emphasised the importance of data collection from strategic clinical trials. The participants understood such limitations and in the manuscript it was stated at the time that 'given the small evidence base, the research agenda is of utmost importance', anticipating a revision of the document 'in about 4 years or 5 years…, when significant evidence accumulates regarding the individual points of the ## Recommendation recommendations' that 'either allow confirmation or modifications' of the conclusions. [bib_ref] Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of..., Smolen [/bib_ref] Subsequently, in line with those expectations, a number of publications in the field have addressed several points raised in the research agenda. Therefore, our objective was to re-evaluate and update the recommendations. # Methods At the beginning of this endeavour, a steering committee (SC) comprising rheumatologists from Europe and North America experienced in SpA clinical research, a patient and a health professional (in total 13 members) was convened in August 2016 in Vienna, Austria, by a rheumatologist (JSS) and a methodologist (DvdH) to discuss the potential need for a recommendation update based on the information available from the literature published in recent years. Research questions for an update of the systematic literature review (SLR) [bib_ref] Treating axial and peripheral spondyloarthritis, including psoriatic arthritis, to target: results of..., Schoels [/bib_ref] were formulated by the SC members; the process adhered to the updated European League Against Rheumatism (EULAR) standard operating procedures (SOPs) for developing recommendations. [bib_ref] Update of the EULAR standardised operating procedures for EULAR-endorsed recommendations, Van Der Heijde [/bib_ref] The SLR, which was performed by MS and covered the period from the last SLR (2011) to the end of 2016 is summarised in the online supplementary material A. It was presented at a 2-day meeting in March 2017 in Düsseldorf, Germany. The detailed SLR was reported to the SC. The SC then carefully reviewed every item of the overarching principles and recommendations developed in 2012 and proposed an amended set of recommendations for discussion by the whole task force. The next day, the task force comprising 36 members was convened (one additional expert, TKK, was involved in the planning of the activity and in the level of agreement voting and manuscript development process). Among these members were four patient representatives (NB, MJ, MM, MdW), 1 (non-MD) health professional (TS), 2 dermatologists (AT, BT) and 28 rheumatologists, 6 of whom came from North America with the remainder coming from Europe. All experts had a significant publication record in the field of SpA. Indeed, several of the experts are also committee members of the Group for Research and Assessment of Psoriatic Arthritis (GRAPPA; www. grappanetwork. org/ committee-list) and coauthors of the 2015 GRAPPA PsA treatment recommendations; another group of experts is involved in Assessment of SpondyloArthritis international Society (ASAS) activities (http:// asas-group. org/ committee. php) and participated in the development of the ASAS-EULAR axial SpA management recommendations [bib_ref] 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis, Van Der Heijde [/bib_ref] and a third group has been involved in the generation of the EULAR PsA management recommendations, 2 with some small overlap among these involvements. In line with the SOPs, no representative of the company providing the unrestricted grant was present to avoid any potential influence on the discussion or development of the recommendations; this position has been and still is a general principle throughout all T2T activities. At the beginning, the convenor summarised the 2012 recommendations together with the 2012 discussions. In particular, the 2012 task force had originally contemplated developing three sets of recommendations, namely one for axial SpA, one for peripheral SpA excluding PsA and one for PsA. During the 2012 process, it became apparent that the three proposed sets had significant overlap such that the final recommendations comprised a common trunk of five overarching principles and nine recommendations, as well as two recommendations each for axial SpA, PsA and peripheral SpA. Given the recent proliferation of instruments (categorical and continuous) for evaluating the multiple domains of PsA, [bib_ref] The development of candidate composite disease activity and responder indices for psoriatic..., Helliwell [/bib_ref] one of the SC members (OF) presented a summary of these measures to the task force. The methodologist (DvdH) addressed the scientific and methodological background of selecting components of composite indices for chronic rheumatic diseases. An abbreviated version of the SLR was then presented to the task force (MS) with residual information available on request. Of note, very few data exist for peripheral SpA and, therefore, in line with the results of the SLR, the current activity focused on axial SpA and PsA. For the discussion and decision-making process of the recommendations, each item of the 2012 version was shown together with the SC proposal for the new version. Each of the items was subjected to a thorough discussion in light of the evidence presented and to a rigorous voting process. The methodologist explained that, as in the previous and similar endeavours, 1 4 13 the initial ballot required at least 75% of votes to accept a proposal for a recommendation. If this result was not achieved, textual amendments were discussed and in the next round 67% of the votes were needed. If that amendment was not sufficient, the process continued and then a member vote of >50% was needed for approval and acceptance. The level of evidence (LoE) and strength or recommendation (SoR) was based on the Oxford Evidence-Based Medicine categorisation.After the meeting, the newly formulated recommendations were compiled in a single table together with the LoE, SoR and voting results at the meeting. All task force members assigned electronically (by email) and anonymously level of agreement (LoA) with each item on a scale of 0 (no agreement at all) to 10 (full agreement). # Results ## General aspects implementation, feasibility and validity A central question, mentioned by the convenor in his introductory remarks, concerned the implementation of the previous recommendations. Implementation may be supported by the fact that both EULAR PsA and ASAS-EULAR axial SpA management recommendations have adopted the T2T approach. The T2T recommendations for RA were also strongly integrated into the respective American College of Rheumatology (ACR) and EULAR management guidance documents. Nevertheless, implementation is often impeded in clinical practice. [bib_ref] Treating Rheumatoid Arthritis to target: multinational recommendations assessment questionnaire, Haraoui [/bib_ref] Learning collaboratives, that is, group-based multisite educational collaboratives, can be successful in this respect. [bib_ref] Implementation of Treat-to-Target in Rheumatoid Arthritis Through a Learning Collaborative: Results of..., Solomon [/bib_ref] In some practice settings, effective implementation is attained when rheumatologists have to enter detailed data into registries. [bib_ref] Adherence to a treat-to-target strategy in early rheumatoid arthritis: results of the..., Vermeer [/bib_ref] However, even if rheumatologists agree with certain principles, the practical application of these principles may be limited. [bib_ref] When rheumatologists report that they agree with a guideline, does this mean..., Gvozdenović [/bib_ref] A recent survey revealed that 'a busy clinical practice, accompanied by a shortage of supporting staff, was identified as the main barrier to full compliance with the T2T recommendations from the physician standpoint'. [bib_ref] Treating rheumatoid arthritis to target: a canadian physician survey, Haraoui [/bib_ref] Indeed, 'limitations arise as a result of … lack of time for the individual patient with RA', despite the fact that the T2T-RA recommendations only call for using a composite measure for RA disease activity that includes joint counts. [bib_ref] Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of..., Smolen [/bib_ref] Since T2T recommendations are developed primarily for clinical practice, feasibility should be a major characteristic, among others, in line with the Appraisal of Guidelines for Research and Evaluation II guidelines, which call for applicability and consideration of resource implications when developing recommendations. [bib_ref] AGREE II: advancing guideline development, reporting and evaluation in health care, Brouwers [/bib_ref] In other words, a measure is feasible when it can 'be applied easily, given constraints of time, money or interpretability' despite the complexity of its development. [bib_ref] Developing core outcome measurement sets for clinical trials: omeract filter 2.0, Boers [/bib_ref] In addition, the composite 'measure must discriminate between situations of interest', be truthful, that is, have face, construct, content and criterion validity and demonstrate reliability. [bib_ref] Developing core outcome measurement sets for clinical trials: omeract filter 2.0, Boers [/bib_ref] Notably, health professionals in rheumatology may support the implementation and practice of T2T recommendations. ## Instruments for psa In the presentation on the measures used for PsA assessment, several different instruments, their components and calculations were addressed and are shown in table 1. They comprise the Composite Psoriatic Disease Activity Index (CPDAI), [bib_ref] Development of a preliminary composite disease activity index in psoriatic arthritis, Mumtaz [/bib_ref] Disease Activity index for PSoriatic Arthritis (DAPSA), [bib_ref] Application of the DAREA/DAPSA score for assessment of disease activity in psoriatic..., Schoels [/bib_ref] GRAppa Composite Exercise (GRACE) index, [bib_ref] Comparison of composite measures of disease activity in psoriatic arthritis using data..., Helliwell [/bib_ref] Minimal Disease Activity (MDA) [bib_ref] Defining minimal disease activity in psoriatic arthritis: a proposed objective target for..., Coates [/bib_ref] and Psoriatic Arthritis Disease Activity Score (PASDAS). [bib_ref] The development of candidate composite disease activity and responder indices for psoriatic..., Helliwell [/bib_ref] Most of these instruments allow calculation of continuous scores, while one (MDA) is dichotomous or categorical. The continuous scales can also be applied to define disease activity categories or states. One measure focuses only on joint activity (DAPSA), the others also include measures of other (non-articular) musculoskeletal domains (such as enthesitis and axial disease), skin manifestations, physical functioning or quality of life . ## Selection of domains for composite measures of disease activity The presentation on the selection of components for composite disease activity measures focused on axial SpA. Issues of methodological rigour, instrument properties pertaining to composite measures and the preference of a unidimensional approach to disease activity assessment were discussed.Additionally, the concern of combining domains into a composite that may not track together, particularly regarding response to therapy, was addressed, since the risk increases of missing true improvement in individual domains, or missing non-response or deterioration in other domains. Moreover, in this situation a good performance of one dimension can 'compensate' for a bad result in another dimension despite being different disease manifestations. This may not be the case when the disease domains are assessed separately with respective validated instruments. For example, uveitis occurs frequently in patients with axial SpA (>20%) and concomitant psoriasis or inflammatory bowel disease (IBD) are not rare. However, uveitis activity 31 since relating to a different domain should not be part of an index for axial SpA. It was also noted that composites should not combine a measure of inflammation with a measure of structural changes or physical functional, since damage and function are different constructs than activity. While they are partly a consequence of the inflammatory process, they do not reflect this process directly (figure 1). Furthermore, when outcome measures are combined with activity measures, the ability to detect improvement might preclude a subgroup of patients with long-standing disease from achieving remission despite experiencing clear-cut absence of inflammation. [bib_ref] A modified sharp score demonstrates disease progression in established psoriatic arthritis, Ravindran [/bib_ref] [bib_ref] Treatment-related improvement in physical function varies with duration of rheumatoid arthritis: a..., Aletaha [/bib_ref] [bib_ref] Measuring function in rheumatoid arthritis: identifying reversible and irreversible components, Aletaha [/bib_ref] [bib_ref] A longitudinal study of the effect of disease activity and clinical damage..., Husted [/bib_ref] Moreover, when the data from these instruments are correlated with physical function as an outcome, circular reasoning may ensue. Therefore, ASAS improvement and partial remission criteria, which include function (table 2), [bib_ref] The Assessment of SpondyloArthritis international society (ASAS) handbook: a guide to assess..., Sieper [/bib_ref] are less discriminative and appropriate than the respective Ankylosing Spondylitis Disease Activity Score (ASDAS) categories. [bib_ref] Sensitivity and discriminatory ability of the Ankylosing Spondylitis Disease Activity score in..., Van Der Heijde [/bib_ref] table 1 Scores for PsA (disease manifestations depicted in green colour are included, those depicted in red colour are not included in the respective score) ## Recommendation In general, composite measures have the advantage of encompassing various aspects linked to a construct, such as inflammation. For example, in RA and also PsA joint swelling and acute phase reactant (APR) levels are more strongly associated with progression of joint damage, than joint tenderness, 38-41 patient global and pain assessments, while the latter are more strongly associated with disability than damage; a composite measure that combines these individual variables reflecting current disease activity will, therefore, relate to the totality of future adverse disease outcomes. [bib_ref] Validity of single variables and composite indices for measuring disease activity in..., Van Der Heijde [/bib_ref] [bib_ref] A methodologic framework for developing and selecting endpoints in clinical trials, Tugwell [/bib_ref] [bib_ref] Criteria for clinically important changes in outcomes: development, scoring and evaluation of..., Goldsmith [/bib_ref] Of note, the term 'outcome' is frequently used interchangeably with the term 'end point' (of an intervention, ie, outcome of a treatment or a study), while here it will be used primarily to reflect the sequel of diseases like axial SpA and PsA. A number of task force members believe that in PsA, as a multidimensional disease, one should be aiming to measure psoriatic disease as a construct and, therefore, the instrument needed to combine individual domains into a single 'snapshot' of the disease; moderate disease activity in several domains may altogether contribute to a single score representing high disease activity and response criteria and cut-offs will reflect the disease as a whole. Others are of the opinion that especially in a multidimensional disease unidimensional scoring of the individual components is pivotal to understand the heterogeneity in an individual patient and especially therapeutic effects on the individual domains. By this reasoning all disease manifestations should be assessed, but separately and not within one index (a unidimensional approach). Indeed, just like in RA or axial SpA, where management recommendations relate to the respective levels of disease activity, the most recent management recommendations for PsA relate to the level of activity of the individual domains and not a total score of psoriatic disease. It is also noteworthy that the recent approvals by regulatory authorities of all novel therapies for PsA were based on clinical trials using unidimensional primary end points, even though they were derived from RA and were thus not specific for PsA joint involvement nor other manifestations of the disease. While the ACR response criteria include a measure of physical function, it is one of five measures (of which three need to be fulfilled) that can only be used if joint counts improve by a minimum of 20%, 50% or 70%. [bib_ref] American College of Rheumatology. preliminary definition of improvement in rheumatoid arthritis, Felson [/bib_ref] In post hoc subanalyses, however, several of the newer composite scores such as PASDAS were evaluated [bib_ref] Comparison of composite measures of disease activity in psoriatic arthritis using data..., Helliwell [/bib_ref] and newer trials are including composite multidimensional measures related to all domains and/or the unidimensional DAPSA as key outcomes. During the meeting and in the process of developing the manuscript, no clear agreement emerged between these two schools of thought. Most of the participants who advocated multidimensional scores were members of GRAPPA committees, while most of those advocating unidimensional scoring approaches were not. Thus, it appears that this is still an area of research that needs to be growing and methods of defining validity are developing. To this end, several ongoing studies are aiming to further define the optimal outcome measures for PsA. ## The consensus overarching principles Providing a framework to embed the individual recommendations was important. Such a framework has been studied rarely in a methodological fashion. Therefore, the previous document already included 'principles' that govern and underscore the realisation of the recommendations. [bib_ref] Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of..., Smolen [/bib_ref] The current task force adhered to this approach and agreed on five overarching principles, in line with the 2012 recommendations. A. The treatment target must be based on a shared decision between patient and rheumatologist. This first principle remained unchanged. It is fundamental to good clinical practice and constitutes a quality indicator of patient care in other diseases. [bib_ref] Development of patient-centred standards of care for rheumatoid arthritis in Europe: the..., Stoffer [/bib_ref] There was discussion whether the term 'target' should be changed to 'targets', because SpA exhibits clinical heterogeneity and patients and rheumatologists wish to achieve the treatment target across disease domains, whether musculoskeletal or extramusculoskeletal. A counterargument addressed the point that the singular 'target', which focuses on a state to be attained, pertains to the outcome of all domains. Furthermore, 'treatment targets' is a term that is rarely, if ever used and might require [fig_ref] 1: Total back pain [/fig_ref] Relationships between inflammation, damage and disability. Inflammation, by virtue of pain and stiffness, elicits disability which is reversible on reversal of disease activity. Inflammation also induces damage which is usually irreversible. Damage also induces disability; due to its irreversible nature, damage-induced disability is irreversible, meaning that with increasing damage the floor of physical functioning that can be reached on reversal of disease activity rises. clarification for patients and rheumatologists. The patients felt strongly about the need for physicians to adhere to evidence-based therapies and to educate patients on the importance of such therapies versus unproven approaches. While there was broad agreement here, this aspect was felt to be more appropriate for the individual recommendations (to be discussed subsequently) and to drug management guidance documents. In a first ballot, the 75% majority needed was not obtained; the principle as worded and the original singular version of 'target' then received 69.4% approval in the second ballot. B. Treatment to target by measuring disease activity, and adjusting therapy accordingly, improves outcomes. Since the previous version of these recommendations, evidence for the benefit of a T2T strategy compared with routine care has been obtained for PsA in the TICOPA trial. [bib_ref] Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a..., Coates [/bib_ref] Therefore, it was proposed to replace the previous wording 'contributes to short-term and/or long-term outcomes' simply by 'improves outcomes'. Although no T2T study has been performed in axial SpA, it was deemed that such an approach could also improve outcomes in axial SpA, given the correlation of damage progression with disease activity. T2T studies are currently ongoing in axial SpA (eg, TICOSPA, NCT 03043846, and STRIKE, NCT 02897115). In the course of the deliberations, it was mentioned that the efficacy benefit of a T2T approach in PsA was somewhat counterbalanced by more adverse events in the TICOPA trial, [bib_ref] Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a..., Coates [/bib_ref] however, this may be related to therapy choice (rapid csDMARD escalation and combinations) and partially due to reporting bias (T2T patients were reviewed every 4 weeks, controls every 12 weeks) rather than the T2T strategy itself. Nevertheless, as will be detailed in the individual recommendations 3. How would you describe the overall level of pain/swelling in joints other than neck, back or hips you had? 4. How would you describe the overall level of discomfort you have had from any areas tender to touch or pressure? 5. How would you describe the overall level of morning stiffness you have had from the time you wake up? 6. How long does your morning stiffness last from the time you wake up? AsdAs Parameters calculations ## Recommendation and mentioned in principle C, safety aspects have to be considered when using a T2T approach. Thus, it was suggested to mention that for axial SpA this principle should currently be read as 'T2T is based on the assumption that it improves outcomes'. Despite these caveats, the new wording was accepted by a majority of task force members (83.3%) in the first ballot. C. SpA and PsA are multifaceted systemic diseases; the management of musculoskeletal and extra-articular manifestations should be coordinated, as needed, between the rheumatologist and other specialists (such as dermatologists, gastroenterologists, ophthalmologists). The original version: 'SpA and PsA are often complex systemic diseases' was changed in two aspects: first, 'complex' was deemed by some to suggest that these diseases are too complicated to be understood, while it was used in 2012 to address the disease heterogeneity. Various additional aspects, especially concerning the term 'extra-articular manifestations', were discussed and are provided in online supplementary material B. The term 'extra-articular' will refer to nonmusculoskeletal abnormalities, such as the skin or the eye; indeed, current management recommendations separate these domains regarding specific treatment approaches. However, the management recommendations also separate arthritis from other musculoskeletal manifestations; therefore, we will refer to axial disease, dactylitis and enthesitis as 'non-articular musculoskeletal manifestations' for the sake of semantic consistency and differentiation from 'extra-articular' manifestations. Furthermore, replacing 'specialists' by 'specialties' was discussed, but did not find popularity. Finally, it was suggested to expand 'extra-articular' to 'extra-articular and other manifestations' to also account for cardiovascular risk and other comorbidities; however, this also did not find major agreement, since these comorbidities, while serious and to be taken into account when following patients with SpA, constitute primarily consequences of chronic inflammation in general, rather than extra-articular manifestations of the underlying SpA, which are the focus of the current endeavour. Changing 'complex' to 'multifaceted' achieved 100% approval, maintaining 'specialists' rather than changing to 'specialties' achieved 86% approval, and leaving 'extra-articular' unchanged attained 69.4% of votes in a second ballot. D. The goals of treating the patient with axial SpA or PsA are to optimise long-term health-related quality of life and social participation through control of signs and symptoms, prevention of structural damage, normalisation or preservation of function, avoidance of toxicities and minimisation of comorbidities. Compared with the previous version, the qualification 'primary', in the sense of 'main', for the goal was felt to be confusing, since several goals (and not just one) were mentioned thereafter. Therefore, it was suggested to simply delete 'primary' and replace goal by its plural form. This found an 86% approval. In a second ballot, the previous term 'maximise' was replaced by 'optimise' (72%). Discussions on specifying MRI regarding structural damage assessment and mentioning acute phase reactants in the context of this principle were not taken further here and postponed to deliberations on the specific recommendations. Of note and in reference to discussions mentioned above, comorbidities are specifically included here. E. Abrogation of inflammation is important to achieve these goals. Compared with previous principle D, which stated that 'abrogation of inflammation is presumably important', 'presumably' was now deleted, since sufficient evidence had accumulated over the last 5 years that inflammation is pivotal for progression of damage. Therefore, even though PsA is not a homogeneous disease and up to one-third of patients may have non-progressive arthritis where this paradigm may not apply, [bib_ref] Natural history, prognosis and socio-economic aspects of psoriatic arthritis, Helliwell [/bib_ref] in the majority of patients, interference with inflammation is needed to achieve good outcomes. It was also suggested to exchange the word 'abrogation' by 'elimination' because this might be better understood; however, reference to the patient version of RA recommendations revealed that this term can be easily transposed for lay people. [bib_ref] Treating rheumatoid arthritis to target: the patient version of the international recommendations, De Wit [/bib_ref] There was 94.4% agreement with the above version in the first ballot. ## Recommendations The task force next evaluated potential changes to the recommendations. All options were acceptable, namely: to be left as they had originally been constructed, amended, deleted or expanded in number and/or changed in sequence. Adherence to the evidence available was the pivotal driver during this process. The previous recommendations and the proposals for amendment by the SC were presented and discussed. This process resulted in a total of 11 bullet points. 1. The treatment target should be clinical remission/inactive disease of musculoskeletal (arthritis, dactylitis, enthesitis, axial disease) and extra-articular manifestations. This bullet point previously read: 'A major treatment target should be clinical remission/inactive disease of musculoskeletal involvement (arthritis, dactylitis, enthesitis, axial disease), taking extra-articular manifestations into consideration'. Thus, from the perspective of the content, the updated recommendation remained similar, but it was shortened and a few items deleted. For example, it was not deemed necessary to call the target a 'major' one, since remission should be the aim in essentially all patients, while the term 'should' inherently suggests that this may not always be achievable (see item 4). Also, the phrase 'taking extra-articular manifestations into consideration' already suggested that their reversal should be accounted for. Importantly, however, no clinical trial used remission or inactive disease as a target for a strategic trial. The only strategic trial currently published focused on MDA, which likely corresponds to a low disease activity state as it allows for residual activity in some items. [bib_ref] Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a..., Coates [/bib_ref] On the other hand, there is sufficient indirect evidence to suggest that in axial SpA and PsA, progression of damage is most strongly inhibited in states of remission/ inactive disease; low disease activity including MDA also conveys good structural outcomes and physical function is maximised in remission. [bib_ref] Disease activity states of the DAPSA, a psoriatic arthritis specific instrument, are..., Aletaha [/bib_ref] This recommendation was voted for by 75% of the participants in the first ballot. 2. The treatment target should be individualised based on the current clinical manifestations of the disease; the treatment modality should be considered when defining the time required to reach the target. The first part of this recommendation constituted the previous point 2; the term 'according to' was just replaced by 'based on'. It was also suggested that the term 'current' was deleted or changed, since one treats 'active' disease; however, the group preferred to adhere to 'current', since rheumatologists would understand what was meant. In the course of the discussions, several task force members suggested to add a time aspect, since the T2T concept generally calls for timely adaptation of therapy if a treatment is insufficiently effective and that the target and the time to reach the target are related concepts. On the other hand, the time point at which one can discern a good from a minor or no response differs depending on the drugs used (eg, shorter with non-steroidal anti-inflammatory drugs) than biologic (b) DMARDs or methotrexate). Thus, an interim proposal for this recommendation read: 'The treatment target and the time to reach the target should be individualised based on the current clinical manifestations of the disease and the treatment modality'. The opinion was then expressed that the target and the time to reach the target, while related, constituted separate concepts and, therefore, should be separated. With respect to timelines, treatment with DMARDs should show significant improvement within 3 months and attainment of the target within 6 months. These considerations resulted in the present version which attained a 94.4% approval. 3. Clinical remission/inactive disease is defined as the absence of clinical and laboratory evidence of significant disease activity. This recommendation, which defines item 1, ultimately remained almost unchanged compared with 2012, but three discussion points were raised. First, it was suggested to exclude the need for laboratory evidence in the definition, because MDA, and also clinical DAPSA, [bib_ref] Application of the DAREA/DAPSA score for assessment of disease activity in psoriatic..., Schoels [/bib_ref] did not include C reactive protein (CRP) or erythrocyte sedimentation rate (ESR) in their formulae and were still associated with good outcomes. The opposite view related to the fact that APR levels were significantly associated with progression of damage both in PsA and axial SpA, and therefore should not be excluded from assessment of disease activity. Moreover, APRs are the only objective measure of articular or spinal disease activity (especially in axial SpA) and reflect the same dimension as activity of arthritis or of spondylitis. It is noteworthy that this recommendation refers to 'clinical remission/inactive disease', in other words, it does not call for remission/inactive disease by imaging techniques such as sonography or MRI. Nevertheless, both DAPSA remission and a Boolean remission definition focusing on musculoskeletal items, but not MDA or CPDAI, were associated with minimal sonographic activity in PsA. Finally, the question was raised whether having the concept of remission was necessary or rather the terms inactive disease or minimal disease activity would be sufficient. However, in the course of the discussion several participants mentioned that the concept of remission was essential for rheumatic diseases, since it implies a cure-like state with no further progression of damage; importantly in this context, damage is associated with active joint or spinal disease, potentially even progressing slightly in low disease activity. [bib_ref] Inflammation in an individual joint predicts damage to that joint in psoriatic..., Cresswell [/bib_ref] As a result of these deliberations, this recommendation was approved in the first ballot by 88.9% of the task force members. 4. Low/minimal disease activity may be an alternative treatment target. Stringent remission, as defined in point 3, may be difficult to achieve in many patients in clinical practice, especially in those with long-standing disease or substantial comorbidities. The discussion focused on the need to understand the potential failure to attain a state named remission, since this failure could be a consequence of the instruments used; in particular, including physical function in an index may preclude attaining remission in those patients in whom function is severely impaired due to significant damage. This has been seen in ankylosing spondylitis (AS), where ASAS partial remission includes function [bib_ref] The Assessment of SpondyloArthritis international society (ASAS) handbook: a guide to assess..., Sieper [/bib_ref] and is less frequently achieved than ASDAS inactive disease. [bib_ref] Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results..., Sieper [/bib_ref] Of note, ASDAS terminology refers to low disease activity as moderate disease activity, since the disease activity states include 'very high' in addition to 'high'; this should be considered when interpreting ASDAS data or using ASDAS in practice. It was then discussed that the Health Assessment Questionnaire Disability Index (HAQ) was just one item of several in the MDA criteria set or other indices, such as the CPDAI or GRACE, and patients could fulfil the other elements. However, allowing only six items to be achievable in the MDA, for example, may still decrease the chances of reaching a satisfactory status. MDA was applied as target in TICOPA, an open-label but controlled clinical trial, which allowed the SLR to adjudicate a high level of evidence (2b) to the trial and to this item with a grade of recommendation of B 10 (table 3). All task force members acknowledged the importance of this first-in-disease randomised strategic trial. By corollary, since low disease activity is an alternative target to remission, higher disease activity states are unacceptable, unless these are due to explicit patient preferences or reduction of disease activity is precluded by comorbidities or risks. Thus, ultimately the agreement on the treatment target should be based on a shared decision making between clinicians and patients. This recommendation achieved a 97.2% approval. 5. Disease activity should be measured on the basis of clinical signs and symptoms, and acute phase reactants. Initially, the question was raised if imaging should also be included when speaking of disease activity assessments. However, this suggestion was refuted because there are no data justifying the use of imaging in follow-up as yet and it is not feasible to perform MRI every few weeks in axial SpA. In early RA, following patients using ultrasound to target sonographic remission was not superior to clinical follow-up and a waste of healthcare resources. In light of the deliberations on point 3, no further discussions on the use of APRs in clinical practice ensued. This item remained unchanged compared with the 2012 version and achieved a 88.9% majority vote. 6. Validated measures of musculoskeletal disease activity and assessment of cutaneous and/or other relevant extra-articular manifestations should be used in clinical practice to define the target and to guide treatment decisions; the frequency of the measurements depends on the level of disease activity. This item is related to recommendation 10 of the 2012 version. However, it was one of the recommendations, which had been separately developed for axial SpA, peripheral SpA and PsA. Since all three recommendations had many components in common, it was deemed appropriate to combine them into a single recommendation. Previously, this item partly referred to specific instruments, such as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [bib_ref] A new approach to defining disease status in ankylosing spondylitis: the Bath..., Garrett [/bib_ref] plus APRs or ASDAS, with or without measures of function such as Bath Ankylosing Spondylitis Functional Index 63 ' for axial SpA, or 'arthritis, dactylitis, enthesitis, axial disease' and 'cutaneous manifestations' for PsA. It was felt that the aspect of specific scores should be separated from the more general parts and that extra-articular manifestations should be considered in PsA and in peripheral and axial SpA, given the potential for wideranging clinical manifestations, by which they are also classified. [bib_ref] The development of Assessment of SpondyloArthritis International Society classification criteria for Axial..., Rudwaleit [/bib_ref] Thus, this general comment was expanded and somewhat reworded to include cutaneous and 'other relevant extra-articular manifestations', indicating that eye (uveitis) and bowel (IBD) manifestations should also be considered, in line with overarching principle C. The ## Recommendation 2012 recommendation included the notion that the validated measures should also be 'documented regularly'; this was now omitted, but it should be part of standard of care in the context of the T2T recommendations that results of measuring disease activity must be recorded in the patients' charts. Also, in line with the previous version, it is recommended that patients with high disease activity should be rheumatologically evaluated at short intervals (every 1-3 months), while those who achieved the treatment target could be followed less frequently, such as every 6-12 months; hence, the dependence on disease activity. As ultimately worded, this recommendation obtained 84.4% of the votes. 7. In axial SpA, ASDAS is a preferred measure and in PsA DAP SA or MDA should be considered to define the target. This bullet point addresses the clinical assessment of axial SpA and PsA, which was a focus of intensive debates during the consensus meeting. The discussion addressed both SpA subentities separately for some time, although there was some intermix in the course of these deliberations. Regarding axial SpA, the 2012 version had suggested the assessment of ASDAS and/or BASDAI plus CRP. However, it was mentioned that the discrimination of BASDAI plus CRP is not as good as that of ASDAS and a model with ASDAS versus one including BASDAI and CRP was more closely correlated with syndesmophyte formation. [bib_ref] ASDAS, a highly discriminatory ASAS-endorsed disease activity score in patients with ankylosing..., Van Der Heijde [/bib_ref] Indeed, ASDAS is more associated with various biomarkers of inflammation than BASDAI [bib_ref] Responsiveness of the Ankylosing Spondylitis Disease Activity score (ASDAS) and clinical and..., Pedersen [/bib_ref] and correlates better with MRI changes. [bib_ref] MRI inflammation and its relation with measures of clinical disease activity and..., Machado [/bib_ref] When ASAS partial remission was brought into the discussion, it became clear that, as stated before, it comprises physical function which is primarily an outcome variable and partly dependent on spinal damage, making it less responsive and discriminative than ASDAS. However, colleagues from the USA felt that the requirement of a laboratory measure (CRP) in the ASDAS could decrease feasibility in the USA in daily clinical practice, since laboratory testing may not always be possible on or sometimes even close to the date of the visits. It was counter-argued that CRP from the previous visit could be used when the patient was in the office and ASDAS could be corrected once the new laboratory evaluation was available, or a CRP could already be collected before the office visit, but this may not be generally feasible. Moreover, recommendation 3 states that remission should also be defined by laboratory markers, so a CRP value should be obtained to be able to comply with this recommendation. After this discussion on assessment of axial SpA, scoring systems for disease activity of PsA became again a heavily debated topic. It was restated by some members that from a methodological viewpoint composite measures should ## 10. Once the target is achieved, it should ideally be maintained throughout the course of the disease 2c B ideally be unidimensional. This view was opposed by others stating that a multidimensional measure such as CPDAI and PASDAS allowed the physician to see individual jmgdomain responses while providing a comprehensive measure of inflammatory disease activity. The discussion continued with the question, why one needed to bring them together and then still look at them separately rather than leaving them separate; to calculate the composite scores one must have the individual component scores. Those suggesting separate assessments mentioned that not all drugs have similar efficacy on all domains, based on the genetic and pathogenic heterogeneity of the disease [bib_ref] Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype, Fitzgerald [/bib_ref] ; consequently, a drug may convey a good result when using a multidimensional score due to an excellent effect on the skin, but lack efficacy on an individual aspect of the disease, such as the joints. They further asked if a drug should be approved for PsA on the basis of results of such a composite measure. The dermatologists among the task force members mentioned that fumarates, which are primarily used in Europe, have significant effects on the skin and only modest benefit on the articular disease. Similarly, cyclosporine has only little effect on arthritis [bib_ref] A randomised, double blind, placebo controlled, multicentre trial of combination therapy with..., Fraser [/bib_ref] and inhibition of interleukin-17 has similar efficacy as tumour necrosis factor-inhibition on joints but a more profound effects on the skin. [bib_ref] Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE..., Mcinnes [/bib_ref] Additional information on PsA scores comes from a post hoc analysis of the Psoriasis Randomised Etanercept STudy in subjects with psoriatic Arthritis (PRESTA) trial in which a 100 mg weekly dose of etanercept was compared with 50 mg weekly. At 12 though not at 24 weeks the CPDAI but not the DAPSA distinguished treatment response between the two doses. [bib_ref] Application of composite disease activity scores in psoriatic arthritis to the PRESTA..., Fitzgerald [/bib_ref] In the original trial, however, no significant difference of articular, dactylitis and enthesitis scores was observed between the doses at any time point; only the Psoriasis Area and Severity Index (PASI) differentiated between the doses at 12 but not 24 weeks. [bib_ref] Comparison of two etanercept regimens for treatment of psoriasis and psoriatic arthritis:..., Sterry [/bib_ref] Etanercept is approved at 50 mg weekly for PsA and at 100 mg weekly (for the first 12 weeks) for psoriasis. Notably management recommendations by both GRAPPA and EULAR suggest different treatment algorithms when patients present with a predominance of arthritis, enthesitis or skin involvement. Generally T2T recommendations are not dealing with recommendations on individual therapies but, as stated before, are of generic nature; the treatment-related considerations addressed here have been specifically mentioned during the meeting or in the course of manuscript development in relation to the validity of instruments used to assess PsA activity and are thus pertinent for the general aspects of the discussion and not to make any therapeutic inferences. Importantly, it was generally agreed that all manifestations of PsA needed to be assessed and that for each of the domains validated measures existed, but there was disagreement whether to bring them together into one score or evaluate them separately. One task force member stated that recommendations are also important to educate rheumatologists to include assessment of the skin and other manifestations when dealing with patients with PsA; dermatologists should at least also enquire about joint manifestations. Recommendations should provide a goal for attaining better disease control and should not be based solely on feasibility considerations. Others asked if rheumatologists should then be forced to perform detailed skin and other assessments, given that their main focus is the arthritic component and that scores needed to be feasible in light of the time constraints in clinical practice that have been identified as factors limiting T2T. Some rheumatologists may prefer to cooperate with a dermatologist when making treatment decisions for patients with more severe skin disease rather than making their own decisions, in line with overarching principle C. Feasibility was seen as an important aspect of the applicability of a score [bib_ref] Developing core outcome measurement sets for clinical trials: omeract filter 2.0, Boers [/bib_ref] and from this perspective separate assessment of individual domains (musculoskeletal and cutaneous), in line with items 1 and 6 of the recommendations, was regarded by some to be more feasible and informative than combining them in a global composite measure. Furthermore, the question whether evidence existed for the contribution of skin involvement, or other measures that are not joint-related, to progression of joint damage in patients with PsA is unresolved; however, quality of life is strongly influenced by both musculoskeletal and skin disease. Regarding skin involvement, the dermatologists mentioned that a PASI of 1 or a Bosy Surface Area (BSA) of 3, as would be compatible with MDA or even fulfilment of very low disease activity (VLDA) criteria, that is, seven out of the seven components of the MDA, was less relevant than the contextual aspects: a BSA of 1, being equal to one palm of overall skin involvement, would be seen differently depending on the localisation of the skin affection (eg, face) and the patients' illness perception. However, the BSA thresholds of 1 and 3 are in line with the new T2T recommendations in psoriasis developed by the National Psoriasis Foundation. [bib_ref] From the Medical Board of the National Psoriasis Foundation: treatment targets for..., Armstrong [/bib_ref] A proposal to revalidate the DAPSA with the addition of a skin component was contested in light of the methodological aspect of unidimensionality. Likewise, the suggestion to revalidate MDA by deleting skin involvement and HAQ and adding CRP was countered by those who felt that skin should be included for face validity considering a construct of overall disease activity and that MDA had been used in the TICOPA trial as originally constructed. At some point, the discussion was stopped because all arguments had already been heard with no resolution of the methodological dissent. Given this difference of opinions, it was suggested that further research needed to be performed in PsA. In the field of axial SpA, the situation was much clearer, even though the evidence was less direct. Therefore, the way was paved for voting just on axial SpA. Thus, the initial ballot involved only the first part of the current recommendation. However, the first proposal stating that ASDAS was 'the' preferred measure attained only 59.4% of the votes, rather than the necessary 75%. The ensuing discussion focused around the fact that a recommendation to use the ASDAS did not imply that it was mandatory to use the ASDAS and it was proposed to replace '"the" preferred measure' by '"a" preferred measure'. At this point in time, a task force member voiced the disappointment regarding the sole focus on instruments for axial SpA, in light of the significant advancements in the PsA field since the days of the last T2T consensus. It was propositioned to also include PsA-specific assessments in the recommendation. It was remarked that neither had a strategic trial been performed in axial SpA hitherto nor had the ASDAS been used in such strategy; therefore, it was felt that the overall levels of information for axial SpA and PsA were not so disparate as to justify focusing on axial SpA alone. It was further argued that the only strategic trial published in the wide field of SpA had been performed in PsA, using ## Recommendation MDA as an anchor for advancing therapy, [bib_ref] Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a..., Coates [/bib_ref] and that, just as much as ASDAS, both the continuous DAPSA (focusing on joint involvement) and MDA (a binary measure of disease state covering important domains of PsA including joints, skin and entheses) had been shown to have construct validity and were easy to perform in clinical practice. MDA defines a state; DAPSA allows definition of all disease activity states as well as levels of response to treatment. [bib_ref] Disease activity in psoriatic arthritis (PsA): defining remission and treatment success using..., Schoels [/bib_ref] It was further stated that several items of the research agenda developed in 2012 (validation of scores, definition of disease activity states, response criteria, remission definition, therapeutic strategic trial) 1 had been fulfilled for PsA and that, therefore, indeed the focus should not only be on axial SpA. After this plea, the second part of the current recommendation was proposed, but attained only 53.1% of the votes. Subsequent proposals also failed to now achieve a two-thirds majority. In a final ballot, the wording as stated in the recommendation was accepted by a simple majority of 51.6% of the participants. Of note, >70% of the task force members assigned a level of agreement of 8 or higher in the anonymous vote after the meeting (see below). 8. The choice of the target and of the disease activity measure should take comorbidities, patient factors and drug-related risks into account. This recommendation is similar to item 6 in 2012. An interim proposal read: 'Comorbidities, patient factors and drug characteristics including risks should be considered when choosing the target and interpreting disease activity scores and the level of the target; drug characteristics including risks, should also be taken into account'. The discussion centred around the need to incorporate 'drug characteristics including risks', since drug-related risks would not influence the choice of the instrument but rather only of the target. The term patient factors refers to patient preferences or individual patient situations, such as a particular profession which may require a more or a less stringent treatment target. The question arose if patient input should also be addressed here, but it was argued that this aspect was already comprised in the overarching principles. Also, some felt that the recommendation was quite lengthy. Nevertheless, a ballot on the interim version took place, but attained only a 68.6% rather than a 75% majority. After further debates and reformulation attempts, the recommendation as now worded achieved a 91.4% majority. 9. In addition to clinical and laboratory measures, imaging results may be considered in clinical management. This is a new recommendation which relates to previous item 9 from the common trunk and the various items 11 from the specific recommendations approved in 2012. The part on 'functional impairment, extra-articular manifestations, comorbidities and treatment risks' was deleted from previous bullet point 9, since it was addressed in other items. The portion on 'clinical and laboratory measures' was reworded and brought to the front of the recommendation, since these measures should be the main focus of assessment. Of note, the term imaging results relates to all imaging modalities, conventional radiography, MRI and sonography, in line with what had been stated in points 9 and 11 in 2012. While imaging is not recommended as a target, it may assist where there is doubt if a target has been reached (ie, if the target was not reached because of inflammation or other reasons). This recommendation, as a replacement of previous numbers 9 and 11, achieved a 93.9% majority. 10. Once the target is achieved, it should ideally be maintained throughout the course of the disease. This recommendation is almost identical to no. 7 from 2012 version. It was deemed a logical consequence of the items related to attainment of the target and there was almost no discussion-100% of the participants voted for this wording. 11. The patient should be appropriately informed and involved in the discussions about the treatment target, and the risks and benefits of the strategy planned to reach this target. This recommendation is identical to no. 8 of the 2012 version. Some slight rewordings did not appeal to the task force. Also, a discussion on the addition of the term 'treatment goals' rather than 'treatment target' took place, but it was ultimately agreed that the term 'target' was used throughout the document and should not be weakened. The current wording was approved by 76.5% of the task force members. After the task force meeting, the overarching principles and specific recommendations were placed into a logical sequence and then subjected to anonymised electronic voting regarding the levels of agreement. These results, together with the levels of evidence and strengths of recommendations are presented next to each item (table 3). The task force members' LoA with the overarching principles ranged from 9.2 to 9.9 out of 0-10, reflecting a high level of agreement. Likewise, the LoA with 10 of the individual recommendations ranged from 9.1 to 9.9. Only recommendation 7 reached a lower LoA, namely 7.9. It is noteworthy that two participants did not agree at all (score of 0), nine gave scores of 5-7, but the majority (70.3%) still bestowed scores between 8 and 10 (13 scored 10) to this recommendation. The updated recommendations are also captured in an algorithm (figure 2). ## Research agenda While several points of the previous research agenda have been answered now, other items remained open and new research questions arose. These are listed in table 4. # Discussion T2T has been widely used for several decades to improve outcomes of non-rheumatic diseases. [bib_ref] Diabetes Control and Complications Trial Research Group. The effect of intensive treatment..., Nathan [/bib_ref] [bib_ref] Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension:..., Hansson [/bib_ref] [bib_ref] Moving toward new statin guidelines in a post-JUPITER world: principles to consider, Ridker [/bib_ref] More recently, T2T strategies have also entered the field of rheumatology and T2T recommendations for RA were published at the beginning of this decade. [bib_ref] Treating rheumatoid arthritis to target: recommendations of an international task force, Smolen [/bib_ref] In the interim, T2T recommendations have also been developed for gout and systemic lupus erythematosus (SLE). In 2012, an international task force had also developed T2T recommendations for treating SpA, including AS and PsA. [bib_ref] Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of..., Smolen [/bib_ref] While treatment recommendations should be based on available evidence, neither the T2T recommendations for gout or SLE nor the previous ones for SpA derived from clear evidence showing the superiority of such steered treatment approach. They arose from a strong belief that this would be the case, with support from indirect information. Moreover, the recommendations elicited awareness of an important unresolved question and a pertinent research agenda. This agenda was indeed published as part of the SpA recommendations and many research questions raised several years ago have now been answered. For example, one research question related to the validation and definition of disease activity and response criteria. Subsequently, several composite measures were validated, 12 disease activity states defined and response criteria developed. [bib_ref] Disease activity in psoriatic arthritis (PsA): defining remission and treatment success using..., Schoels [/bib_ref] A further quest was the definition of remission, which was also attained for PsA (remission) and axial SpA (inactive disease). The research question regarding the importance of including all domains of PsA or axial SpA in the remission definition is still unresolved. There are conflicting data on the magnitude of influence of psoriasis on physical function as measured by the HAQ. Yet another research question related to differences between low disease activity and remission in terms of outcomes which was clearly the case. Likewise, the question regarding the relationship between disease activity and damage found a clear answer. [bib_ref] Predictors for radiological damage in psoriatic arthritis: results from a single centre, Bond [/bib_ref] Finally, the pursuit of designing and performing a therapeutic trial comparing steered therapy aiming at remission or low disease activity with non-steered treatment was also completed in PsA. [bib_ref] Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a..., Coates [/bib_ref] Thus, a large part of the research agenda posed in 2012 was addressed over the last few years; therefore, it was deemed timely to re-evaluate the recommendations. The committee went through at times lengthy discussions, but ultimately formulated 5 overarching principles and 11 recommendations, which received very high levels of agreement in a final anonymous ballot. Most importantly, while all recommendations developed in 2012 had a very low LoE and GoR (5 and D, respectively), 5 of the 11 recommendations in 2017 are now based on B grades of recommendation, a clear advancement in 5 years. Another aspect deserves mention: the 2012 task force originally planned to develop three separate sets of recommendations, one each for axial SpA (AS), PsA and peripheral SpA (such as reactive and IBD arthritis) and finally arrived at nine common and two additional separate recommendations for each of the SpA subsets. Now the task force did not even discuss separate recommendations ## Recommendation for axial SpA, peripheral SpA and PsA, since all respective items 10 and 11 in 2012 were very similar, indeed. 1 Thus, while 9 plus 2×3 recommendations had been developed in 2012, this committee arrived at a total of 11 rather than 15 points. While trials in patients with peripheral SpA other than PsA were not found in the SLR, it is noteworthy that DAPSA had originally been derived and validated in reactive arthritis. [bib_ref] Application of the DAREA/DAPSA score for assessment of disease activity in psoriatic..., Schoels [/bib_ref] The wording of the overarching principles, for which no evidence was sought as they relate to very general conduct and treatment approaches, was more focused and the sequence slightly amended compared with the 2012 recommendations. Shared decision-making between patients and rheumatologists, recognition of the multiple facets of SpA, adjustment of therapy according to disease activity and targeting optimisation of health-related quality of life by abrogating inflammation continue to be their major aspects. Thus, the overarching principles remained essentially similar. With respect to the individual recommendations, items 1-5 are very similar when compared with 2012. Targeting remission/inactive disease (item 1) and, as an alternative, low/ minimal disease activity (number 4) are the mainstays of treatment to target. Remission was defined as the absence of clinical and laboratory evidence of significant disease activity (item 3). Likewise, the need to individualise therapy in line with disease manifestations (number 2) and disease activity assessment by measuring clinical signs and symptoms as well as acute phase reactants (item 5) was upheld. The use of validated measures of musculoskeletal disease activity, but also of extra-articular manifestations, previously presented as the 10th and 11th recommendations, is now addressed as point 6. Item 7 is now more specific than previous item 10 in terms of the recommendation of specific instruments. For axial SpA, ASDAS is now more clearly highlighted as assessment tool. Some discussion arose around this instrument, since it comprises CRP which is often not immediately available in clinical practice, although it was clarified that a previous CRP measurement could be used until the new laboratory result became available. Moreover, recommendations no. 3 and 5 state that the target should include clinical and laboratory measures, which implies that CRP should be obtained irrespective of whether it is included in the ASDAS or kept separately. The focus on ASDAS in this recommendation puts the previous inclusion of BASDAI plus CRP into the background, which also respects the high discriminative capacity and sensitivity to change of ASDAS. [bib_ref] Responsiveness of the Ankylosing Spondylitis Disease Activity score (ASDAS) and clinical and..., Pedersen [/bib_ref] For PsA, DAPSA and MDA are now explicitly mentioned, although other instruments are not discounted, awaiting further evaluation. DAPSA includes CRP, but as it is unidimensional it focuses only on joint involvement, incorporating patient global and pain assessments, but does not include a measurement of skin abnormalities nor non-articular musculoskeletal involvement; these manifestations need to be separately evaluated, as mentioned in items 1 and 6. MDA comprises peripheral arthritis, enthesitis and skin involvement, but since it does not include a laboratory variable (as addressed in items 3 and 5), this should be separately evaluated. It is the only target evaluated in a T2T study to date. [bib_ref] Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a..., Coates [/bib_ref] There is concern about the inclusion of physical function in MDA as this may reflect damage as well as activity and thus be less appropriate for patients with longstanding disease and irreversible disability. Of note, MDA is a state and thus useful as a target. DAPSA allows one to all define states, includingremission or low disease activity. It constitutes a more PsA-specific joint-related measure than those applied in numerous pivotal clinical trials performed for the approval of new drugs and advancement of our treatment armamentarium, which used RA-derived assessments. Disease activity states have also been defined for the various multidimensional indices, such as CPDAI, GRACE and PASDAS. The subsequent three recommendations, items 8-10, focus on the necessity to take comorbidities and risks of therapy into consideration, the possibility to consider using imaging tools in addition to clinical and laboratory assessments (not instead) and the importance of sustaining a good outcome, once achieved. The final point reiterates overarching principle A by addressing information on and discussion of the treatment approaches with the patient. Thus, in their totality, these recommendations are 'framed' by the basic aspect of thorough physician-patient interactions in the context of planning for and making any therapeutic decisions. With the exception of one item, the level of agreement with the recommendations was generally very high, on average exceeding a level of 9 on a scale between 0 and 10. Item 7, which addressed specific tools, attained a somewhat lower level of agreement based on the various controversies around this issue as detailed previously. Nevertheless, even this recommendation achieved a mean level of agreement of almost 8 (out of 10), corroborating the decision made by the task force. However, it should be acknowledged that the task force did not reach agreement about the use of unidimensional versus multidimensional instruments for assessing disease activity in PsA. In contrast, the unidimensional approach to evaluate disease activity in axial SpA, which can also exhibit multiorgan involvement although less frequently than PsA, was not disputed. Of particular importance, the current recommendations do not address any specific type of treatment but rather deal with a general approach to treating SpA; management recommendations, in contrast, deal with specific drugs for particular situations and have been specifically developed by respective committees, focusing on differences in management depending on the predominance of activity in specific disease domains. [bib_ref] European League against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis..., Gossec [/bib_ref] [bib_ref] Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment..., Coates [/bib_ref] [bib_ref] 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis, Van Der Heijde [/bib_ref] The current task force comprised a large number of experts which included several patients and a health professional. Among the rheumatologists, all had experience in the treatment of axial and peripheral SpA and most even had clinical trial experience. The development of the recommendations adhered to the EULAR SOPs for developing recommendations 11 and the recommendations are aimed at healthcare providers and patients as well as at clinical trialists, regulators and hospital or health insurance administrators. Also, a new research agenda has been developed. In summary, an update of recommendations to treat SpA to target is presented based on new evidence accrued over the past 5 years. These recommendations are summarised in a Table, but all textual explanations are part and parcel of the recommendations. They are also depicted in a simple algorithm presented in [fig_ref] Figure 2: Algorithm based on the 2017 update of the treat-to-target recommendations for spondyloarthritis [/fig_ref]. Adhering to these recommendations may significantly improve outcomes in patients with axial and peripheral SpA and PsA. [fig] 1: Total back pain (BASDAI question 2) ASDAS-CRP: 0.121 x total back pain+0.110 x patient global+0.073 x peripheral pain/swelling+0.058 x duration of morning stiffness+0.579xln(CRP+1); ASDAS-ESR: 0.113xpatient global+0.293x√ESR+0.086 x peripheral pain/ swelling+0.069 x duration of morning stiffness+0.079xtotal back pain Assess each question on an NRS of 0 (none) to 10 (very severe) protein (CRP) in mg/L (or erythrocyte sedimentation rate (ESR)) (the lowest value for CRP can be 2 mg/L) Improvement criteria ASAS 20 90 Improvement ≥20% and absolute improvement of ≥1 unit (on a scale of 0-10; or 10 units on a scale of 0-100) in at least three of the four mean of morning stiffness-related BASDAI VAS scores for questions 5 and 6) No worsening of ≥20% and ≥1 unit in the remaining domain ASAS 40 91 Improvement ≥40% and absolute improvement of ≥2 unit (on a scale of 0-10; or 10 units on a scale of 0-100) in at least three of the four mean of morning stiffness-related BASDAI VAS scores for questions 5 and 6) No worsening at all in the fourth domain Remission criteria ASAS partial remission 90 A value not above two units on a 0-10 scale in each of the four domains: patient global, pain, function, inflammation (mean of morning stiffnessrelated BASDAI VAS scores for questions 5 and 6)* ASDAS inactive disease 84 ASDAS <1.3 ASAS, Assessments of SpondyloArthritis international Society 90 ; ASDAS, Ankylosing Spondylitis Disease Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index 62 ; BASFI, Bath Ankylosing Spondylitis Functional Index; VAS, Visual Analogue Scale. [/fig] [fig] Figure 2: Algorithm based on the 2017 update of the treat-to-target recommendations for spondyloarthritis. axSpA, axial SpA; CRP, C-reactive protein; DAPSA, Disease Activity index for PSoriatic Arthritis; MDA, Minimal Disease Activity; PsA, psoriatic arthritis; SpA, spondyloarthritis. [/fig] [table] table 2: Clinical assessment of axial spondyloarthritis How would you describe the overall level of ankylosing spondylitis neck, back or hip pain you have had? [/table] [table] table 4: Research agenda Axial involvement in PsA ► Do spinal and peripheral involvements respond similarly or differently? Enthesitis, dactylitis ► More data need to be attained on the response of dactylitis or enthesitis to different therapies when compared with arthritis and skin disease. ► How does dactylitis or enthesitis affect physical function, health-related quality of life, social participation or cardiovascular risk? ► To what extent does their inclusion in composite measures increase or decrease validity and sensitivity to change? Skin involvement ► More data need to be attained on the response of psoriasis to different therapies when compared with arthritis and other musculoskeletal symptoms. ► How does skin involvement affect physical function or cardiovascular risk? ► To what extent does its inclusion in composite measure increase or decrease validity and sensitivity to change? ► To what extent do skin changes affect quality of life, work participation and social inclusion beyond the respective effects of arthritis and other musculoskeletal manifestations? Imaging ► Is imaging useful for follow-up in axial SpA and PsA? ► Should imaging remission be a treatment target in axial SpA and PsA? Functioning/disabillity ► What is the impact of functioning/disability in composite measures developed for PsA? Strategic trials ► Strategic trials in axial SpA and at least one additional strategic trial in PsA. Maintenance of response ► How can response be maintained? ► Can the dose of the therapy employed be reduced or the interval of applications be expanded and outcome maintained? Care by specialists ► Is care of axial SpA, peripheral SpA or PsA by a specialist (such as a rheumatologist) advantageous for outcomes when compared with care by a non-specialist? Patient ► Is outcome different when patients are informed in a structured way when compared with more general means of information? Harmonisation ► Nomenclature should be harmonised-remission vs inactive disease; minimal disease activity vs low disease activity, etc. Structural damage ► Does achievement of the treatment target result into prevention or retardation of structural damage development in the spine/peripheral joints in SpA? Biomarkers ► We need better biomarkers of disease activity than CRP for both axial SpA and PsA.AS, ankylosing spondylitis; CRP, C-reactive protein; PsA, psoriatic arthritis; SpA, spondyloarthritis. [/table]	None	https://ard.bmj.com/content/annrheumdis/77/1/3.full.pdf	Therapeutic targets have been defined for axial and peripheral spondyloarthritis (SpA) in 2012, but the evidence for these recommendations was only of indirect nature. These recommendations were re-evaluated in light of new insights. Based on the results of a systematic literature review and expert opinion, a task force of rheumatologists, dermatologists, patients and a health professional developed an update of the 2012 recommendations. These underwent intensive discussions, on site voting and subsequent anonymous electronic voting on levels of agreement with each item. A set of 5 overarching principles and 11 recommendations were developed and voted on. Some items were present in the previous recommendations, while others were significantly changed or newly formulated. The 2017 task force arrived at a single set of recommendations for axial and peripheral SpA, including psoriatic arthritis (PsA). The most exhaustive discussions related to whether PsA should be assessed using unidimensional composite scores for its different domains or multidimensional scores that comprise multiple domains. This question was not resolved and constitutes an important research agenda. There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA. As instruments to assess the patients on the path to the target, the Ankylosing Spondylitis Disease Activity Score (ASDAS) for axial SpA and the Disease Activity index for PSoriatic Arthritis (DAPSA) and Minimal Disease Activity (MDA) for PsA were recommended, although not supported by all. Shared decision-making between the clinician and the patient was seen as pivotal to the process. The task force defined the treatment target for SpA as remission or low disease activity and developed a large research agenda to further advance the field.
1d20ade0a48bd069e07be5143c2c2bb048d1f79c	pubmed	Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous blood sampling	Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous blood sampling Phlebotomy is one of the most complex medical procedures in the diagnosis, management and treatment of patients in healthcare. Since laboratory test results are the basis for a large proportion (60-80%) of medical decisions, any error in the phlebotomy process could have serious consequences. In order to minimize the possibility of errors, phlebotomy procedures should be standardised, well-documented and written instructions should be available at every workstation. Croatia is one of the few European countries that have national guidelines for phlebotomy, besides the universally used CLSI (Clinical Laboratory Standards Institute) H3-A6 Procedures for the Collection of Diagnostic Blood Specimens by Venipuncture; approved Standard-Sixth Edition (CLSI, 2007) and WHO (World Health Organization) guidelines on drawing blood: best practices in phlebotomy (WHO, 2010). However, the growing body of evidence in importance of preanalytical phase management resulted in a need for evidence based revision and expansion of existing recommendations. The Croatian Society for Medical Biochemistry and Laboratory Medicine, Working Group for the Preanalytical Phase issued this recommendation. This document is based on the CLSI guideline H3-A6, with significant differences and additional information. # Introduction Today, the analytical phase of laboratory work is perfected through automation. Errors in laboratory medicine occur most frequently in the extra-analytical phase of laboratory testing [bib_ref] Errors in clinical laboratories or errors in laboratory medicine?, Plebani [/bib_ref]. The preanalytical phase and especially pre-preanalytical phase are major sources of laboratory errors [bib_ref] The prevalence of preanalytical errors in Croatian ISO 15189 accredited laboratory, Simundic [/bib_ref]. Out of all processes that happen outside the laboratory (e.g. test ordering, patient preparation, blood sampling, transportation of samples), phlebotomy is the most complex and most vulnerable to errors [bib_ref] Phlebotomy issues and quality improvement in results of laboratory testing, Lippi [/bib_ref]. Phlebotomy is a pivotal invasive procedure in diagnosis, management and treatment of patients in healthcare [bib_ref] Venepuncture: best practice, Lavery [/bib_ref]. Since a large proportion (60-80%) of medical decisions is based on the results of the laboratory tests [bib_ref] Establishing reference intervals for clinical laboratory test results: is there a better..., Katayev [/bib_ref] , any error in the phlebotomy process could have serious consequences primarily for the patients, but also for medical professionals and healthcare system in general [bib_ref] The cost of poor blood specimen quality and errors in preanalytical processes, Green [/bib_ref]. Phlebotomy is a complex procedure and includes a large number of steps. Small variations in each of them can create a large cumulative effect. In addition, there is a large heterogeneity in the education of medical staff performing phlebotomy (nurses, laboratory technicians, phlebotomists), introducing another layer of variability into the system [bib_ref] Survey of national guidelines, education and training on phlebotomy in 28 European..., Simundic [/bib_ref]. Therefore, in order to minimize the possibility of errors, this procedure should be standardised, well-documented and written instructions should be available at every workstation. . Some European countries are using these widely accepted standards, while some have nationally adopted/adjusted/translated phlebotomy guidelines. Based on the recently published survey of the European Federation of Clinical Chemistry and Laboratory Medicine, Working Group for the Preanalytical Phase (EFLM WG-PA) [bib_ref] Survey of national guidelines, education and training on phlebotomy in 28 European..., Simundic [/bib_ref] , only seven European countries have national guidelines for phlebotomy: Ireland, UK, Spain, Slovenia, Sweden, Italy and Croatia. The main reasons for not having national guidelines are: 1) lack of time or leadership to perform the work or 2) implementation of CLSI or WHO guidelines eliminated the need for national guidelines [bib_ref] Survey of national guidelines, education and training on phlebotomy in 28 European..., Simundic [/bib_ref]. However, based on the self-reported questionnaire, estimated compliance with the guidelines is poor, indicating the need for continuous education and implementation of existing procedures [bib_ref] Staff require training in phlebotomy to ensure accurate blood test results, Lipley [/bib_ref]. Although Croatia is one of the few European countries that already have national guidelines for phlebotomy, the growing evidence supporting the importance of preanalytical phase management resulted in a need for evidence-based revision and an expansion of existing recommendations. # Background and scope In Croatia, clinical chemistry is a recognized and regulated profession and is almost exclusively practiced by specialists in medical biochemistry and laboratory medicine [bib_ref] Clinical chemistry and laboratory medicine in Croatia: regulation of the profession, Simundic [/bib_ref]. Only medical professionals work in laboratories. Venous blood sampling is performed in hospital wards, primary care offices and laboratories. While nurses perform blood sampling in hospital wards and primary care dispensaries, in medical laboratories blood sampling is performed by laboratory technicians and bachelors of medical laboratory diagnostics. During high school education for laboratory techni-cians, students are required to comprehend theoretic and practical principles of phlebotomy, however a specialised course in phlebotomy is not part of the curriculum (9). Phlebotomy is not thought of in higher forms of education in clinical chemistry (undergraduate and graduate), and even specialists are not required to be qualified to perform phlebotomy. In addition, there is no specific training in phlebotomy as a continuous educational recourse. The scope of medical biochemistry and laboratory medicine in Croatia includes clinical biochemistry, haematology, coagulation, toxicology and therapeutic drug monitoring, immunology and molecular diagnostics. Fields outside of the scope of profession are microbiology, blood-banking and cytogenetics (17). This recommendation was issued by the Croatian Society for Medical Biochemistry and Laboratory Medicine, Working Group for the Preanalytical Phase after a review of relevant literature sources in phlebotomy procedures. Although other medical professionals (i.e. nurses and physicians) can use this document, it is intended primarily for laboratory staff when performing venous blood sampling within medical biochemistry laboratories. This document is based on the CLSI guideline H3-A6 (10), however there are some significant differences. In Croatian laboratories, blood sampling using catheters is never performed; therefore, that part of CLSI H3-A6 guideline is omitted. In addition, since evacuated tubes are generally accepted as standard and are used in almost every laboratory in Croatia, blood sampling with syringes is not described in this document. As stated earlier, microbiology is not within the scope of medical biochemistry in Croatia, thus parts referring to microbiology testing are significantly shortened. Certain procedures are modified according to some recent evidence in the field of preanalytics. Additional information is provided and rationale for modification in comparison with the CLSI H3-A6 guideline is explained in highlighted boxes. In addition, some instructions (i.e. order of draw and requirements for mixing) are specified for manufacturers of phlebotomy supplies that are most commonly used in Croatia: BD -Becton, Dickinson and Company (Franklin Lakes, NJ, USA) and Greiner Bio-One (Kremsmünster, Austria). ## Procedure ## Sanitizing hands The phlebotomist should sanitize his hands immediately before the first contact with the patient, using warm water and soap or disinfectant gels, tissues or foams according to the nationally accepted guidelines. This approach ensures that all surfaces touched by phlebotomists prior to venipuncture are free of pathogens. ## Inspecting test request form It is advisable to modify the test request form according to ISO 15189 requirements. Request form should include, but not be limited to, the following information: Name, surname, gender, date of birth and con-- tact details (address, telephone number) of the patient and unique identifier (health insurance number or personal identification number) Identification of the doctor who requested ex-- aminations and contact details (address of primary healthcare provider or hospital ward full name) Requested tests - Any clinically relevant information about the - patient, his preparation and therapy in order to properly conduct examinations and interpret the results. In comparison with the CLSI H3-A6 guideline, we have separated data that should be present on the test request form for the samples drawn outside the laboratory. For blood samples drawn outside the laboratory, test request form should, in addition, contain following items: Date and time of sample collection; - Name of the medical staff who performed - collection; Type of primary sample (i.e. full blood, serum, - plasma), additive (if any), and where relevant, anatomic origin of the sample. ## Identifying the patient Identification of the patient is the key point in patient laboratory processing [bib_ref] Providers do not verify patient identity during computer order entry, Henneman [/bib_ref] [bib_ref] Patient misidentification in oncology care, Schulmeister [/bib_ref]. Proper identification relies on at least two independent identifications. Data from the request form should never be solely used for identification. Patient identification should be performed according to following instructions: Phlebotomist should ask the patient to state - the full name, address and/or birth date. The questions should be phrased as such: "Please state your name" and "Please state your date of birth;" not "Are you John Smith?" and "Is your birth date June 1, 1977" Compare obtained information with the infor-- mation on the request form Any discrepancies should be reported, record-- ed and resolved before sample collection. There are circumstances that may limit proper patient identification, such as unconscious or semiconscious patients, children that are too young, deaf and cognitively impaired patients or non-native speakers. In such cases, identification of the patient must be completed with the assistance of ward nurse, legal guardian, parent or accompanying person. All data must be identical with the data on the request form and the name of the person who verified identity must be documented. ## Verifying patient preparation for venipuncture preparing the supplies for blood sampling This section brings additional information in comparison with the CLSI guideline H3-A6. CLSI guideline only verifies the patient's fasting status. It is recommended that laboratory staff verify the patient's preparation for laboratory testing, including specific preparation for certain tests. Lack of this information can result in acquiring an inadequate sample for analysis. Results from unsuitable specimens are not reliable. In comparison with the CLSI H3-A6 guideline, the use of blood sampling devices other than evacuated blood tubes is not described. Therefore, syringes are not listed as necessary equipment. In addition, since Croatia is a European Union member, an EU Council Directive 2010/32/ EU (35) applies for handling sharp medical devices and is added and referenced in the text. Patient preparation before sample collection is essential for accurate test results. Depending on requested examinations, patient preparation usually involves special diet restrictions or therapy protocols. Depending on the tests ordered, a list of questions that the phlebotomist should ask the patient before venipuncture is provided in [fig_ref] Table 1: Verification of patient's preparation for venipuncture [/fig_ref]. If the patient is not properly prepared for sample collection, the phlebotomist should inform him of the effects on the laboratory results and postpone the venipuncture giving the patient all information needed for proper preparation. If, for some reason, phlebotomy cannot be postponed, observed nonconformity should be documented on the request form and comment provided on the laboratory report. All required materials must be assembled prior to venipuncture and according to requested tests. Only supplies with an appropriate expiry date must be available to the phlebotomist and the handling procedure must minimize the possibility of occupational exposure. The supplies that should be available are: [bib_ref] Influence of a regular, standardized meal on clinical chemistry analytes, Lima-Oliveira [/bib_ref]. Also, lipemia of the sample can cause interference in measurement even for analytes that are not influenced by fasting status [bib_ref] Lipemia interferences in routine clinical biochemical tests, Calmarza [/bib_ref]. ## All Fasting Only water drinking is allowed prior to venipuncture. Did you have anything else to drink this morning? Most drinks contain sugar that could influence the results of glucose measurement. In addition, a large proportion of drinks contain active substances that can affect laboratory tests with known (i. e. enzyme induction or inhibition, substrate competition) and unknown mechanisms [bib_ref] Mechanisms underlying food-drug interactions: inhibition of intestinal metabolism and transport, Won [/bib_ref]. ## All ## Fasting, therapy Are you taking any vitamins, food supplements, herbal or natural based medicines? These supplements may have known or unknown biological effects, medicinal effects, or even technical effects on measuring (e.g. vitamin C in faecal occult blood test, riboflavin in dipstick urine testing). Any information about taking these supplements should be documented [bib_ref] Review of abnormal laboratory test results and toxic effects due to use..., Dasgupta [/bib_ref]. ## All ## Patient position Were you resting for 15 minutes prior to blood sampling? If patient is excited and is not rested prior to blood sampling, increased production of hormones (i.e. catecholamines and corticosteroids) can alter concentration of a large number of proteins, lipids and carbohydrates. ## Coagulation tests Therapy Are you receiving any kind of anticoagulant therapy? PT INR should be measured prior to taking OAT. Also, thrombophilia screening tests (LAC, protein C, protein S, APCR) cannot be performed if the patient is already receiving OAT [bib_ref] Pre-analytical Variables in Coagulation Testing Associated With Diagnostic Errors in Hemostasis, Favaloro [/bib_ref]. ## Female hormones ## Menstrual cycle What is the current day of your menstrual cycle? Concentration of female hormones depends on the day of the menstrual cycle. ## Homocysteine dietary habits Are you fasting for 12 hours? Did you have protein-rich meal within last 48 hours? Protein-rich meals can cause falsely elevated homocysteine concentration [bib_ref] Clinical Significance and Laboratory Measurement, Hortin [/bib_ref]. ## Iron ## Therapy Were you receiving any oral or intravenous supplements containing iron within the last 10 days? Consumption of iron supplements or too little time after discontinuing of taking those preparations causes falsely elevated iron concentration. ## Lipid status dietary habits When did you have your last meal? Did you have any changes in diet within the last two weeks? Did you consume alcohol within the last 48 hours? Were you engaged in extreme physical activity within the last 48 hours? For the measurement of the lipid status, compliance to the recommended protocol is required since any discrepancies influence results of the measurement and, in most cases, cause falsely elevated concentrations of lipids [bib_ref] Blood lipid measurements. Variations and practical utility, Cooper [/bib_ref]. ## Postprandial glucose Therapy Do you have your usual therapy with you (i. e. insulin or oral hypoglycaemics)? When performing measurement of postprandial glucose, the patient should simulate an everyday meal and therapy regime. If receiving oral hypoglycaemics, the patient should take their meal and therapy after sampling for fasting glucose has been done. Deviation from the usual protocol can cause variations in the result of the test (31). ## Therapeutic drug monitoring Therapy When did you take last dose of the drug? What is the name of the drug you are receiving? Therapeutic drug monitoring should be done after the drugs are at a steady state and blood collection performed immediately prior to taking the next dose of the drug [bib_ref] Just a repeat' -When drug monitoring is indicated, Lucas [/bib_ref]. The time of the application of the previous dose will help to interpret results of the test. Errors in interpretation can occur if the sample is obtained at the wrong time [bib_ref] Digoxin therapeutic drug monitoring: an audit and review, Sidwell [/bib_ref]. ## Thyroid hormones (t4, free t4) Therapy When did you take last dose of levothyroxine? Levothyroxine should not be taken in the morning before blood sampling is done, since hormones cause falsely elevated concentration of T4/freeT4 [bib_ref] Thyroid hormone levels affected by time of blood sampling in thyroxine-treated patients, Ain [/bib_ref]. PT INR -prothrombin time, international normalized ratio; OAT -oral anticoagulant therapy; LAC -lupus anticoagulant; APCR -activated protein C resistance ## Putting on gloves Although CLSI guideline H3-A6 resolutely states that tubes must be labelled after the collection, there is no undisputable evidence to support that recommendation. Therefore, this document recommends tube labelling just after identification of the patient and verification of his appropriate preparation for the laboratory testing and prior to venipuncture procedure. If the tube is to be labelled after venipuncture, it should be done in front of the patient, while he is still sitting in front of the phlebotomist. Otherwise, there is possibility that the tube will be left unlabelled. Identification of phlebotomist. - Not all of them have to be listed on the tube, but they all have to be documented in a way so that the tube is traceable and unambiguously connected to the patient, collected sample or phlebotomist. It is recommended that the tube is labelled with a barcode, as barcodes can contain all abovementioned information. If not on the tube, this information should be recorded in the paper documentation or laboratory information system. It is recommended that the tube is identified with at least two independent pieces of information. The more information present on the tube, the more the patient's safety is increased and the possibility of patient identification errors is reduced. CLSI H3-A6 guideline recommends putting gloves on after applying tourniquet. However, there is evidence that the time of tourniquet application on patient's hand is longer than the recommended 60 seconds [bib_ref] Impact of the phlebotomy training based on CLSI/NCCLS H03-a6 -procedures for the..., Lima-Oliveira [/bib_ref]. In order to reduce potential errors that may occur because of prolonged blood stasis [bib_ref] Influence of short-term venous stasis on clinical chemistry testing, Lippi [/bib_ref] [bib_ref] New ways to deal with known preanalytical issues: use of transilluminator instead..., Lima-Oliveira [/bib_ref] [bib_ref] Influence of tourniquet application on venous blood sampling for serum chemistry, hematological..., Cengiz [/bib_ref] , we propose putting on gloves prior to tourniquet application. Before each venipuncture, the phlebotomist should put on gloves. The phlebotomist should use new gloves for each patient. ## Applying tourniquet A tourniquet is used for easier location of the vein. It increases intravascular pressure and makes veins more visible, which reduces the possibility of erroneous puncture and possible damage of local arteries and nerves. Tourniquets should never be applied for longer than one minute, in order to avoid local hemoconcentration that may result in erroneous laboratory findings. When the tourniquet is applied for longer than one minute, it should be released and reapplied after minimum two minutes. Tourniquets should be applied between 7 and 10 cm above the venipuncture site. If the skin has lesions where tourniquet is to be applied a different venipuncture site must be considered. Alternatively, a tourniquet can be applied over the gauze pad, tissue or patient's clothes. For better visualization of the preferred puncture site, the patient can form a fist. However, the patient should not pump his hand vigorously. It should be noted CSMBLM: recommendations for phlebotomy that the tourniquet must not be applied when specific tests are required, because blood stasis can significantly alter concentrations of certain analytes: lactate (10), ammonia, albumin [bib_ref] New ways to deal with known preanalytical issues: use of transilluminator instead..., Lima-Oliveira [/bib_ref] and calcium [bib_ref] New ways to deal with known preanalytical issues: use of transilluminator instead..., Lima-Oliveira [/bib_ref]. ## Selecting venipuncture site The preferred venipuncture sites are antecubital veins that lie near the skin surface. When those veins are not available, venipuncture can be performed on the veins on the back of the hand. Veins on the underside of the wrist are not recommended for venipuncture, because the arteries and tendons are too close to the skin surface. Arterial punctures should never be considered as an alternative for difficult venipuncture without consulting the physician first. Blood should never be drawn from sites of extensive scaring, on the hand on the side on which mastectomy was performed, hematoma (if not avoidable the sample should be drawn distal to the hematoma), arm with an intravenous therapy application, cannula, fistula and vascular graft. There are two basic vein distributions in antecubital fossa, H and M shaped patterns. Names of the patterns are based on the shapes that form most prominent veins of that area, cephalic, median chepalic, median cubital, median basilic and basilic vein [fig_ref] Figure 1: Veins of the Forearm [/fig_ref]. The selection of the vein for blood collection must be done carefully. Median cubital and median veins should be considered first for venipuncture. If those veins are not accessible, the cephalic vein should be considered next. Basilic veins are to be considered last for venipuncture, as they are too close to the brachial artery and median nerve. Any form of discrepancy from recommended venipuncture procedure should be documented. There should be written procedures available for dealing with the accidental artery puncture or nerve damage. With the aid of the tourniquet, the phlebotomist should palpate the selected vein with the index finger. The thumb should not be used, because it has a pulse beat. Palpation also helps in differentiating veins from arteries. ## Cleaning venipuncture site After selecting the vein, the venipuncture site must be properly disinfected, in order to avoid microbial contamination of the patient and collected sample. The skin is cleaned with sterile cotton or gauze pads with 70% isopropyl alcohol or ethanol. The skin should be cleansed with circular motions from centre to periphery. CLSI guideline H3-A6 states that disinfectant should be left to dry before performing venipuncture in order to avoid possible hemolysis and avoid patient discomfort. However, evidence has shown that this procedure is often unattended in practise [bib_ref] Primjena CLSI smjernica za uzorkovanje venske krvi, Ćelap [/bib_ref]. In addition, there is no evidence that hemolysis rate will increase if the venipuncture is done immediately after applying disinfectant [bib_ref] Avoidance to wipe alcohol before venipuncture is not a source of spurious..., Salvagno [/bib_ref]. Therefore, we recommend that, in order to reduce time of tourniquet application, it is not necessary to wait for disinfectant to dry. When blood alcohol determination is requested, a non-alcoholic based disinfectant should be used, often ether or benzine. When there are difficulties with venipuncture and the vein must be palpated again, the skin should be cleansed again. Special consideration must be given to the duration of tourniquet application. ## Performing venipuncture The recommended blood collection sets are those with evacuated tube systems. Place a cotton or gauze pad on the wound and - remove the needle from the vein. Dispose of the needle. - Inform patient to press cotton or gauze pad on - the wound. Bandage the venipuncture site (see section - Bandaging the skin after venipuncture). When all the tubes are drawn, mix the tubes ac-- cording to recommendations (see section Tube mixing). ## Order of draw When collecting more than one tube special attention has to be given to order of draw. This recommendation is crucial, in order to avoid additive or anticoagulant carryover and to avoid potential tissue contamination. Failure to follow this procedure could result in significant errors [bib_ref] Effect of carryover of clot activators on coagulation tests during phlebotomy, Fukugawa [/bib_ref] [bib_ref] Incorrect order of draw could be mitigate the patient safety: a phlebotomy..., Lima-Oliveira [/bib_ref]. The recommended order of draw for different types of tubes (with or without gel, with or without additive) is shown in [fig_ref] Table 2: Order of draw [/fig_ref]. Clot activators or tissue factors released during venipuncture can affect coagulation testing. Therefore, the coagulation tube has to be drawn before any other tube with additive. This recommendation does not suggest blood drawing using syringes; therefore, this drawing technique is omitted in comparison to CLSI guideline H3-A6. For the proper venipuncture technique, the manufacturer's instructions should be followed. Venipuncture should be performed as follows: Place the appropriate needle into the needle - holder. Position the patient's arm in a downward posi-- tion to prevent reflux from the collection tube into the vein. Hold the patient's arm distal to the puncture - site. Use the thumb to anchor the vein 2.5 to 5 cm below the venipuncture site. Inform the patient that venipuncture is about - to occur. Insert the needle at the angle 30° or less and - keep it stable in the vein. Connect the first tube onto the needle. ## - As soon as blood starts to fill the tube, release - the tourniquet. Allow the tube to fill until blood flow ceases. ## - This ensures correct blood volume and ratio of blood to additive. Remove the full tube from the needle and re-- place it with the next tube (if any). When collecting several tubes, always follow - the recommended order of draw (see section Order of draw). Always remove the last tube from the needle - holder before removing the needle from the vein. CLSI guideline H3-A6 recommends that a discard tube should be drawn if coagulation assays other than prothrombin time, international normalized ratio and activated partial thromboplastin time should be determined. However, there is published evidence in the literature that there is no difference in the results of other specialized coagulation tests determined with and without discard tube [bib_ref] Collection of blood specimens by venipuncture for plasmabased coagulation assays: necessity of..., Raijmakers [/bib_ref] [bib_ref] Discard tubes are not necessary when drawing samples for specialized coagulation testing, Smock [/bib_ref] [bib_ref] Effect of tube filling order on specific coagulation parameters in healthy subjects, Serin [/bib_ref]. Therefore, this recommendation does not support CLSI H3-A6 recommendation of drawing a discard tube for specialized coagulation tests. However, when using winged blood collection set and any coagulation test is requested, then the discard tube has to be drawn prior to the coagulation tube. This ensures proper anticoagulant and blood ratio, which can be compromised because ## Needle disposing Disposable equipment used in collection procedure has to be properly removed according to manufacturer's recommendations. Needles have to be immediately disposed into the sharps container according to local regulations. Any potential injuries or blood contamination of the personnel during or after the phlebotomy proc-ess should be handled according to institution policies. Written documents explaining procedures should be available at each phlebotomy site. ## Tube mixing Since all tubes generally contain some kind of additive (anticoagulant or clot activator), all of them have to be properly mixed immediately after collection. The exception is a glass BD serum tube with clot activator (all Greiner Bio-One tubes are plastic and all should be mixed). Recommendations for proper tube mixing given by two manufacturers commonly used in our country are given in [fig_ref] Table 3: Recommendations for tube mixing by two manufacturers commonly used in Croatia -BD [/fig_ref]. Mixing cycle stands for one full inversion of the tube (180°) and returning the tube to the initial position [fig_ref] Figure 2: One mixing cycle [/fig_ref]. Full inversion is when the air bubble moves from one end of the tube to the other. ## Bandaging the skin after venipuncture After blood collection, the phlebotomist should gently put cotton or gauze pads over the venipuncture site and then remove the needle. The patient has to hold the pad on the vein and should not bend their arm. After 30 seconds to 1 minute (when all tubes are properly mixed), the phlebotomist should bandage the arm and advise the patient to hold the bandage for at least 15 minutes. In case of prolonged (longer than 5 minutes) or excessive bleeding, the physician should be noted and more pressure should be applied until bleeding stops. Personnel involved in phlebotomy should be educated to help patient in case of emergencies like fainting, nausea, vomiting or convulsions. There should be written procedure for handling such cases. ## Removing gloves Dispose of the gloves after venipuncture. ## Recording additional information Laboratory staff should record any nonconformity that occurs during the phlebotomy according to laboratory protocol. ## Special handling requirements Some specimens need special handling procedures after blood collection. There are thermolabile analytes or those that are sensitive to light exposure. Analytes that require special handling during transportation to the laboratory are listed in [fig_ref] Table 4: Analytes that require special handling procedures after blood collection [/fig_ref]. In addition to [fig_ref] Table 4: Analytes that require special handling procedures after blood collection [/fig_ref] , laboratory managers are required to follow any additional manufacturer's recommendations regarding special handling conditions. ## Additional considerations Phlebotomy for a child younger than six years should be done with previous consultation with physician. Special attention has to be paid to appropriate equipment for venipuncture of children. All before stated steps in phlebotomy procedure must be applied when collecting blood from a child. This recommendation does not refer to collection of capillary blood by skin puncture. ## Flowchart A step-by-step phlebotomy procedure is presented in [fig_ref] Figure 3: Figure 3 [/fig_ref]. # Acknowledgments We thank Clinical Laboratory Standards Institute for granting permission for the use of CLSI's internationally copyrighted material. ## Potential conflict of interest None declared. To chill a specimen, place it immediately in a mixture of ice and water (ice slurry not big ice cubes). Do not put the specimen in direct contact with ice or dry ice to avoid hemolysis. Chilling whole blood specimens for longer than two hours is contraindicated for determination of potassium levels. ## Specimen transportation at 37 °c Cold agglutinin Cryofibrinogen Cryoglobulins (10) (10) For determination of cold agglutinins, an EDTA tube should be used. For cryofibrinogen and cryoglobulins, use tubes that do not contain any additives, all collection supplies must be pre-warmed, keep the sample at water bath heated at 37°C until serum can be separated from the cells, separate the serum from the cells within 1 hour of collection. ACE -angiotensin-converting enzyme. Reference numbers are presented in parenthesis. Step 20 Recording additional information Step 1 Sanitizing hands Step 2 Inspecting test request form Step 3 Identifying the patient Step 4 Verifying patient preparation for venipuncture Step 5 Preparing the supplies for blood sampling Step 6 Labeling the tubes ## Step 7 Positioning the patient Step 8 Putting on gloves Step 9 Applying tourniquet Step 19 ## Removing gloves Step 18 Bandaging the skin after venipuncture Step 17 Tube mixing Step 16 Needle disposing ## Step 15 Drawing other tubes if more than one (Order od draw!) Step 14 ## Releasing the tourniquet Step 13 Drawing first tube Step 12 Performing venipuncture Step 11 Cleaning venipuncture site Step 10 Selecting venipuncture site Step-by-step phlebotomy procedure. [fig] Figure 1: Veins of the Forearm. [/fig] [fig] Figure 2: One mixing cycle. air in the system can cause under filling of coagulation tube(54). [/fig] [fig] Figure 3: Figure 3. Step-by-step phlebotomy procedure. [/fig] [table] Table 1: Verification of patient's preparation for venipuncture. [/table] [table] Table 2: Order of draw(10,48,49). [/table] [table] Table 3: Recommendations for tube mixing by two manufacturers commonly used in Croatia -BD (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and Greiner Bio-One (Kremsmünster, Austria). [/table] [table] Table 4: Analytes that require special handling procedures after blood collection. [/table]	None	https://www.biochemia-medica.com/assets/images/upload/xml_tif/Nikolac_N__et_al_-CSMBLM_recommendations_for_phlebotomy-korr_0.pdf	Phlebotomy is one of the most complex medical procedures in the diagnosis, management and treatment of patients in healthcare. Since laboratory test results are the basis for a large proportion (60–80%) of medical decisions, any error in the phlebotomy process could have serious consequences. In order to minimize the possibility of errors, phlebotomy procedures should be standardised, well-documented and written instructions should be available at every workstation. Croatia is one of the few European countries that have national guidelines for phlebotomy, besides the universally used CLSI (Clinical Laboratory Standards Institute) H3-A6 Procedures for the Collection of Diagnostic Blood Specimens by Venipuncture; approved Standard-Sixth Edition (CLSI, 2007) and WHO (World Health Organization) guidelines on drawing blood: best practices in phlebotomy (WHO, 2010). However, the growing body of evidence in importance of preanalytical phase management resulted in a need for evidence based revision and expansion of existing recommendations. The Croatian Society for Medical Biochemistry and Laboratory Medicine, Working Group for the Preanalytical Phase issued this recommendation. This document is based on the CLSI guideline H3-A6, with significant differences and additional information.
b44978c5e791ea16545a3f94cbb8a7f072de3eb0	pubmed	3rd ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3)	3rd ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3) Note: These Guidelines were developed by ESO and ESMO and are published simultaneously in Annals of Oncology (2016; doi:10.1093/annonc/mdw544) and The Breast and should both be cited. # Introduction Advanced Breast Cancer (ABC) comprises both locally advanced (LABC) and metastatic breast cancer (MBC). Although treatable, MBC remains an incurable disease with a median overall survival of $2-3 years and a 5-year survival of only $25% [bib_ref] SEER data submission, posted to the SEER web site, Howlader [/bib_ref] [bib_ref] Trends in survival in metastatic breast, Sundquist [/bib_ref]. Some more recent series seem to indicate an improvement in median overall survival [bib_ref] Impact of immunohistological subtypes on the long-term prognosis of patients with metastatic..., Kobayashi [/bib_ref] [bib_ref] The impact of new chemotherapeutic and hormone agents on survival in a..., Chia [/bib_ref]. A recent comprehensive reportof the advances in this field in the last decade shows that progress has been slow in terms of improved outcomes, quality of life, awareness and information regarding ABC. The level of evidence used to base many recommendations remains low, and more and better designed trials are needed to address clinically important questions. An improved understanding of the biology of ABC, its heterogeneity, and of the mechanisms of resistance to the different types of therapies is being acquired and it is anticipated that the application of new technologies, such as next generation sequencing, patient xenographs, systems V C The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits noncommercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work properly cited. For commercial re-use, please contact journals.permissions@oup.com ## Guideline statement loe consensus The ABC community strongly calls for clinical trials addressing important unanswered clinical questions in this setting, and not just for regulatory purposes. Clinical trials should continue to be performed, even after approval of a new treatment, providing real world performance of the therapy. The ABC guidelines are developed as a joint effort from ESO (European School of Oncology) and ESMO (European Society of Medical Oncology), and are endorsed by EUSOMA (European Society of Breast Cancer Specialists), ESTRO (European Society of Radiation Oncology), UICC (Union for International Cancer Control), SIS (Senologic International Society) and FLAM (Federati on LatinoAmericana de Mastologia). There was also official representation of ASCO (American Society of Clinical ## Section i continued ## Guideline statement loe consensus Strong consideration should be given to the use of validated PROMs (patient-reported outcome measures) for patients to record the symptoms of disease and side effects of treatment experienced as a regular part of clinical care. These PROMs should be simple, and user-friendly to facilitate their use in clinical practice, and thought needs to be given to the easiest collection platform, e.g. tablets or smartphones. Systematic monitoring would facilitate communication between patients and their treatment teams by better characterizing the toxicities of all anticancer therapies. This would permit early intervention of supportive care services enhancing quality of life 1 C Voters: 39 Yes: 87.1% [bib_ref] Weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast..., Smyth [/bib_ref] Abstain: 5.1%As survival is improving in many patients with ABC, consideration of survivorship issues should be part of the routine care of these patients. Health professionals should therefore be ready to change and adapt treatment strategies to disease status, treatment adverse effects and quality of life, patients' priorities and life plans. Attention to chronic needs for home and family care, job and social requirements, should be incorporated in the treatment planning and periodically updated. Expert opinion Voters: 40 Yes: 95% [bib_ref] PALOMA-2: primary results from a phase III trial of palbociclib (P) with..., Finn [/bib_ref] Abstain: 5% (2) ABC patients who desire to work or need to work for financial reasons should have the opportunity to do so, with needed and reasonable flexibility in their working schedules to accommodate continuous treatment and hospital visits. [bib_ref] Locoregional treatment versus no treatment of the primary tumour in metastatic breast..., Badwe [/bib_ref] Breast imaging should also be performed when there is a suspicion of loco-regional progression. Expert opinion Voters: 40 Yes: 100% A biopsy (preferably providing histology) of a metastatic lesion should be performed, if easily accessible, to confirm diagnosis particularly when metastasis is diagnosed for the first time. If the results of tumour biology in the metastatic lesion differ from the primary tumor, it is currently unknown which result should be used for treatment-decision making. Since a clinical trial addressing this issue is difficult to undertake, we recommend considering the use of targeted therapy (ET and/or anti-HER-2 therapy) when receptors are positive in at least one biopsy, regardless of timing. ## Expert opinion 87% To date, the removal of the primary tumor in patients with de novo stage IV breast cancer has not been associated with prolongation of survival, with the possible exception of the subset of patients with bone only disease. However, it can be considered in selected patients, particularly to improve quality of life, always taking into account the patient's preferences. Of note, some studies suggest that surgery is only valuable if performed with the same attention to detail (e.g. complete removal of the disease) as in patients with early stage disease. Additional prospective clinical trials evaluating the value of this approach, the best candidates and best timing are currently ongoing 2 B Voters: 44 Yes: 70.4% [bib_ref] The SystHERs registry: an observational cohort study of treatment patterns and outcomes..., Tripathy [/bib_ref] A small but very important subset of patients with ABC, for example those with oligo-metastatic disease or low volume metastatic disease that is highly sensitive to systemic therapy, can achieve complete remission and a long survival. A multimodal approach, including local-regional treatments with curative intent, should be considered for these selected patients. ABC IMPORTANT DEFINITIONS VISCERAL CRISIS is defined as severe organ dysfunction as assessed by signs and symptoms, laboratory studies, and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases but implies important visceral compromise leading to a clinical indication for a more rapidly efficacious therapy, particularly since another treatment option at progression will probably not be possible. ## Expert opinion 95 PRIMARY ENDOCRINE RESISTANCE is defined as: Relapse while on the first 2 years of adjuvant ET, or PD within first 6 months of 1st line ET for MBC, while on ET. SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE is defined as: Relapse while on adjuvant ET but after the first 2 years, or Relapse within 12 months of completing adjuvant ET, or PD ! 6 months after initiating ET for MBC, while on ET. Note: resistance is a continuum and these definitions help mainly clinical trials and not necessarily clinical practice Expert opinion 67 # General statements The management of ABC is complex and, therefore, involvement of all appropriate specialties in a multidisciplinary team (including but not restricted to medical, radiation, surgical oncologists, imaging experts, pathologists, gynecologists, psycho-oncologists, social workers, nurses and palliative care specialists), is crucial. ## Expert opinion 100 From the time of diagnosis of ABC, patients should be offered appropriate psychosocial care, supportive care, and symptom-related interventions as a routine part of their care. The approach must be personalized to meet the needs of the individual patient. ## Expert opinion 100 Following a thorough assessment and confirmation of MBC, the potential treatment goals of care should be discussed. Patients should be told that MBC is incurable but treatable, and that some patients can live with MBC for extended periods of time (many years in some circumstances). This conversation should be conducted in accessible language, respecting patient privacy and cultural differences, and whenever possible, written information should be provided. ## Expert opinion 97 Patients (and their families, caregivers or support network, if the patient agrees) should be invited to participate in the decision-making process at all times. When possible, patients should be encouraged to be accompanied by persons who can support them and share treatment decisions (e.g. family members, caregivers, support network). ## Expert opinion 100 There are few proven standards of care in ABC management. After appropriate informed consent, inclusion of patients in well-designed, prospective, independent trials must be a priority whenever such trials are available and the patient is willing to participate. ## Expert opinion 100 The medical community is aware of the problems raised by the cost of ABC treatment. Balanced decisions should be made in all instances; patients' well-being, length of life and preferences should always guide decisions. ## Expert opinion 100 Specialized oncology nurses (if possible specialized breast nurses) should be part of the multidisciplinary team managing ABC pts. In some countries this role may be played by a physician assistant or another trained and specialized health care practitioner. ## Expert opinion 92 All ABC patients should be offered comprehensive, culturally sensitive, up-to-date and easy to understand information about their disease and its management. ## B 97 The age of the patient should not be the sole reason to withhold effective therapy (in elderly patients) nor to overtreat (in young patients). Age alone should not determine the intensity of treatment. ## B 100 ASSESSMENT GUIDELINES Minimal staging workup for MBC includes a history and physical examination, hematology and biochemistry tests, and imaging of chest, abdomen and bone. ## C 67 Brain imaging should not be routinely performed in asymptomatic patients. This approach is applicable to all patients with MBC including those patients with HER-2þ and/or TNBC MBC. ## Expert opinion 94 The clinical value of tumor markers is not well established for diagnosis or follow-up after adjuvant therapy, but their use is reasonable (if elevated) as an aid to evaluate response to treatment, particularly in patients with nonmeasurable metastatic disease. A change in tumor markers alone should not be used to initiate a change in treatment. ## C 89 Evaluation of response to therapy should generally occur every 2-4 months for ET or after two to four cycles for CT, depending on the dynamics of the disease, the location and extent of metastatic involvement, and type of treatment. Imaging of target lesions may be sufficient in many patients. In certain patients, such as those with indolent disease, less frequent monitoring is acceptable. Additional testing should be performed in a timely manner, irrespective of the planned intervals, if PD is suspected or new symptoms appear. Thorough history and physical examination must always be performed. ## Expert opinion 81 Continued Annals of Oncology In the absence of medical contraindications or patient concerns, anthracycline or taxane based regimens, preferably as single agents, would usually be considered as first line CT for HER-2 negative MBC, in those patients who have not received these regimens as (neo)adjuvant treatment and for whom chemotherapy is appropriate. Other options are, however, available and effective, such as capecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient. ## A 71 In patients with taxane-naive and anthracycline-resistant MBC or with anthracycline maximum cumulative dose or toxicity (i.e. cardiac) who are being considered for further CT, taxane-based therapy, preferably as single agents, would usually be considered as treatment of choice. Other options are, however, available and effective, such as capecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient. ## A 59 In patients pre-treated (in the adjuvant and/or metastatic setting) with an anthracycline and a taxane, and who do not need combination CT, single agent capecitabine, vinorelbine or eribulin are the preferred choices. Additional choices include gemcitabine, platinum agents, taxanes, and liposomal anthracyclines. The decision should be individualized and take into account different toxicity profiles, previous exposure, patient preferences, and country availability. ## B 77 If given in the adjuvant setting, a taxane can be re-used as 1st line therapy, particularly if there has been at least 1 year of disease-free survival. ## A 92 Duration of each regimen and the number of regimens should be tailored to each individual patient. Expert opinion 96 Usually each regimen (except anthracyclines) should be given until progression of disease or unacceptable toxicity. What is considered unacceptable should be defined together with the patient. ## B 72 ## Other agents Bevacizumab combined with a chemotherapy as 1st or 2nd line therapy for MBC provides only a moderate benefit in PFS and no benefit in OS. The absence of known predictive factors for bevacizumab efficacy renders recommendations on its use difficult. Bevacizumab can only therefore be considered as an option in selected cases in these settings and is not recommended after 1st/2nd line. ## A 74 SPECIFIC POPULATIONS: TREATMENT OF METASTATIC MALE MBC For ERþ Male MBC, which represents the majority of the cases, ET is the preferred option, unless there is concern or proof of endocrine resistance or rapidly progressive disease needing a fast response. ## Expert opinion 100 For ERþ Male MBC tamoxifen is the preferred option. Expert opinion 83 For male patients with MBC who need to receive an AI, a concomitant LHRH agonist or orchidectomy is the preferred option. AI monotherapy may also be considered, with close monitoring of response. Clinical trials are needed in this patient population. ## Expert opinion 86 SPECIFIC SITES OF METASTASES BONE METASTASES Radiological assessments are required in patients with persistent and localized pain due to bone metastases to determine whether there are impending or actual pathological fractures. If a fracture of a long bone is likely or has occurred, an orthopaedic assessment is required as the treatment of choice may be surgical stabilization, which is generally followed by RT. In the absence of a clear fracture risk, RT is the treatment of choice. ## A 96 Neurological symptoms and signs which suggest the possibility of spinal cord compression must be investigated as a matter of urgency. This requires a full radiological assessment of potentially affected area as well as adjacent areas of the spine. MRI is the method of choice. An emergency surgical opinion (neurosurgical or orthopaedic) may be required for surgical decompression. If no decompression/stabilization is feasible, emergency radiotherapy is the treatment of choice and vertebroplasty is also an option. ## Brain metastases Patients with a single or small number of potentially resectable brain metastases should be treated with surgery or radiosurgery. Radiosurgery is also an option for some unresectable brain metastases. ## B 92 If surgery/radiosurgery is performed it may be followed by whole brain radiotherapy but this should be discussed in detail with the patient, balancing the longer duration of intracranial disease control and the risk of neurocognitive effects. ## B 72 Because patients with HER2þve MBC and brain metastases can live for several years, consideration of long-term toxicity is important and less toxic local therapy options (e.g. stereotactic RT) should be preferred to whole brain RT, when available and appropriate (e.g. in the setting of a limited number of brain metastases). 1C 89 ## Liver metastases Prospective randomized clinical trials of local therapy for BC liver metastases are urgently needed, since available evidence comes only from series in highly selected patients. Since there are no randomized data supporting the effect of local therapy on survival, every patient must be informed of this when discussing a potential local therapy technique. Local therapy should only be proposed in very selected cases of good performance status, with limited liver involvement, no extra-hepatic lesions, after adequate systemic therapy has demonstrated control of the disease. Currently, there are no data to select the best technique for the individual patient (surgery, stereotactic RT, intra-hepatic CT. . .). ## Expert opinion 83 MALIGNANT PLEURAL EFFUSIONS Malignant pleural effusions require systemic treatment with/without local management. Thoracentesis for diagnosis should be performed if it is likely that this will change clinical management. False negative results are common. Drainage is recommended in patients with symptomatic, clinically significant pleural effusion. Use of an intrapleural catheter or intrapleural administration of talc or drugs (e.g. bleomycin, biological response modifiers) can be helpful. Clinical trials evaluating the best technique are needed. ## 2b 86 CHEST WALL AND REGIONAL (NODAL) RECURRENCES Due to the high risk of concomitant distant metastases, patients with chest wall or regional (nodal) recurrence should undergo full restaging, including assessment of chest, abdomen and bone. ## Expert opinion 100 Chest wall and regional recurrences should be treated with surgical excision when feasible with limited risk of morbidity. ## B 97 Locoregional radiotherapy is indicated for patients not previously irradiated. 1 B 97 For patients previously irradiated, re-irradiation of all or part of the chest wall may be considered in selected cases. Expert opinion 97 In addition to local therapy (surgery and/or RT), in the absence of distant metastases, the use of systemic therapy (CT, ET and/or anti-HER-2 therapy) should be considered. CT after first local or regional recurrence improves long-term outcomes primarily in ER negative disease. ET in this setting improves long-term outcomes for ER positive disease. The choice of systemic treatment depends on tumor biology, previous treatments, length of disease free interval, and patient-related factors (co-morbidities and preferences). ## B 95 In patients with disease not amenable to radical local treatment, the choice of palliative systemic therapy should be made according to principles previously defined for metastatic BC. These patients may still be considered for palliative local therapy. ## Expert opinion 97 SUPPORTIVE AND PALLIATIVE CARE Supportive care allowing safer and more tolerable delivery of appropriate treatments should always be part of the treatment plan. ## A 100 Early introduction of expert palliative care, including effective control of pain and other symptoms, should be a priority. ## A 100 Access to effective pain treatment (including morphine, which is inexpensive) is necessary for all patients in need of pain relief. ## A 100 Optimally, discussions about patient preferences at the end of life should begin early in the course of metastatic disease. However, when active treatment no longer is able to control widespread and life-threatening disease, and the toxicities of remaining options outweigh benefits, physicians and other members of the healthcare team should initiate discussions with the patient (and family members/friends, if the patient agrees) about end-of-life care. Expert Opinion ## 96 ABC STATEMENTS FOR LABC (Note: For the purpose of these recommendations, LABC means inoperable, non-metastatic locally advanced breast cancer) Before starting any therapy, a core biopsy providing histology and biomarker (ER, PR, HER-2, proliferation/grade) expression is indispensable to guide treatment decisions. # Methodology Prior to the ABC 3 Conference, a set of preliminary recommendation statements on the management of ABC were prepared, based on available published data and following the ESMO guidelines methodology. These recommendations were circulated to all 44 panel members by email for comments and corrections on content and wording. A final set of recommendations was presented, discussed and voted upon during the consensus session of ABC 3. All panel members were instructed to vote on all questions, with members with a potential conflict of interest or who did not feel comfortable answering the question (e.g. due to lack of expertise in a particular field) instructed to vote 'abstain'. Additional changes in the wording of statements were made during the session. The statements related to management of side effects and difficult symptoms, included under the Supportive and Palliative care section, were not voted on during the consensus session, but discussed and unanimously agreed by email, and are considered to have 100% agreement. Supplementary [fig_ref] Table 1: Grading system[7] [/fig_ref] , available at Annals of Oncology online, lists all members of the ABC 3 consensus panel and their disclosures of any relationships with the pharmaceutical industry that could be perceived as a potential conflict of interest. [fig_ref] Table 1: Grading system[7] [/fig_ref] describes the grading system used [bib_ref] Grading strength of recommendations and quality of evidence in clinical guidelines: report..., Guyatt [/bib_ref]. ABC1 [bib_ref] 1st International consensus guidelines for advanced breast cancer (ABC1), Cardoso [/bib_ref] and ABC2statements with only minor updates or with no updates are listed in. ## General recommendations The continuous increase in cancer care costs has inevitably led to inequalities in access both between countries and within each country. Cost, value and access are now central discussion points and important factors in treatment-decision making. Both ESMO and ASCO have put considerable effort into the development of validated objective scales aiming at evaluating the real magnitude of benefit provided by each new treatment, including efficacy measures (e.g. impact on DFS, OS or PFS) and toxicity/ quality of life measures. The ESMO Magnitude of Clinical Benefit Scale [bib_ref] A standardised, generic, validated approach to stratify the magnitude of clinical benefit..., Cherny [/bib_ref] and the ASCO Value Framework [bib_ref] American Society of Clinical Oncology Statement: a conceptual framework to assess the..., Schnipper [/bib_ref] are user-friendly tools that can greatly assist decision-makers at the country and/or hospital level in the difficult decisions regarding approval and reimbursement. If LABC remains inoperable after systemic therapy and eventual radiation, 'palliative' mastectomy should not be done, unless the surgery is likely to result in an overall improvement in quality of life. ## Expert opinion 100 A combined treatment modality based on a multidisciplinary approach (systemic therapy, surgery and radiotherapy) is strongly indicated in the vast majority of cases. ## A 100 For Triple Negative LABC, Anthracycline-and-taxane-based chemotherapy is recommended as initial treatment. 1 A 85 For HER-21 LABC, concurrent taxane and anti-HER-2 therapy is recommended since it increases the rate of pCR. 1 A 92 For HER-21 LABC, anthracycline-based chemotherapy should be incorporated in the treatment regimen. 1 A 72 When an anthracycline is given, it should be administered sequentially with the anti-HER-2 therapy. 1 A 87 Options for HR1 LABC include an anthracycline-and taxane-based chemotherapy regimen, or endocrine therapy. 1 A 85 The choice of CT versus ET, as initial treatment, will depend on tumor (grade, biomarker expression) and patient (menopausal status, performance status, comorbidities, preference) considerations. Expert Opinion ## 85 Following effective neoadjuvant systemic therapy with or without radiotherapy, surgery will be possible in many patients. This will consist of mastectomy with axillary dissection in the vast majority of cases, but in selected patients with a good response, breast conserving surgery may be possible. ## B 98 INFLAMMATORY LABC For inflammatory LABC, overall treatment recommendations are similar to those for non-inflammatory LABC, with systemic therapy as first treatment. ## B 93 Mastectomy with axillary dissection is recommended in almost all cases, even when there is good response to primary systemic therapy. ## I b 95 Immediate reconstruction is generally not recommended in patients with inflammatory LABC. Expert opinion 95 Loco-regional radiotherapy (chest wall and lymph nodes) is required, even when a pCR is achieved with systemic therapy. ## B 98 The ABC3 experts also emphasize the responsibility of the academic and medical communities to advance the knowledge on breast cancer and other relevant unanswered issues, by involvement in clinical research aimed at addressing important clinical questions, and not only in studies conducted for regulatory purposes. The importance of providing patients with full information in appropriate, understandable and culturally sensitive way, as well as involving them in sharing the decision-making regarding all aspects of their management has been repeatedly stressed in all ABC guidelines [bib_ref] 1st International consensus guidelines for advanced breast cancer (ABC1), Cardoso [/bib_ref]. A high standard of patient centred care includes the following elements: appropriate information, good communication with health professionals, patient education, proactive advocacy, sensitivity to the patient's preferences, values and needs, and providing patients with the capabilities to improve their own quality of life [bib_ref] Delivering high-quality cancer care: charting a new course for a system in..., Levit [/bib_ref]. Although the overall survival of ABC has remained stable, for some subtypes, and in particular HER-2-positive metastatic breast cancer, prolonged survival, well beyond the median 2-3 years, has become a frequent reality. For these long-term survivors, survivorship issues which are specific for advanced cancer patients, have emerged and need appropriate attention, research and management. Work-related issues are central and solutions not easy to implement. A recently published survey [bib_ref] Evolving psychosocial, emotional, functional, and support needs of women with advanced breast..., Cardoso [/bib_ref] , found that approximately half of the women in employment had to change their work situation due to ABC and that 37% of them had to give up work temporarily or permanently. Due to these income problems and those related to the cost of care, the same survey found that 56% of ABC patients experienced a decline in household income as a result of their disease. The ABC community strongly advocates for the right of ABC patients to return or maintain their work, since a substantial proportion of these patients are in their most productive years. Furthermore, in some countries, health coverage is dependent on being employed. For that to occur, we need flexibility of working schedules, new communication technologies and home-based work which the ABC community supports. In many countries this may imply a change in the current labour-related laws. Survivorship issues also include the potential discussion of breast reconstruction, in those cases where the metastatic disease is either in complete remission or in a durable stable situation. No consensus could be reached regarding the use of breast imaging to follow-up the unaffected breast, but the experts agreed that imaging should be performed in case of suspicion of disease progression in the breast. Regarding the need to biopsy metastatic disease and re-evaluate the common biomarkers, the ABC recommendations had only minor changes. There are situations where the need for a biopsy in the metastatic setting is very clear, such as single lesions, history of two or more malignancies, suspicion of benign histology or doubt between progression or post-treatment necrosis. There is also consensus regarding the importance of such biopsy in situations where when a change in biomarkers would impact the treatment choice, which would mainly occur when biomarkers were negative in the primary tumor. There is some controversy about the benefits of a biopsy in situations where there is no doubt about the nature of the lesion(s) and where all receptors were positive in the primary tumor, since the clinical implementation of new technologies such as next generation sequencing for management decision-making s not yet validated. However, the exact nature of a lesion is hard to ascertain without the confirmation by a biopsy as shown in some retrospective and prospective studies [bib_ref] Breast cancer during followup and progression -a population based cohort on new..., Karlsson [/bib_ref] [bib_ref] Prospective comparison of switches in biomarker status between primary and recurrent breast..., Thompson [/bib_ref] [bib_ref] Prospective study evaluating the impact of tissue confirmation of metastatic disease in..., Amir [/bib_ref]. There is also an undisputable importance of collection of material for research purposes, both ongoing and future. Technical issues should be discussed with the breast pathologist, in particular in case of bone biopsies with the inherent decalcification problems, which may interfere with the biomarker analysis [bib_ref] Recommendations for retesting breast cancer metastases for HER2 and hormone receptor status, Penault-Llorca [/bib_ref] [bib_ref] Influence of decalcification procedures on immunohistochemistry and molecular pathology in breast cancer, Schrijver [/bib_ref] , as experienced in Safir01/UNICANCER trial [bib_ref] Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic..., André [/bib_ref]. For that reason, decalcification using EDTA is recommended for bone biopsies, when it is the only metastatic site [bib_ref] Influence of decalcification procedures on immunohistochemistry and molecular pathology in breast cancer, Schrijver [/bib_ref]. Adding to the complexity of this issue is the fact that negative biomarker results may limit the eligibility for reimbursement of therapies dedicated to specific subtypes, in some countries. A number of prospective randomized trials have assessed or are assessing the role of removing the primary tumor in patients with de novo metastatic disease. So far only two small studies have been published/presented [bib_ref] Locoregional treatment versus no treatment of the primary tumour in metastatic breast..., Badwe [/bib_ref] [bib_ref] A randomized controlled trial evaluating resection of the primary breast tumor in..., Soran [/bib_ref]. A subgroup analysis of the Turkish study suggested a potential benefit in patients with ER/PgRþ, HER-2 negative, solitary bone metastasis, who are younger than 55 years of age, while patients with multiple pulmonary and liver metastasis did worse with an overall 3-year survival of 31% in the surgery group versus 67% for the systemic therapy group [bib_ref] A randomized controlled trial evaluating resection of the primary breast tumor in..., Soran [/bib_ref]. In the Indian trial, a decrease in distant progression-free survival was observed in patients allocated to surgery. Results of larger, prospective studies are awaited. Until then, the recommendation is to discuss surgery on a case-by-case basis and importantly, only (4) For patients with ERþ/HER-2þ MBC, for whom CTþanti-HER2 therapy was chosen as 1st line therapy and provided a benefit, it is reasonable to use ETþanti-HER2 therapy as maintenance therapy, after stopping CT, although this strategy has not been studied in randomized trials. ## C voters: 39 Yes: 79% (31) Abstain: 10% (4) Patients progressing on an anti-HER-2 therapy combined with a cytotoxic or endocrine agent should be offered additional anti-HER-2 therapy with subsequent treatment since it is beneficial to continue suppression of the HER-2 pathway. The optimal duration of anti-HER-2 therapy for MBC (i.e. when to stop these agents) is currently unknown. ## B voters: 43 Yes: 91% (39) Abstain: 7% (3) In patients achieving a complete remission, the optimal duration of maintenance anti-HER2 therapy is unknown and needs to be balanced against treatment toxicity, logistical burden and cost. Stopping anti-HER2 therapy after several years of sustained complete remission may be considered in some patients, particularly if treatment re-challenge is available in case of progression. ## Expert opinion voters: 42 Yes: 93% [bib_ref] Transcriptional control of estrogen receptor in estrogen receptor-negative breast carcinoma, Weigel [/bib_ref] No: 7% (3) Patients who have received any type of (neo)adjuvant anti-HER-2 therapy should not be excluded from clinical trials for HER-2þ MBC. These patients remain candidates for anti-HER-2 therapies. (2) The standard 1st line therapy for patients previously untreated with anti-HER-2 therapy is the combination of CTþtrastuzumab and pertuzumab, because it has proven to be superior to CTþtrastuzumab in terms of OS in this population. In case of progression on trastuzumab-based therapy, the combination trastuzumabþlapatinib is a reasonable treatment option for some patients. There are however, no data on the use of this combination after progression on pertuzumab or T-DM1. ## B voters: 43 Yes: 84% (36) Abstain: 12% (5) All patients with HER-2þ MBC who relapse after adjuvant or any line metastatic anti-HER-2 therapy should be considered for further anti-HER-2 therapy, except in the presence of contraindications. The choice of the anti-HER-2 agent will depend on country-specific availability, the specific anti-HER-2 therapy previously administered, and the relapse free interval. The optimal sequence of all available anti-HER-2 therapies is currently unknown. ## B voters: 40 Yes: 86% (36) Abstain: 12.5% (5) ## Regarding the ct component of her-2 positive mbc treatment: When pertuzumab is not given, 1st line regimens for HER-2 MBC can include trastuzumab combined with vinorelbine or a taxane. Differences in toxicity between these regimens should be considered and discussed with the patient in making a final decision. Other CT agents can be administered with trastuzumab but are not as well studied and are not preferred. Continued consider surgery if it can be performed with a high quality procedure [bib_ref] Initial surgery and survival in stage IV breast cancer in the United..., Thomas [/bib_ref]. The definition of oligometastatic disease (see next section) has been enlarged to encompass low volume metastatic disease, i.e. limited number and size of metastatic lesions (up to five and not necessarily in the same organ) and potentially amenable for local treatment which is aimed at achieving a complete remission. The development of minimally invasive surgical techniques and highly conformal ablative radiotherapy allow for safe and effective ablation of metastatic lesions in most locations. Although some retrospective studies have suggested that achieving a sustained complete remission seems to be associated with a longer survival [bib_ref] Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic..., Greenberg [/bib_ref] , the true impact of these local-regional therapies on long-term outcome remains unknown, and prospective and if possible randomized trials are needed. ## Abc important definitions Most clinical situations occur as a continuum and dividing them into categories of stage, grade, risk group, or other factors is always artificial and based on oversimplification of thresholds. Such a categorization is, however, useful to guide treatment choices, to help assure adherence to guidelines and recommendations, and to facilitate clinical research. Following the effort of previous editions, ABC provides two additional definitions: 'oligometastatic disease' discussed above and the complex clinical situation of 'multiple chronic conditions'. The latter is becoming increasingly important and more frequent in view of the aging of the population in general and of cancer patients in particular. Managing advanced cancer, the consequences of the disease and of the rapidly increasing number and type of pharmacologic and non-pharmacologic interventions in patients with several coexisting conditions is a major challenge. Furthermore, these patients are systematically excluded from clinical trials and hence available data, in particular regarding the use of new agents in these situations, are scarce and eagerly needed. ## Her-2 positive abc Among all breast cancer subtypes, HER2-positive ABC has had the largest progress over the last decade. The introduction of new anti-HER2 therapies, such as pertuzumab and T-DM1 [bib_ref] Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall..., Swain [/bib_ref] [bib_ref] Trastuzumab emtansine for HER2-positive advanced breast cancer, Verma [/bib_ref] [bib_ref] Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast..., Krop [/bib_ref] [bib_ref] Phase III, randomized study of trastuzumab emtansine (T-DM1) 6 pertuzumab (P) vs..., Ellis [/bib_ref] [bib_ref] PHEREXA: a phase III study of trastuzumab (H) þ capecitabine (X) 6..., Urruticoechea [/bib_ref] , was a significant step forward but also created a number of new uncertainties related to optimal combination/sequence of all available treatments. In view of the overall survival (OS) results obtained with most combinations of chemotherapy plus anti-HER-2 agents, the role of endocrine therapy plus anti-HER-2 agents for the subgroup of patients with ERþ/HER-2þ disease has been questioned. Although published studies have not demonstrated an OS benefit of this combination, long-term data were not collected in these trials. Of note, the OS analysis of the TAnDEM trial, excluding patients who crossed over to trastuzumab, demonstrated a borderline OS benefit for the combination arm [bib_ref] Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women..., Kaufman [/bib_ref]. In the absence of valuable biomarkers, this approach should be reserved for highly selected patients, including those with contraindications to chemotherapy, patient's with a strong preference against chemotherapy or those with a long disease-free interval, minimal disease burden, in particular in terms of visceral involvement, and/or strong ER/PgR expression. Trials directly comparing chemotherapy plus anti-HER2 therapy versus endocrine therapy plus anti-HER2 therapy are currently ongoing (Detect V/CHEVENDO (NCT02344472), SYSUCC-002 (NCT01950182) and PERNETTA trials) and their results will allow for better recommendations. In addition, in several countries anti-HER2 therapy, namely trastuzumab, can only be used once in the metastatic setting since its use beyond progression is either not approved or not reimbursed; in those cases, preference should be given to a combination of chemotherapy plus anti-HER-2 therapy. The combination of endocrine therapy plus anti-HER2 therapy is particularly useful as maintenance therapy for ERþ/ HER2þ ABC, after initial cycles of chemotherapy plus anti-HER-2 therapy. Despite the absence of randomized trials, clinical experience and low toxicity (in particular if trastuzumab is used), makes this a reasonable option, most probably delaying disease progression and the consequent need for chemotherapy. The issue of duration of anti-HER-2 therapy in the metastatic setting is of crucial importance, in view of the potential benefits as well as the substantial costs associated with these agents. There are sufficient data [bib_ref] Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast..., Von Minckwitz [/bib_ref] [bib_ref] Trastuzumab beyond progression for HER2 positive metastatic breast cancer: progression-free survival on..., Rayson [/bib_ref] to recommend continuing trastuzumab beyond progression, but the optimal duration of this treatment and how many lines beyond progression should it be used is currently unknown. Data are very scarce related to the use beyond progression of other anti-HER2 agents and no data exist supporting the use of dual blockade beyond progression. ## Section 4. er positive/her-2 negative (luminal) abc ## Guideline statement loe consensus Endocrine therapy (ET) is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance. (3) The combination of a nonsteroidal AI and fulvestrant as first-line therapy for postmenopausal patients resulted in significant improvement in both PFS and OS compared to AI alone in one phase III trial and no benefit in a second trial with a similar design. Subset analysis suggested that the benefit was limited to patients without prior exposure to adjuvant ET (tamoxifen). Based on these data, combination ET may be offered to some patients with MBC without prior exposure to adjuvant ET. ## B voters: 43 Yes: 33% [bib_ref] Prospective comparison of switches in biomarker status between primary and recurrent breast..., Thompson [/bib_ref] No: 53% (23) Abstain: 14% (6) The addition of everolimus to an AI is a valid option for some postmenopausal patients with disease progression after a non-steroidal AI, since it significantly prolongs PFS, albeit without OS benefit. The decision to treat must take into account the individual relevant toxicities associated with this combination and should be made on a case by case basis. Tamoxifen can also be combined with everolimus. (1) The addition of CDK4/6 inhibitor palbociclib to Fulvestrant, beyond 1st line therapy, for pre/peri/postmenopausal patients, provided significant improvement in PFS ($5 months) as well as improvement of QoL, and is a treatment option. OS results are awaited. For pre/peri-menopausal pts, an LHRH-agonist must also be used. At present, no predictive biomarker other than hormone receptor status exists to identify patients who will benefit from these type of agents and research efforts must continue. (2) For pre-menopausal women, for whom ET was decided, ovarian suppression/ablation combined with additional endocrine therapy is the preferred choice. ## B voters: 43 Yes: 93% (40) Abstain: 5% (2) Ovarian ablation by laparoscopic bilateral oophorectomy ensures definitive estrogen suppression and contraception, avoids potential initial tumor flare with LHRH agonist, and may increase eligibility for clinical trials. Patients should be informed on the options of OS/OA and decision should be made on a case by case. ## Expert opinion Voters: 43 Yes: 91% (39) Abstain: 7% (3) For pre-menopausal women, the additional endocrine agent can be AI or tamoxifen, according to type and duration of prior adjuvant endocrine therapy but AI absolutely mandates the use of ovarian suppression/ ablation. Fulvestrant is also a valuable option, but for the moment also mandates the use of ovarian suppression/ ablation. A particularly difficult situation, albeit also a fortunate one, relates to the optimal duration of trastuzumab therapy in patients achieving long-term complete remission. This needs to be balanced against toxicity, logistical burden and cost. Currently no data exist to support therapeutic decisions in this setting, and the panel supported a cautious statement approving consideration of stopping trastuzumab in these circumstances in some patients, particularly if treatment re-challenge is available in case of progression, which is not the case in all countries. Dual blockade with trastuzumab and pertuzumab in combination with chemotherapy as 1st line therapy, provides substantial benefit in terms of OS and PFS [bib_ref] Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall..., Swain [/bib_ref]. It is therefore considered by the panel as the standard of care for patients previously untreated with trastuzumab, in the (neo)adjuvant setting, and an important treatment option for patients previously treated with trastuzumab. The difference in the strength of recommendation is due to the fact that very few patients (only 88) who were previously treated with trastuzumab were enrolled in the Cleopatra trial. In addition, in the Marianne trial [bib_ref] Phase III, randomized study of trastuzumab emtansine (T-DM1) 6 pertuzumab (P) vs..., Ellis [/bib_ref] the dual blockade strategy did not prove to be superior to chemotherapy and trastuzumab, albeit with a different combination of agents-T-DM1 and Pertuzumab. The reasons for this lack of benefit are currently unknown and could be related to the different patient populations enrolled in both trials (more (30%) patients in Marianne had been previously treated with trastuzumab), the choice of agents with the presence or absence of synergistic effects, the absence of standard chemotherapy agents (DM1 being a cytotoxic agent not used as single agent) or other factors. After the discussion and voting during ABC3, the Pherexa [27] study was presented, evaluating the role of dual blockade with trastuzumab þ pertuzumab þ capecitabine for patients previously treated with a taxane and trastuzumab in the metastatic setting. Surprisingly, a non-significant benefit of only 2 months was seen in the primary endpoint PFS, while an 8-month benefit was observed in OS albeit non-statistically significant (in view of the lack of significant PFS benefit). Many questions remain unanswered in the management of HER-2þ ABC. We have no data on the role of dual blockade for patients relapsing during and within 12 months of adjuvant trastuzumab, since these patients have been excluded from clinical trials. This aggressive situation is a clear unmet need for which data must be generated. Following the approval, both by FDA and EMA, of pertuzumab use in the neoadjuvant setting, there is an urgent need to evaluate the best treatment options for the patients who relapse after receiving chemotherapy þ trastuzumab þ pertuzumab in the early setting. It is also currently unknown how trastuzumab þ pertuzumab þ chemotherapy compares to T-DM1, as 1st or later lines of therapy. We also have no data on the best treatment option after progression on dual blockade with pertuzumab þ trastuzumab, namely how T-DM1 performs in this setting. While trastuzumab þ lapatinib (without chemotherapy) is a valuable option for some patients, after progression on chemotherapy þ trastuzumab, there are no data on the use of this combination after progression on pertuzumab or T-DM1. All these unanswered questions and the definition of the best sequence of therapies for the individual patient may prove difficult to evaluate in prospective, randomized trials, with the absence of specific biomarkers. In this scenario, registry studies, such as the SystHERs Registry Study [bib_ref] The SystHERs registry: an observational cohort study of treatment patterns and outcomes..., Tripathy [/bib_ref] and registHER, as well as collection of treatment and outcome data beyond progression in all HER-2-positive ABC clinical trials, are of great importance. In ABC3, the optimal chemotherapy component for the treatment of HER-2þ disease was discussed. The panel has stressed the importance of treatment decisions that are based not only on efficacy, but also on toxicity profile, and patients' preferences. For 1st line therapy, when trastuzumab is used as sole anti-Her2 agent, the preferred agents are vinorelbine or a taxane. Importantly, single agent vinorelbine in association with trastuzumab has shown superior or equal efficacy compared to either paclitaxel or docetaxel, in the TRAVIOTA and HERNATA trials, and has a better tolerability [bib_ref] Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab..., Andersson [/bib_ref] [bib_ref] Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the..., Burstein [/bib_ref]. For later lines of therapy, trastuzumab can be administered with almost all chemotherapy agents, including but not limited to, vinorelbine (if not given in 1st line), taxanes (if not given in 1st line), capecitabine, eribulin, liposomal anthracyclines, platinum, gemcitabine, or metronomic CM (low dose, oral, cyclophosphamide and methotrexate). The decision should be individualized and take into account different toxicity profiles, previous exposure, patient preferences, and country availability. Combinations of other anti-HER2 agents, namely TKIs, with chemotherapy are more limited due to toxicity. There are currently no data to decide on the best sequence for each individual patient. When dual blockade with trastuzumab and pertuzumab is used, possible agents to combine are docetaxel [bib_ref] Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall..., Swain [/bib_ref] , weekly paclitaxel [bib_ref] Weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast..., Smyth [/bib_ref] , vinorelbine [bib_ref] The co-administration of pertuzumab (P) and trastuzumab (T) as a single infusion,..., Andersson [/bib_ref] and nab-paclitaxel [bib_ref] Nab-paclitaxel versus solventbased paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG..., Untch [/bib_ref]. After the voting that took place in ABC3, the Pherexa trial [bib_ref] PHEREXA: a phase III study of trastuzumab (H) þ capecitabine (X) 6..., Urruticoechea [/bib_ref] , presented at ASCO 2016, provided some evidence regarding the combination of dual blockade with capecitabine. ## Er positive/her-2 negative (luminal) abc One of the most important recommendations relates to the preferred treatment for luminal ABC, which should be endocrine therapy in the majority of cases, excluding those with visceral crisis and concern or proof of endocrine resistance. All breast cancer guidelines concur with this recommendation but unfortunately real life data studies show that most of these patients still receive chemotherapy as their first treatment, despite the lower efficacy [bib_ref] In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer..., Lobbezoo [/bib_ref]. Visceral crisis and endocrine resistance have been defined during ABC 2 and published. However, better predictive factors are urgently needed to clearly identify those patients whose tumors have primary endocrine resistance and are responsible for the early and rapid progression seen in $20-25% of luminal ABC patients treated with endocrine therapy [bib_ref] PALOMA-2: primary results from a phase III trial of palbociclib (P) with..., Finn [/bib_ref]. Possible reasons may include ER loss [bib_ref] Transcriptional control of estrogen receptor in estrogen receptor-negative breast carcinoma, Weigel [/bib_ref] or ER mutations [bib_ref] Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer, Fribbens [/bib_ref]. The most important advance in the management of luminal ABC over the last 2 years has undoubtedly been the introduction of a new class of agents, the CDK4/6 inhibitors, in combination with an endocrine agent. The value of the CDK4/6 inhibitor palbociclib, combined with an aromatase inhibitor as 1st line therapy was evaluated initially in a randomized phase II study, the PALOMA 1 trial [bib_ref] The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole..., Finn [/bib_ref] , which showed a substantial 10-month benefit in progression-free-survival (PFS) coupled with a favorable toxicity profile (main toxicity being neutropenia). Based on these results, FDA granted accelerated approval, which resulted in the drug being commercially available in USA. At the 2016 ASCO meeting, the phase III PALOMA 2 trial was presented and confirmed the 10-month benefit in PFS, with the main toxicities being hematological (mainly neutropenia) and fatigue [bib_ref] The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole..., Finn [/bib_ref]. OS results are still awaited. In view of these results, the initial statement developed at ABC3 was modified and re-voted by email and considers this option as one of the preferred treatment options, where available. Very recently (September 2016) EMA also started the approval process of Palbociclib. However, its approval/reimbursement in all individual countries is still pending and the issue of cost is of crucial importance for its implementation in clinical practice, as it is for many targeted agents namely anti-HER-2 agents. Beyond 1st line endocrine therapy, addition of palbociclib to fulvestrant resulted in significant albeit lower 5-month PFS prolongation in the PALOMA 3 phase III trial [bib_ref] Palbociclib in hormone-receptorpositive advanced breast cancer, Turner [/bib_ref]. The quality of life substudy has shown both an overall improvement and a delayed deterioration of this important endpoint, with greater improvement in baseline pain, in the palbociclib arm [bib_ref] Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive,..., Harbeck [/bib_ref]. Importantly, the PALOMA-3 study accrued both postmenopausal and pre/perimenopausal (in combination with ovarian function suppression) patients, allowing for assessment of the drug efficacy in a breast cancer population usually excluded from ABC endocrine therapy trials. OS results are still awaited. In view of available results, the ABC panel considers this as a treatment option, where available. The ESMO Magnitude of Clinical Benefit Scale (MCBS) was calculated for the recently approved Palbociclib, for use in 1st line and in 2nd line. As a reminder, the MCBS scores a given treatment in a given setting, and based on published trials. At the time of publishing the ABC3 guidelines, PALOMA 2 main results and the accompanying quality of life substudy have been presented but not yet published. For this reason, the MCBS for the use of palbociclib in 1st line was calculated using the PALOMA 1 trial efficacy data, which scores a 3 for efficacy. Once the PALOMA 2 data is published the MCBS will be updated an e-update made available through the ESMO guidelines website. For the use of palbociclib as 2nd line therapy, data from PALOMA 3, both efficacy and quality of life, were used. The MCBS was 3 for efficacy, and due to the improvement in quality of life upgraded to 4, which is the final score for this setting. Another possible therapy is the combination of endocrine therapy with the mTOR inhibitor, everolimus. This combination has shown a PFS benefit of $6 months, without a significant OS benefit, and with significant toxicity [bib_ref] Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast..., Piccart [/bib_ref] [bib_ref] Randomized phase II trial of everolimus in combination with tamoxifen in patients..., Bachelot [/bib_ref]. However, as with many agents, as more experience is gained regarding the use of everolimus and the management of its toxicities, its clinical use becomes easier. In addition, patient education is fundamental for prevention and early management of associated side effects. Of particular attention is the possibility of an excess mortality of this combination in elderly patients (>70 years of age) [bib_ref] Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast..., Piccart [/bib_ref] [bib_ref] Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly..., Pritchard [/bib_ref]. Currently, and in spite of intensive research, no predictive biomarker, other than hormone receptor status, exists to identify patients who will benefit the most from either m-TOR or CDK4-6 inhibitors and research efforts must continue. The panel did not support (53.4% against) the 1st line combination of non-steroidal aromatase inhibitor and fulvestrant based on the results of the SWOG S0226 trial [bib_ref] Combination anastrozole and fulvestrant in metastatic breast cancer, Mehta [/bib_ref]. There may be a benefit for the minority of postmenopausal patients who are endocrine-naïve. The definition of the best 1st line approach for postmenopausal patients will soon have additional data through the phase III FALCON data that will be presented this year. The optimal sequence of single endocrine agents and combinations with targeted agents is currently unknown and is a research priority. It is crucial to collect data from clinical trials beyond progression to better understand the efficacy of each class of agent when given after the other (e.g. CDK4-6 inhibitors after m-TOR inhibitors and vice-versa). ## Triple negative abc The treatment of triple-negative breast cancer (TN-ABC) still remains the largest unmet need within ABC. In spite of extensive research, no treatments apart from chemotherapy have so far proven to be effective for this population. For this reason, no specific recommendations can be made for this ABC subtype, with the possible exception of platinum compounds for BRCA-mutated patients. Probably the largest achievement of the last 2 years was the TNT study, comparing 'standard' docetaxel to carboplatin in unselected TNBC patients (with pre-specified subgroup analysis of BRCA-mutation carriers). The superiority of carboplatin was demonstrated only among BRCA-positive patients, while in the SECTION 5. TRIPLE NEGATIVE ABC ## Guideline statement loe consensus For non-BRCA-associated triple negative ABC, there are no data supporting different or specific CT recommendations. Therefore, all CT recommendations for HER-2 negative disease also apply for triple negative ABC. ## A voters: 44 Yes: 98% (43) Abstain: 2% (1) In triple-negative ABC patients (regardless of BRCA status), previously treated with anthracyclines with or without taxanes in the (neo)adjuvant setting, carboplatin demonstrated comparable efficacy and a more favorable toxicity profile, compared to docetaxel, and is therefore an important treatment option. unselected TN-ABC population docetaxel and carboplatin seem to have a similar efficacy [bib_ref] TNT: a randomized phase III trial of carboplatin compared to docetaxel for..., Tutt [/bib_ref] , although the study was not designed as a non-inferiority study. Of note, in this study, 15% of patients had no prior adjuvant chemotherapy and only 35% had received (neo)adjuvant taxanes. Importantly, due to the significantly better toxicity profile of carboplatin, it remains an attractive treatment choice even for unselected TN-ABC patients. Unfortunately, other putative predictive factors of increased sensitivity to platinum, such as homologous recombination deficit (HRD) and the basal-like Prosigna PAM50 signature were not proven of value for making treatment decisions in this setting. The future of TN-ABC treatment seems to lie in a better biological characterization of this breast cancer subtype into further subgroups, followed by the development of specific therapies for each of the subgroups. An example is the Luminal AR subtype, characterized by the expression of the androgen receptor; antiandrogens have recently demonstrated some activity and are being further evaluated, and where a potential predictive marker, the Predict AR assay, is also being tested [bib_ref] Overall survival (OS) from the phase 2 study of enzalutamide, an androgen..., Cortes [/bib_ref]. ## Other recommendations Several options exist for chemotherapy both for first and subsequent lines of therapy. The ABC panel maintains that for patients pretreated with anthracyclines and taxanes the preferred agents, based on their efficacy and toxicity profile, are capecitabine, vinorelbine and eribulin. The latter is one of the few agents to provide a survival gain, albeit small (2.5 months) in a heavily pretreated population of ABC patients [bib_ref] Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast..., Cortes [/bib_ref]. In a head-to-head comparison between eribulin and capecitabine, as first or second line therapy, there were no major differences between the drugs in efficacy but a different toxicity profile [bib_ref] Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients..., Kaufman [/bib_ref]. It is also possible to re-challenge with anthracyclines, particularly if there has been at least 1 year of disease-free survival, and if the cumulative dose has not been reached, a common situation nowadays because of the lower doses of anthracyclines used in the adjuvant setting. Re-challenge with taxanes is also possible, provided that there has been at least 1 year of disease-free survival. Another very attractive option is the use of metronomic chemotherapy, defined as the use of low doses and short intervals, which has been evaluated in the advanced setting with interesting efficacy results and an excellent toxicity profile [bib_ref] Clinical overview of metronomic chemotherapy in breast cancer, Munzone [/bib_ref]. The best evaluated regimen is oral cyclophosphamide and oral methotrexate but other agents are being studied such as vinorelbine and capecitabine. In view of the lack of substantial efficacy differences among the different available options, their toxicity profile must be discussed with the patient and her/his preferences taken into account. ABC3 also further endorsed the use of bone-modifying agents (bisphosphonate, denosumab) in combination with (2) OTHERÅBIOMARKERS Multigene panels, such as those obtained using next generation sequencing (NGS) or other technology, regarding evolving molecular changes in ABC tumors has not yet proven beneficial in clinical trials, their impact on outcome remains undefined and should only be considered investigational. [bib_ref] Denosumab compared with zoledronic acid for the treatment of bone metastases in..., Stopeck [/bib_ref] , having the advantage of a subcutaneous route of administration and the disadvantage of a substantially higher cost in most countries; where available, it can be considered a preferred option. Currently available data support replacing routine 4 weekly administration of intravenous bisphosphonates by 3monthly zoledronic acid after an initial period of monthly use [bib_ref] Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment..., Amadori [/bib_ref] [bib_ref] Efficacy and safety of continued zoledronic acid every 4 weeks versus every..., Hortobagyi [/bib_ref]. Early 3-monthly use seems associated with increased need for major surgeries [bib_ref] Alliance): a randomized phase III study of standard dosing vs. longer interval..., Himelstein [/bib_ref] , so a reasonable compromise may be to start with the monthly schedule for the first year and then change to 3monthly regimen. No data exist on the optimal overall treatment duration of bone modifying agents, and their efficacy must be ## Management of cdk inhibitor induced neutropenia Neutropenia is the most common toxicity associated with CDK 4/6 inhibition and is not generally associated with febrile neutropenia although an increase in infections has been reported. Treatment should be delayed until neutrophils have recovered to at least 1000/ll; dose reduction can also be considered. ## A 100% Management of Non-Infectious Pneumonitis (NIP) NIP is an uncommon complication of mTOR inhibition. Patient education is critical to ensure early reporting of respiratory symptoms. Treatment interruption and dose reduction are generally effective for grade 2 symptomatic NIP with use of systemic steroids and treatment discontinuation for grade 3 or greater toxicity. ## A 100% Management of MUCOSITIS/STOMATITIS Mild toothpaste and gentle hygiene are recommended for the treatment of stomatitis. Early intervention is recommended. For grade 2 or higher stomatitis, delaying treatment until the toxicity resolves and considering lowering the dose of the targeted agent are also recommended. Consider adding steroid dental paste to treat developing ulcerations. Steroid mouthwash can be used for prevention of stomatitis (suggested schedule: 0.5 mg/5 ml dexamethasone, 10 ml to swishÂ2 min then spit out qid). There is a need to study nausea and vomiting related to chronic use of anticancer drugs. Expert Opinion 100% Management of endocrine toxicities of mTOR inhibition Hyperglycemia and hyperlipidemia are common sub-acute complications of mTOR inhibition. Evaluation of preexisting diabetes or hyperglycemia at baseline is essential. Regular careful monitoring of glycemia and lipid panel is needed to identify these toxicities. Management of grade 1 and 2 hyperglycemia include treatment with oral antidiabetics and basal insulin, in accordance with international recommendation for diabetes mellitus treatment. Statins are indicated to treat grade 2 and 3 hypercholesterolemia, and fibrates should be introduced if triglyceride level >500 mg/dl (with attention to possible drug-drug interaction between everolimus and fibrates). Treatment interruption and dose reduction are generally effective for grade 2 and 3. Treatment should be discontinued for grade 4 toxicity. ## A 100% LoE, available level of evidence; consensus, percentage of panel members in agreement with the statement; QoL, quality of life. NOTE: The statements of this section were not voted during the ABC Consensus panel but were developed and agreed upon by email, by all panel members. weighed against long-term toxicity (such as osteonecrosis of the jaw and atypical fractures). When a bone modifying agent is given, supplements of calcium and vitamin D are mandatory, except in the presence of contraindications. Unfortunately, no multigene testing technology has been proven to be beneficial in supporting treatment choices in ABC patients [bib_ref] Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic..., André [/bib_ref] and the panel strongly discourages their use in clinical practice. They should continue to be considered investigational. ## Supportive and palliative care The ABC panel decided to dedicate several recommendations to the management of disease and treatment-related symptoms, a problem faced daily by patients and every practicing oncologist, that can significantly affect a patient's quality of life Unfortunately, little high-quality data exist in many areas of symptom management, probably due to difficulties in conducting research in this field, including the lack of well-defined endpoints, of patient-reported symptoms and side effects, and of optimal tools to evaluate impact on quality of life for advanced cancer patients. New classes of drugs introduced into breast cancer management have brought into the clinical practice new toxicities, poorly understood in the beginning and unfamiliar to most oncologists. Undoubtedly this is an area of unmet need, which should be a research priority. The ABC3 guidelines provide guidance on the management of drug-induced pneumonitis, mucositis [bib_ref] Evaluation of miracle mouthwash (MMW) plus hydrocortisone versus prednisolone mouth rinses as..., Jones [/bib_ref] [bib_ref] Prevention of everolimus/exemestane (EVE/EXE) stomatitis in postmenopausal (PM) women with hormone receptor-positive..., Rugo [/bib_ref] , endocrine and metabolic disorders and CDK4/6 inhibitor-related neutropenia. For nausea and vomiting ABC fully endorses the guidelines developed by ESMO/MASCC [bib_ref] MASCC and ESMO Consensus Guidelines for the prevention of chemotherapy and radiotherapyinduced..., Roila [/bib_ref]. The ABC panel continues to discuss and provide guidance on the management of frequent and difficult to manage cancerassociated symptoms. In this edition, dyspnea and fatigue were discussed. Cancer related fatigue is frequently experienced by advanced cancer patients, exerts a deleterious impact on their quality of life and limits physical, functional, psychological and social well-being. Its etiology is complex and therefore effective management needs to be multidimensional [bib_ref] Interventions for fatigue and weight loss in adults with advanced progressive illness, Payne [/bib_ref] [bib_ref] Screening, evaluation and management of cancer-related fatigue: ready for implementation to practice, Berger [/bib_ref] [bib_ref] A practical approach to fatigue management in colorectal cancer, Aapro [/bib_ref]. It is important to assess cancer related fatigue using appropriate patientreported outcome measures before implementing various pharmacological and non-pharmacological interventions. Randomized studies have suggested improvement of fatigue by various types of exercise quite convincingly [bib_ref] Effects of an 18-week exercise programme started early during breast cancer treatment:..., Travier [/bib_ref] , and meditation and some pharmacologic interventions are under evaluation. The use of good evidence-based algorithms for management of cancer related fatigue can also be helpful [bib_ref] Management of fatigue in patients with cancer -a practical overview, Koornstra [/bib_ref]. # Conclusions Since the ABC3 Conference two important initiatives have already been initiated. The ESMO Magnitude of Clinical Benefit Scale (MCBS) [bib_ref] A standardised, generic, validated approach to stratify the magnitude of clinical benefit..., Cherny [/bib_ref] has been published and is being applied to all new anticancer treatments approved by EMA. The latest drug for which EMA started the approval process was Palbociclib in September 2016 and its MCBS evaluation is included in the present article. Should another agent be approved before the next ABC Consensus Conference, the ESMO Committees will apply the MCBS and the result will be made available as an e-update to the present guidelines. Following on the success of the ABC Consensus Conference, the ABC community has come together to create the ABC Global Alliance. This Alliance will function as a platform where all involved partners (advocacy groups, pharma, cooperative groups, societies, individuals) will be able to work together, in projects designed to improve the lives of ABC patients. The Global Status of ABC Decade Reporthas highlighted several areas of unmet needs. Based on these findings, a global Call-To-Action is being developed, with tangible objectives that need to be achieved within the next decade to meaningfully impact the outcomes of ABC patients. # Funding None declared. # Disclosure Detailed CoI for all panel members are described in online supplement. [table] Table 1: Grading system[7] [/table]	None	https://academic.oup.com/annonc/article-pdf/28/1/16/24168764/mdw544.pdf	F. Cardoso*, A. Costa, E. Senkus, M. Aapro, F. André, C. H. Barrios, J. Bergh, G. Bhattacharyya, L. Biganzoli, M. J. Cardoso, L. Carey, D. Corneliussen-James, G. Curigliano, V. Dieras, N. El Saghir, A. Eniu, L. Fallowfield, D. Fenech, P. Francis, K. Gelmon, A. Gennari, N. Harbeck, C. Hudis, B. Kaufman, I. Krop, M. Mayer, H. Meijer, S. Mertz, S. Ohno, O. Pagani, E. Papadopoulos, F. Peccatori, F. Penault-Llorca, M. J. Piccart, J. Y. Pierga, H. Rugo, L. Shockney, G. Sledge, S. Swain, C. Thomssen, A. Tutt, D. Vorobiof, B. Xu, L. Norton & E. Winer
3cab3eaa36192f5da352c69133edc84f05f4ea4e	pubmed	Cancer of the endometrium	Cancer of the endometrium ## Classification The pathological report must specify the precise origin of the tumour, its size and macroscopic features. It must document the extent of macroscopic infiltration of the myometrium, and if there is invasion of the cervix, parametrium and/or adnexae (standard). The diagnosis of endometrial carcinoma is based on histological examination. This determines both the histological type and grading of the tumour (standard). Immunohistochemistry and evaluation of hormone receptors may be carried out (option). In the case of diagnostic difficulty, immunohistochemistry is recommended. Use of the FIGO 1988 classification is standard (standard). ## Prognostic factors The following prognostic factors must be determined: FIGO classification, grade, differentiation, cervical invasion, depth of myometrial invasion, involvement of pelvic nodes, ovarian involvement, peritoneal cytology and histological type (papillary serous and clear cell carcinomas tend to behave more aggressively) (standard). A number of other prognostic factors may be considered: involvement of para-aortic nodes, initial CA125, hormone receptors, ploidy, growth factors (option). The use of FACS (fluorescent activation cytology scanning) is not currently recommended outside clinical research protocols. CA125 is correlated with prognosis but it is impossible to know if the assay provides any real benefit to the patient. It is of little value after treatment. The value of other markers is not yet clear. ## Surgical treatment of stage i and ii disease Surgery must always include the exploration, systematic inspection and palpation of the entire abdomen (standard) . All abnormal areas must be biopsied (standard). A sample must be taken for peritoneal cytology (standard, expert agreement). The hysterectomy must be at least total and extrafascial (standard, level of evidence B) with bilateral salpingo-oophorectomy (BSO) (standard, level of evidence B) . A modified radical hysterectomy (Piver type II) is undertaken for stage II cancers with macroscopic cervical lesions (standard) [fig_ref] Figure 4: Treatment of stage I or II disease and confirmed stage II disease [/fig_ref]. Lymphadenectomy can be undertaken by laparotomy or laparoscopy (option, level of evidence B). Hysterectomy can be by laparotomy, by the vaginal route or by laparoscopy (option, level of evidence B). An omentectomy is undertaken in the case of serous papillary forms (level of evidence B). When preoperative ## Cancer of the endometrium A Brémond 1 , A Bataillard 1,2 , L Thomas 3 , JL Achard 4 , B Fervers 1,2 , E Fondrinier 5 , J Lansac 6 , C Bailly 4 , S Hoffstetter 7 , JP Basuyau 8 , J d'Anjou 8 , P Descamps 9 , F Farsi 1 , JP Guastalla 1 , F Laffargue 10 , JF Rodier 11 , P Vincent 12 and J Pigneux 3 staging has failed to show macroscopic invasion of the cervix, a modified radical hysterectomy (Piver type II) gives no added benefit over a simple hysterectomy. ## Place of pelvic lymphadenectomy in stage i and ii disease Pelvic lymphadenectomy can be done by laparotomy or by laparoscopy (options). Pelvic lymphadenectomy (option) should not be undertaken when there are bad prognostic factors (i.e. grade 3 pathology, greater than 50% infiltration of myometrium, stage II disease) that will necessitate postoperative radiotherapy [fig_ref] Figure 4: Treatment of stage I or II disease and confirmed stage II disease [/fig_ref]. Pelvic lymphadenectomy is undertaken if the patient is of good performance status and if surgery is likely to be uncomplicated [fig_ref] Figure 4: Treatment of stage I or II disease and confirmed stage II disease [/fig_ref]. Lymphadenectomy must not be undertaken in a patient of poor performance status; the uncertainty as to any benefit on survival does not justify the operative risk. Pelvic lymphedenectomy is recommended by the International Federation of Obstetricians and Gynaecologists (FIGO) for the purposes of precise staging. Published data do not differentiate between the benefit of routine extended pelvic lymphadenectomy done in order to obtain optimum histopathological information, and a more selective approach whereby lymphadenectomy is only done in patients with a good prognosis. Randomized studies with comparable treatment in each sub-group are necessary to clarify this. ## Place of para-aortic lymphadenectomy in stage i and ii disease Para-aortic lymphadenectomy does not constitute standard therapy in cancer of the endometrium. Excision of enlarged nodes can be [fig_ref] Figure 4: Treatment of stage I or II disease and confirmed stage II disease [/fig_ref]. Selective lymphadenectomy of enlarged para-aortic nodes is recommended. Routine para-aortic nodal clearance is not recommended. Although the recommendations of the Gynaecological Oncology Group (GOG) argue in favour of routine para-aortic lymphadenectomy, primarily for the purpose of staging, the following factors need to be taken into consideration: q extent of the surgery q presence of altered patient anatomy (due to age, or multiple concomitant disorders) q rarity of isolated para-aortic invasion q high predictive value of the involvement of pelvic nodes by para-aortic involvement q correlation between nodal involvement and other main prognostic factors (invasion of the myometrium, ovaries, occult peritoneal disease, etc) q controversy over the efficacy of adjuvant therapies (with the possible exception of occult nodal invasion). The importance of these factors awaits confirmation from other studies. Experimental studies using injected coloured markers are underway to determine the pathways of uterine lymphatic drainage in order to facilitate selective lymphadenectomy. ## Surgery for stages iii and iv Clinical stage III and IV cancers of the endometrium carry a bad prognosis. If the performance status of the patient permits it, cytoreductive surgery remains the best way to improve overall survival. Radical surgery must be the intention (standard) [fig_ref] Figure 1: Evaluation of operability for cancer of the endometrium an option [/fig_ref]. Resection, as extensive as possible, followed by radiotherapy, or sub-optimal surgery followed by irradiation are possibilities Standards · inspection and palpation of the peritoneum, nodes and the omentum · biopsy/excision of abnormal areas · cytology Confirmed stage I disease see Probable stage I or II or definite stage II see [fig_ref] Figure 4: Treatment of stage I or II disease and confirmed stage II disease [/fig_ref] Stage III see Stage IV see [fig_ref] Figure 1: Evaluation of operability for cancer of the endometrium an option [/fig_ref]. It is recommended that cytoreduction surgery be carried out as follows: paramedial approach, total hysterectomy with BSO, colpectomy extending to adjacent healthy tissue, excision of pelvic and para-aortic nodes that are macroscopically involved, excision of free omentum in the case of ovarian involvement and location by clips of unresectable macroscopically involved nodes [fig_ref] Figure 6: Treatment of stage III disease where radical surgery is impossible Standard anterior... [/fig_ref]. If the performance status of the patient is poor, a total hysterectomy plus BSO by an abdominal approach is preferable to treatment with radiotherapy alone. ## Surgical treatment of stage iv disease Cytoreduction surgery is undertaken with a paramedial approach, total hysterectomy plus BSO, gut resection (if this allows for complete resection or if it is necessary to avoid obstruction) and partial or total bladder resection with urinary diversion (standard). ## Radiotherapy ## Additional treatment for stage i disease after surgery For grade 1 and 2 stage IA tumours, follow-up alone is standard . Vaginal brachytherapy (option) can be undertaken for grade 3 stage IA disease, or for tumours localized adjacent to the cervix or involving the whole uterine cavity . For grade 1 and 2 stage IB tumours, the options are vaginal brachytherapy or follow-up alone . For grade 3, stage IB tumours and stage IC disease whatever the grade is or may be, there are two treatment options : external pelvic radiotherapy with or without a vaginal brachytherapy boost (level of evidence B) or vaginal brachytherapy (level of evidence C). Preoperative radiotherapy (either external or brachytherapy) is not recommended for stage I disease, as it cannot be planned according to specific histoprognostic factors of the tumour or to its exact extent and would therefore constitute overtreatment for some stage I tumours. ## Additional treatment for stage ii disease When stage II disease has been proven by positive endocervix or cervix biopsy, there are two options; external radiotherapy with brachytherapy or brachytherapy followed by surgery, or surgery, ## Post-operative pelvic radiotherapy± brachytherapy boost Options · abdomino-pelvic radiotherapy · extended postoperative radiotherapy (pelvic and para-aortic) ## Stage iiic, para-aortic nodes involved Standard extended postoperative radiotherapy (pelvic and para-aortic) ± brachytherapy ## Follow-up Stage III when radical surgery is not possible see [fig_ref] Figure 6: Treatment of stage III disease where radical surgery is impossible Standard anterior... [/fig_ref] yes no ## Figure 5 treatment of stage iii disease Stage III disease where radical surgery is impossible SURGERY Standard debulking surgery: · total hysterectomy with salpingo-oophorectomy · bowel resection if possible · partial or total bladder resection if possible Options · total hysterectomy + cervix ablation = radical hysterectomy · para-aortic nodal clearence ## Additional treatment standard there is no standard Options · postoperative external radiotherapy ± brachytherapy · therapeutic trial of hormone therapy or chemotherapy Follow-up Options · post-operative pelvic radiotherapy ± brachytherapy · para-aortic nodal clearance · clinical trial of hormone therapy or chemotherapy ## Stage iv ## Stage iva stage ivb Peritoneal disease? Management of metastatic disease Follow-up no yesTreatment of stage IV disease as primary treatment, followed by adjuvant radiotherapy given according to prognostic factors [fig_ref] Figure 1: Evaluation of operability for cancer of the endometrium an option [/fig_ref]. If involvement of the cervix is not confirmed, primary surgery is recommended. Postoperative vaginal brachytherapy is given for stage IIA tumours if the penetration of the myometrium is less than 50% or if the tumour is grade 1 or 2 (standard) [fig_ref] Figure 4: Treatment of stage I or II disease and confirmed stage II disease [/fig_ref]. When the myometrial penetration is more than 50% or for grade 3 disease, external radiotherapy with a brachytherapy boost has to be undertaken routinely (standard) [fig_ref] Figure 4: Treatment of stage I or II disease and confirmed stage II disease [/fig_ref]. After primary surgery for stage IIB disease, postoperative external pelvic radiotherapy with a brachytherapy boost must routinely be undertaken (standard) [fig_ref] Figure 4: Treatment of stage I or II disease and confirmed stage II disease [/fig_ref]. ## Additional treatment for stage iii disease For stage IIIA disease involving the ovaries only or with positive peritoneal cytology only, either external pelvic radiotherapy or abdomino-pelvic radiotherapy is advisable (option) . For stage IIIA tumours involving several extrauterine sites, standard treatment is abdomino-pelvic radiotherapy (standard), with additional medical treatment in certain patients (option). For stage IIIB tumours, postoperative external radiotherapy with brachytherapy (if possible) should be undertaken (standard) . For stage IIIC tumours, (involvement of pelvic nodes), standard treatment is external pelvic radiotherapy followed by a brachytherapy boost (standard) . Extended-field radiotherapy to para-aortic nodes is an option. If there are extra-uterine sites involved abdomino-pelvic radiotherapy is recommended (option). For stage IIIC tumours involving para-aortic nodes, extended external radiotherapy including pelvic and para-aortic nodes with or without brachytherapy is recommended . ## Treatment of inoperable disease Standard treatment for inoperable stage I and II disease is external radiotherapy and brachytherapy (standard) [fig_ref] Figure 8: Treatment of inoperable disease [/fig_ref]. There are three possible options, radiotherapy alone, brachytherapy alone for stage I, or radiotherapy plus medical treatment (options). For patients with inoperable stage III or IV disease, treatment is often symptomatic, combining palliative external radiotherapy with medical treatment [fig_ref] Figure 8: Treatment of inoperable disease [/fig_ref]. ## Complications of radiotherapy Late complications of external radiotherapy are most commonly gastrointestinal. Their frequency is correlated with the dose delivered to critical organs. The complications of postoperative brachytherapy include rectal injury and vaginal stenosis. These complications are closely linked to the dose delivered and to the length of vagina irradiated. If radiotherapy is the only treatment, both external radiotherapy and brachytherapy must be carefully planned to give good local control with the minimum of complications. ## Adjuvant hormone therapy There is no evidence to support the use of adjuvant hormone therapy (level of evidence A) Adjuvant hormonal therapy (option) should only be given within the context of a therapeutic trial (standard). ## Chemotherapy in cancer of the endometrium Chemotherapy can be used for palliation (option). Doxorubicin and cisplatin are the drugs most commonly used. New Drugs are in the process of evaluation (option). The role of chemotherapy in metastatic cancer of the endometrium is limited in that the rate of response is less than 50%. Any benefit with respect to survival or quality of life has yet to be determined. No randomized study has compared chemotherapy with best supportive care. ## Adjuvant chemotherapy No study has shown a benefit from adjuvant chemotherapy in cancer of the endometrium. Few randomized trials have been published; some have included only a small number of patients, others have not given final results. The inclusion criteria for trial entry are variable, making it difficult to compare results. There are prospective uncontrolled studies, but the small number of patients and the absence of randomization prevents any definitive conclusions to be made as to the efficacy of adjuvant chemotherapy. Adjuvant chemotherapy should be given within therapeutic trials (option). ## Follow-up In the absence of specific symptoms or signs, follow-up is based on general and gynaecological examination (standard). The ideal timing of follow-up examinations has not been formally established; once every 6 months for the first 3 years then yearly is sufficient (standard). All patients presenting with symptoms Options · external radiotherapy and brachytherapy · external radiotherapy · external radiotherapy and hormone therapy · therapeutic trial of hormone therapy and chemotherapy Follow-up should have a full work-up (standard). There is no indication to carry out supplementary examinations looking for relapse or metastases in the absence of clinical signs. The CA125 assay is one examination which enables early diagnosis of recurrence, but this has no proven benefit with respect to prognosis and cannot be recommended as routine. It has not been demonstrated that hormonal replacement therapy in women of low risk with difficult menopausal symptoms increases the risk of recurrence or of metastases (option). Prospective studies are necessary before hormone replacement therapy can be recommended for women previously treated for carcinoma of the endometrium. [fig] Figure 1: Evaluation of operability for cancer of the endometrium an option. Para-aortic lymphadenectomy by laparotomy or laparoscopy (for those teams trained in this technique) can be undertaken (option) [/fig] [fig] Figure 2, Figure 3: Management of operable disease: surgical staging Standard hysterectomy with bilateral oophorectomy Option pelvic lymphadenectomy Postoperative staging according to FIGO, determination of histoprognostic factors ADDITIONAL TREATMENT STAGE IA Standard follow-up Option vaginal brachytherapy for grades 3 tumours, or extended to the whole uterine cavity or disease localized near the cervix STAGE IB grade 1 or 2 Standard there is no standard Options · vaginal brachytherapy · follow-up STAGE IB grade 3, STAGE IC Standard there is no standard Options · pelvic radiotherapy ± brachytherapy boost · vaginal brachytherapy Follow-up Confirmed stage I disease Treatment of stage I disease confirmed by surgical staging [/fig] [fig] Figure 4: Treatment of stage I or II disease and confirmed stage II disease (options) ( [/fig] [fig] Figure 6: Treatment of stage III disease where radical surgery is impossible Standard anterior or posterior pelvectomy depending on location with pelvic clearance [/fig] [fig] Figure 8: Treatment of inoperable disease [/fig]	None	https://europepmc.org/articles/pmc2408833?pdf=render	1Centre Leon Berard, Lyon; 2FNCLCC, Paris; 3Institut Bergonie, Bordeaux; 4Centre Jean Perrin, Clermont-Ferrand; 5Centre Paul Papin, Angers; 6CHU Bretonneau, Tours; 7Centre Alexis Vautrin, Nancy; 8Centre Henri Becquerel, Rouen; 9CHU, Angers; 10CHU, Hopital Arnaud de Villeneuve, Montpellier; 11Centre Paul Strauss, Strasbourg; 12Clinique Sainte-Catherine, Avignon, France British Journal of Cancer (2001) 84(Supplement 2), 31–36 © 2001 FNCLCC doi: 10.1054/ bjoc.2001.1760, available online at http://www.idealibrary.com on
6bd9567f34291fc517b29e3c84083ed2219e83be	pubmed	Recommendations on vaccination for Asian small animal practitioners: a report of the WSAVA Vaccination Guidelines Group	Recommendations on vaccination for Asian small animal practitioners: a report of the WSAVA Vaccination Guidelines Group EXECUTIVE SUMMARYIn 2012 and 2013, the World Small Animal Veterinary Association (WSAVA) Vaccination Guidelines Group (VGG) undertook fact-finding visits to several Asian countries, with a view to developing advice for small companion animal practitioners in Asia related to the administration of vaccines to dogs and cats. The VGG met with numerous first opinion practitioners, small animal association leaders, academic veterinaria ns, government regulators and industry representatives and gathered further information from a survey of almost 700 veterinarians in India, China, Japan and Thailand.Although there were substantial differences in the nature and magnitude of the challenges faced by veterinarians in each country, and also differences in the resources available to meet those challenges, overall, the VGG identified insufficient undergraduate and postgraduate training in small companion animal microbiology, immunology and vaccinology. In most of the countries, there has been little academic research into small animal infectious diseases. This, coupled with insufficient laboratory diagnostic support, has limited the growth of knowledge concerning the prevalence and circulating strains of key infectious agents in most of the countries visited.Asian practitioners continue to recognise clinical infections that are now considered uncommon or rare in western countries. In particular, canine rabies virus infection poses a continuing threat to animal and human health in this region. Both nationally manufactured and international dog and cat vaccines are variably available in the Asian countries, but the product ranges are small and dominated by multicomponent vaccines with a licensed duration of immunity (DOI) of only 1 year, or no description of DOI.Asian practitioners are largely unaware of current global trends in small animal vaccinology or of the WSAVA vaccination guidelines. Consequently, most practitioners continue to deliver annual revaccination with both core and non-core vaccines to adult animals, with little understanding that "herd immunity" is more important than frequent revaccination of individual animals within the population.In this paper, the VGG presents the findings of this project and makes key recommendations for the Asian countries. The VGG recommends that(1)Asian veterinary schools review and increase as ttp://www.bsava.com/ M. J. Day et al.countries) and makes a series of recommendations for future actions that might benefit the profession, pet owners and dogs and cats in these countries.METHODOLOGYThe membership of the VGG was revised for the duration of the Asian project. Core members of the committee (M. J. Day and R. D. Schultz) were joined by experts with first-hand experience of the Asia-Pacific region (H. Tsujimoto, R. Squires and U. Karkare). The principal aim of the project was to gather as much information concerning small companion animal practice, infectious disease and vaccination as possible, to form a firm basis for the recommendations to be made subsequently. To that end, in 2012 to 2013, the VGG undertook a series of fact-finding visits to Japan (Tokyo and Osaka), India (Delhi and Mumbai), China (Beijing and Shanghai) and Thailand (Bangkok). Each of these visits was similarly structured and involved formal discussions with groups including (1) first opinion veterinary practitioners; (2) representatives of small animal veterinary associations and veterinary licensing boards; (3) veterinary academics teaching and conducting research in microbiology, immunology and companion animal medicine and the Deans of several veterinary needed the amount of instruction in small animal vaccinology within their undergraduate curriculum and increase the availability of pertinent postgraduate education for practitioners; (2) national small animal veterinary associations, industry veterinarians and academic experts work together to improve the scientific evidence base concerning small animal infectious diseases and vaccination in their countries; (3) national small animal veterinary associations take leadership in providing advice to practitioners based on improved local knowledge and global vaccination guidelines; (4) licensing authorities use this enhanced evidence base to inform and support the registration of improved vaccine product ranges for use in their countries, ideally with DOI for core vaccines similar or equal to those of equivalent products available in western countries (i.e. 3 or 4 years).The VGG also endorses the efforts made by Asian governments, non-governmental organisations and veterinary practitioners in working towards the goal of global elimination of canine rabies virus infection. In this paper, the VGG offers both a current pragmatic and future aspirational approach to small animal vaccination in Asia. As part of this project, the VGG delivered continuing education to over 800 Asian practitioners at seven events in four countries. Accompanying this document is a list of 80 frequently asked questions (with answers) that arose during these discussions. The VGG believes that this information will be of particular value to Asian veterinarians as they move towards implementing global trends in small companion animal vaccinology. # Introduction The World Small Animal Veterinary Association (WSAVA) Vaccination Guidelines Group (VGG) was established in 2004 with the task of producing globally applicable advice for small companion animal veterinary practitioners on best practice for vaccination of pet dogs and cats. The VGG first released vaccination guidelines for veterinarians in 2007 [bib_ref] Guidelines for the vaccination of dogs and cats, Day [/bib_ref] and these were updated in 2010 [bib_ref] to vaccine-preventable infectious diseases of dogs and cats that was considered to..., Day [/bib_ref]. The 2010 revision was accompanied by a separate document providing information on vaccination for the owners and breeders of dogs and cats and by a series of infectious disease "fact sheets" designed to be used by veterinarians during an annual health check consultation (http:// www.wsava.org/educational/vaccination-guidelines-group). In 2012, the VGG began a new 2-year project that focussed on the vaccination requirements of small companion animals in Asia. The project, which was completed in late 2013, was born of the recognition that there are many unique political, educational and scientific challenges in the Asian countries that may not have been addressed specifically by the previous documents produced by the VGG. The present paper represents the final outcome from this Asian study. It summarises the key challenges faced by small companion animal veterinary practitioners in those parts of Asia studied (many of which may be extrapolated to other Asian Recommendations on vaccination for Asian small animal practitioners animal infectious disease, medicine and surgery. In India and China, veterinary schools are charged with providing practitioners to service the production animal industry and public health. Very little tuition related to small companion animal disease is provided and few academic staff have strong interest or expertise in small animal clinical studies. Therefore, practitioners working in this sector have largely gained their knowledge via postgraduate education. With the exception of some individuals who have worked abroad in other Asian countries or further afield, this postgraduate knowledge is largely gained from CE events provided by the veterinary associations. In Japan and Thailand, there is significantly greater development of small companion animal curricula, supported by well-equipped teaching hospitals and designated academic staff; however, even in these countries, there are relatively few veterinary clinical specialists holding North American or European board certification, and the Asian Board of Veterinary Specialties, and associated speciality colleges, has only been established relatively recently. It was also notable that academics in the Japanese and Thai schools highlighted that there was less than optimal teaching of core clinical practice skills related to the client consultation and the delivery of vaccinations within that setting. ## Small animal infectious disease in asia In the four countries visited, some common themes emerged concerning small companion animal infectious diseases. With the exception of canine rabies (which should be notified to the OIE, although it is widely recognised that gross under-reporting occurs), there is little or no formal surveillance for small companion animal infectious diseases conducted by government, industry or academia. With some notable exceptions, particularly in Japan, there are very few academic staff who conduct research or publish in the area of small companion animal infectious diseases or vaccinology. This also means that practitioners in these countries have insufficient access to research-led diagnostic laboratories that might help confirm diagnoses of infectious diseases in challenging, individual patients. Private diagnostic laboratories are also relatively uncommon in some countries; for example, an international group has only recently established the first veterinary diagnostic laboratory in Shanghai. In India, there are private laboratories only in Delhi and Mumbai. Many practitioners therefore rely on in-practice diagnostic test kits, often manufactured in Asia, for detection of infectious agent antigen or antibody. The VGG identified few peer-reviewed publications dealing with small companion animal infectious diseases and vaccinology that originated from India, China and Thailand. Some key manuscripts, brought to the attention of the VGG, are given as Appendix 3. This situation, which is particularly acute in India and China, relates largely to two factors: (1) academics are not encouraged or supported to investigate diseases of small companion animals within institutions that have a production animal focus and (2) there are virtually no sources of research funding that might permit the investigation of small companion animal diseases. In that respect, the data provided by the VGG survey questionnaire are particularly valuable. Although there are doubtless flaws in such questionnaire-derived data, the collective experience of schools; (4) government officials responsible for the assessment and licensing of small companion animal vaccines; and (5) representatives of international and national vaccine manufacturers and distributors. Given the importance of canine rabies in Asia, the VGG also met with the Deputy Director of the International Organisation for Animal Health (OIE) in the Asia-Pacific region, the Chairman of the Animal Welfare Board of India, and the founder of a major non-governmental organisation undertaking a rabies control programme in Sri Lanka (the Blue Paw Trust). The formal meetings were supplemented with site visits to 12 small animal practices (of a range of size and standards) in India and China. Outwith these committee visits, during 2013, the Chair of the VGG (M. J. Day) also discussed vaccination policy with the small animal veterinary association of South Korea and spoke with practitioners during visits to Hong Kong, Indonesia and Malaysia. In order to expand the information gained from these face-toface meetings, the VGG developed a questionnaire for distribution among first opinion practitioners in the various countries (Appendix 1). In each country surveyed, the questionnaire was translated, administered anonymously and the responses analysed and summarised (in English) by members of local small animal veterinary associations. Through these surveys, the VGG gathered information about (1) the responding practitioners, (2) veterinary practices and their diagnostic laboratory access, (3) canine and feline infectious diseases seen in the practices, and (4) canine and feline vaccines and vaccination protocols used in the practices. Responses to the surveys were excellent with data from 113 practitioners in Japan, 144 practitioners in India, 150 practitioners in China and 267 practitioners in Thailand. The questionnaire was also provided to small animal veterinary associations in Sri Lanka, Malaysia, Indonesia and Vietnam but no responses have been received to date. One of the specific aims of the project was to start to deliver continuing education (CE) in small companion animal vaccinology to Asian practitioners. Therefore, at each location visited, VGG members provided a half-day of CE consisting of a series of lectures accompanied by written (and translated) notes. At each event, the results of the local questionnaire survey were presented by a representative of a local practitioner association. Over the course of the project, these events gave the VGG direct contact with over 800 Asian practitioners, with attendances of 370 in Japan, 180 in India, 180 in China and 80 in Thailand. During the active discussions that formed part of each meeting, a number of important "frequently asked questions" emerged and these (with answers) are given as an appendix (Appendix 2) to this document. ## Current situation in asia Veterinary education in Asia Discussions with Deans, academic teachers and researchers from a total of 14 veterinary schools in the four countries revealed substantial differences between national curricula, in particular with respect to the inclusion of teaching related to small companion in small companion animal vaccination practice. In all of the Asian countries visited, most practitioners continue to adhere to an annual revaccination programme in which all core and noncore components are administered, often with multi-component products containing numerous antigens. In part, this is reinforced by the erroneous belief that in areas of "high infectious disease pressure", individual animals may be better protected by more frequent administration of vaccines. Although practitioners understand the concept of "herd immunity" in the context of mass vaccination campaigns for the control of canine rabies, there is little sense that herd immunity applies also to other key infectious diseases. Together with insufficient education in vaccinology (both at the university and CE levels) and limited access to translated versions of WSAVA and other pertinent guidelines, there are other barriers that currently impede progress with respect to adoption of modern vaccination practices, as has occurred in many countries. The first of these relates to the availability of vaccines with a licensed duration of immunity (DOI) of more than 1 year and the availability of product ranges that permit separate administration of core vaccines (no more frequently than every 3 years) and non-core vaccines (annually where a risk-benefit analysis deems that they are essential for the individual animal). In most Asian countries, vaccines are supplied by the major international companies and by national manufacturers. Most of the core vaccines produced by national manufacturers carry a 1-year licensed DOI or lack a definitive description of DOI, as do the majority of international vaccines, despite the fact that the same international products in many other countries have a 3-or 4-year licensed DOI. The second major problem is that these issues are reinforced by the inflexibility of the national vaccine licensing authorities. In some countries, there appears to be a "protectionist" almost 700 first opinion practitioners provides a useful overview of the perceived occurrence of key infectious diseases in dogs and cats in these four countries [fig_ref] Table 1: Overview of vaccine-preventable canine infectious diseases seen in veterinary practice [/fig_ref]. Practitioners in these countries continue to recognise small companion animal infectious diseases, many of which are now uncommon or rare in western countries. The control of canine rabies is a major issue faced by small companion animal practitioners in many Asian countries. The disease has been eliminated in Japan and is rare in Thailand, but is still highly prevalent in India and, to a lesser extent, in China. There is a minimum estimate of 20,000 human deaths from rabies each year in India and the prevalence of disease relates to the challenges of controlling and vaccinating an estimated population of 25 million free-roaming dogs in that country. The work of numerous NGOs working in various Asian countries has clearly shown that disease can be controlled where at least 70% of the free-roaming dog population can be vaccinated, but this target has only been achieved in selected cities and regions. The veterinary practitioners met by the VGG in the various countries are all highly committed to the goal of global elimination of canine rabies virus infection and many of them are actively engaged in pro-bono vaccination within their own practice areas. ## Vaccines and vaccination practice in asia The small animal veterinary associations in the Asian countries visited, as members of WSAVA, were aware of the WSAVA vaccination guidelines and had discussed these in committee; however, the recommendations had not been actively promoted among association memberships. In Japan and Thailand, academic teachers were also well informed about the guidelines and some had started to include the WSAVA recommendations in their teaching. However, most first opinion practitioners in India and China were unaware of the global trends for change The VGG believes that veterinary schools, or in some Asian countries those responsible for the content of a national veterinary curriculum, should consider the inclusion of increased curricular content in small animal infectious diseases, basic immunology and vaccinology. The inclusion or enhancement of teaching related to client communication skills and companion animal practice management should also be considered. Veterinary students should be taught practical vaccination approaches founded in the principles that underpin the WSAVA vaccination guidelines. The VGG encourages the national small animal veterinary associations to promote the principles of the WSAVA vaccination guidelines to their membership. National associations should form their own expert committees to evaluate the WSAVA guidelines and use them as a basis to formulate national recommendations that account for differences in the field situation in each country. This process was widely adopted by other countries after the release of the 2007 WSAVA vaccination guidelines and reported in the 2010 document [bib_ref] to vaccine-preventable infectious diseases of dogs and cats that was considered to..., Day [/bib_ref]. The VGG recommends that, wherever possible, postgraduate education in small animal vaccinology should be made available to small animal practitioners in the Asian countries. The small animal associations should lead in this area in collaboration with industry veterinarians who might be encouraged to support financially the development of such CE. ## Research Academic veterinary microbiologists and immunologists in the Asian countries should be encouraged to work together with industry and practitioner associations to coordinate the generation of national data to provide fundamental knowledge about the prevalence of key infectious agents in the Asian countries. Such knowledge is currently not available and is often requisite for the introduction of vaccines into a country. In the specific case of leptospirosis, these groups should work together to determine the circulating serovars that are relevant in each country, in order to inform future vaccine development. Furthermore, collaborative research should be conducted that provides proof to veterinarians and governmental regulators as to the efficacy of international modified live virus (MLV) core vaccines when used less frequently than annually (e.g. every 3 or 4 years). approach whereby nationally produced products are permitted but the equivalent international vaccines are not allowed to be imported. The international suppliers have challenges in bringing their products to these countries, where licensing authorities often demand a new and country-specific data package, including epidemiological evidence that a particular infectious disease exists and is of significant concern in the country. Generating such data is difficult in the absence of an appropriate research infrastructure (as discussed earlier). This situation is exemplified by the fact that there are currently no licensed feline vaccines available in India. This has necessitated individual practitioners or distributors sourcing foreign vaccine and importing it into the country. Similarly, in China, there is only one international feline core vaccine combination available on the market. There is also reluctance by licensing authorities to accept that an international vaccine with licensed 3-year DOI in most countries should be used triennially in the local situation. This situation is particularly frustrating with respect to canine rabies vaccines. In many Asian countries, there is a legal requirement for annual rabies vaccination of dogs (but not cats) and this is sometimes linked to the registration of dogs. In a situation where a nationally produced vaccine with a 1-year DOI is the only product available, this might be understandable; however, it is difficult to accept that international products, successfully used in triennial programmes in many other countries, must be administered annually to owned pet animals purely because of legal requirements. A further issue, identified by the VGG during discussions and practice visits, relates to the concept of "vaccine husbandry" in some Asian countries. It is our belief that "vaccine failure" due to inappropriate storage or administration of products in the practice is common in some Asian countries and that this again reflects a lack of fundamental education in this area. In some countries, vaccines are transported long distances from the point of manufacture or importation to the veterinary practice. Most practitioners are well aware of the concept of the "cold chain". However, practitioners may be too quick to blame a breakdown in the cold chain before delivery to the practice for vaccine failure and do not necessarily appreciate the monitoring measures that are put in place by the suppliers of international vaccines. The VGG has identified a number of practices related to vaccine storage and usage by practitioners, which have been highlighted in simple guidelines for correct vaccine husbandry . . Vaccine husbandry: key points for veterinary practitioners - Vaccines (and particularly adjuvanted vaccines) have an optimum storage temperature that is usually between 2 and 8°C (domestic refrigerators should be maintained at 4ºC). These products should not be frozen or positioned adjacent to the freezer compartment of the refrigerator, and refrigerator temperature should be monitored regularly. Vaccines transported into the field should also be subject to continuation of the "cold chain". - Freeze-dried vaccines should be reconstituted immediately before use with appropriate diluent or liquid vaccine given concurrently (as per the manufacturer's recommendations). It is bad practice and contraindicated to make up the vaccines anticipated to be used during the day first thing in the morning. Some vaccine components (e.g. CDV, FHV-1) are particularly labile in this regard and so these vaccines may not induce adequate immunity if not reconstituted just before use. - Vaccines should only be mixed together in the same syringe if this is specified as acceptable in the manufacturer's datasheets. - Syringes and needles for vaccines should not be reutilised. - Vaccine injection sites should not be sterilised with alcohol or other disinfectant as this may inactivate infectious (MLV) vaccines. - Vaccines should be "in date" and precise details of batch numbers, components and site of injection should be noted in the animal's medical record. widely distributed to practitioners and taught within veterinary undergraduate curricula . An aspirational vaccination protocol for Asian practitioners Veterinarians in Asian countries should be encouraged to implement the basic fundamentals of modern companion animal vaccinology as presented in the WSAVA vaccination guidelines [bib_ref] to vaccine-preventable infectious diseases of dogs and cats that was considered to..., Day [/bib_ref] [fig_ref] Table 4: An aspirational vaccination programme for Asian practitioners [/fig_ref]. In particular, practitioners should be educated in understanding the concept of core versus noncore vaccines. Core vaccines are those that every dog or cat must receive as they protect the animal from prevalent diseases that may be lethal or induce significant morbidity. Non-core vaccines are those that might be administered to individual animals whose geographical location or lifestyle places them at risk of contracting those particular infections. Non-core vaccines are not required by every animal and should not be used where there is no evidence that the related disease exists in a country. The VGG also describes some vaccines as not recommended (where there is judged to be insufficient scientific evidence to justify their use). For individual-owned pet animals in a domestic environment, the current WSAVA vaccination guidelines should be applied when quality-assured MLV core vaccines are used in a practice. The VGG is unable to comment on whether nationally produced vaccines confer equivalent protection to those available internationally because of a lack of published, peerreviewed data. Increasing the frequency of vaccination does not provide greater protection to an individual animal and may increase the risk of an adverse reaction. In areas of high infectious disease pressure, it is much more important to ensure that as many of the target population as possible are vaccinated (i.e. increase herd immunity) than to increase the frequency of vaccinations given The importance of such research, particularly where it has a One Health dimension (i.e. for canine rabies or leptospirosis), should be recognised and suitably rewarded by academic institutions. Academics who choose to investigate small companion animal infectious diseases should not be regarded as performing research that is less significant than that related to production animal science. ## Vaccine supply The VGG suggests that veterinarians, animal owners and animals in Asian countries should be able to benefit from availability of companion animal vaccines produced by major global manufacturers that have been proven to be safe and efficacious. Restrictive practices by governments, which favour national producers or require the generation of national disease prevalence data, are unlikely to improve the welfare of pets. Industry should be encouraged to increase the range of products they market within the Asian countries to enable practitioners to develop triennial core/annual non-core programmes in accordance with WSAVA and other international guidelines. This would necessitate the introduction of vaccines with fewer components and separate core and non-core vaccines, as are available in many other countries. Where these international products carry a 3-or 4-year licensed DOI in other countries, industry should make every effort to work with local regulatory authorities to prove the efficacy of their products and to update the vaccine claims and datasheets in the Asian countries. ## Vaccine husbandry The VGG recommends that small companion animal practitioners in the Asian countries be educated in the fundamental aspects of storage and use of veterinary vaccines. To that end, we have produced a list of key requirements that we hope will be Start at 8 to 9 weeks of age with first vaccine; give a second vaccine 3 to 4 weeks later with a third vaccine to be given at 16 weeks of age or older A booster vaccine should be given 12 months later or at 12 months of age Revaccination with core, quality-assured MLV vaccines should be no more frequent than every 3 years. Serology might be used to monitor protective immunity (for CDV, CAV, CPV and FPV) and aid decision making on revaccination intervals The single exception to this may be cats at high risk of contacting upper respiratory virus, in which these components may be given annually Quality-assured canine rabies vaccine for dogs or cats According to datasheet recommendations; one dose from 12 weeks of age. The VGG recommends that in high-risk areas a second dose may be given 4 weeks later Quality-assured canine rabies vaccines all carry a 3-year licensed DOI in most countries outside of Asia Non-core vaccines are generally given annually unless the datasheet specifically recommends otherwise (e.g. some quality-assured FeLV vaccines carry a longer DOI) Not recommended vaccines These include vaccines against coronavirus (canine or feline), feline immunodeficiency virus and Giardia The generic information in this table should be read in conjunction with the more detailed recommendations provided in the current WSAVA vaccination guidelines [bib_ref] to vaccine-preventable infectious diseases of dogs and cats that was considered to..., Day [/bib_ref]. Vaccination according to WSAVA guidelines is possible only where available product ranges separate core from non-core vaccine components. Note that these recommendations apply only to quality-assured vaccines, most of which are produced by large, international companies ## Recommendations on vaccination for asian small animal practitioners ## A pragmatic current vaccination protocol for asian practitioners The ability of small companion animal practitioners in Asia to adopt the current WSAVA vaccination guidelines is hampered by the issues of product availability, product licensed DOI and knowledge of infectious disease prevalence and risks. In many countries, there is a limited range of international multicomponent canine vaccines incorporating both core and noncore antigens, and where feline vaccines are available at all, the product range is similarly limited. Practitioners should begin to understand that while current datasheet recommendations for international MLV core vaccines recommend annual revaccination of adult animals, the same vaccines are given triennially in many other countries. Practitioners and their national associations should therefore continue to lobby industry and government regulators for changes that will bring recommendations concerning international products into line with current global standards and practices. [fig_ref] Table 5: A pragmatic vaccination programme for Asian practitioners in 2014 [/fig_ref] presents some pragmatic recommendations that may assist Asian practitioners make the transition from the current situation to the newer global trends in small animal vaccinology. Practitioners should opt for a quality-assured vaccine product range that enables them to deliver core components [i.e. canine distemper virus (CDV), canine adenovirus-2 (CAV-2) and canine parvovirus-2 (CPV-2) for dogs; feline parvovirus (FPV), feline to individual animals. With respect to international core MLV vaccines, key changes to current protocols would be introduction of a final puppy and kitten primary core vaccination at or after 16 weeks of age and revaccination of adult dogs and cats with MLV core vaccines no more frequently than every 3 years. The unnecessary annual use of international MLV core revaccination may be regarded as an inappropriate use of limited client financial resources that may be better applied to address other health issues in the pet. Even though the international products in most Asian countries do not carry datasheet recommendations for use in this way, it would be useful if local professional guidance permitted practitioners to use these products "off label" with informed client consent. This approach was used successfully for a number of years in other countries before datasheet recommendations were updated. As discussed earlier, the VGG hopes that in due course the international core MLV vaccines will have datasheet changes made in the Asian countries. The use of non-core vaccines in an individual animal should be based on available local knowledge of the prevalence of the pertinent infectious disease(s) and the risk of that individual animal's lifestyle placing it in contact with the pertinent infectious agent(s). These are currently difficult decisions for Asian practitioners, where there is such a small scientific evidence base related to the regional distribution of these infectious agents. Select a quality-assured MLV product that allows the minimum combination of core antigens to be given (CDV, CAV-2, CPV-2 for dogs; FPV, FHV-1, FCV for cats) Use an alternative diluent rather than reconstitute with a non-core vaccine if that non-core vaccine is not essential for that animal Start at 8 to 9 weeks of age with first vaccine; give a second vaccine 3 to 4 weeks later with a third vaccine to be given at 16 weeks of age or older A booster vaccine should be given 12 months later or at 12 months of age Discuss with clients the new global approach to core revaccination and obtain consent for administration of core quality-assured MLV vaccine no more often than every 3 years The single exception to this may be cats at very high risk of contacting upper respiratory virus. These cats might be vaccinated annually, but be aware that the FPV component of the vaccine combination is not actually required Canine rabies vaccine for dogs or cats ## Select a quality-assured product if available According to datasheet recommendations; one dose from 12 weeks of age. The VGG recommends that in high-risk areas a second dose may be given 4 weeks later Conform to local legal requirements for annual revaccination, but continue to actively lobby associations and governments to allow triennial revaccination using quality-assured products with a licensed 3-year DOI. Continue to lobby industry to register these products with a 3-year DOI in your country Non-core vaccines Examples for dogs: Leptospira, canine infectious respiratory disease complex (kennel cough) Examples for cats: feline leukaemia virus, Bordetella or Chlamydophila Discuss the individual animal's lifestyle and exposure risk with the client -is the vaccine really necessary for this animal? Choose a quality-assured product that contains just the desired antigen or the antigen in the least possible combination with other non-essential components Give according to the manufacturer's recommendations: generally two doses 2 to 4 weeks apart Non-core vaccines are generally given annually unless the datasheet specifically recommends otherwise Not recommended vaccines These include vaccines against coronavirus (canine or feline), feline immunodeficiency virus and Giardia Consider whether these vaccines are required for the individual animal and whether there is sufficient scientific evidence to support their use The generic information in this table should be read in conjunction with the more detailed recommendations provided in the current WSAVA vaccination guidelines [bib_ref] to vaccine-preventable infectious diseases of dogs and cats that was considered to..., Day [/bib_ref]. Note that these recommendations apply only to quality-assured vaccines, most of which are produced by large, international companies Journal of Small Animal Practice - Vol 56 - February 2015 - © 2014 WSAVA calicivirus (FCV) and feline herpesvirus-1 (FHV-1) for cats] in combination with the minimum number of non-core antigens. Such products might be administered, where professional guidelines permit and with client consent, no more often than every 3 years to adult animals where the added benefit of the noncore component is questionable (i.e. where the individual animal has minimal risk of coming into contact with that infectious agent). Where a non-core component (e.g. canine Leptospira) can be separated from a multi-component vaccine, and risk-benefit analysis suggests that the individual animal would benefit from that component, then that component must be given annually to adult animals. The VGG recognises that at the present time, such decisions can only be made by individual practitioners on the basis of the product ranges that they have available. In the 2007 WSAVA vaccination guidelines, the VGG recognised that in many parts of the world, veterinary medical health care of owned individual pet animals is restricted by financial factors. The VGG proposed that where a pet owner might only be able to ever afford a single vaccine for their animal, that this should be one dose of quality-assured MLV vaccine (and rabies vaccine) given at a time when that single dose might induce longterm protective immunity in the absence of maternally derived antibody (i.e. at 16 weeks of age or older). This rule-of-thumb is likely to have particular resonance in many of the Asian countries. ## Rabies control The VGG was encouraged to see plans for further mass vaccination campaigns for the control of canine rabies virus infection in endemic areas of Asia. The VGG hopes that governments and NGOs will continue to work towards the goal of global elimination of canine rabies virus infection by 2030 as proposed by a recent joint statement from the WSAVA and OIE (http:// www.wsava.org/sites/default/files/OIE-WSAVA%20Joint%20 Statement%20November%202013_final-1.pdf ). The VGG admires the dedication of practitioners in Asian countries to the goal of elimination of canine rabies virus infection. In some countries, practitioners devote 10 to 20% of their working hours to pro-bono vaccination of street dogs. This contribution should be encouraged and recognised by governments. The VGG differentiates between rabies vaccination of individual-owned and housed pet animals versus rabies vaccination delivered in the context of a mass vaccination campaign for freeroaming dogs. In the case of vaccination of individual pet animals, the current pragmatic approach is to adhere to legislation that requires annual revaccination of adult dogs, while accepting that if quality-assured international vaccines are used, they would protect that animal for a 3-year period. Again, practitioners and the national associations should be lobbying for changes that permit use of international rabies vaccines (that have a 3-year licensed DOI in other countries) to individual pet animals every 3 years. In the case of mass vaccination campaigns, the VGG accepts the logic of annual revaccination of populations within which long-term identification of individual vaccinated animals is impractical. In such free-roaming populations, there is often high turnover of the animals, with new puppies being born and older dogs dying during the period between vaccination campaigns. In order to achieve the requisite 70% vaccination coverage of these populations, annual revaccination should be maintained for such campaigns. Finally, the VGG was surprised to learn of the widespread use of rabies postexposure prophylaxis (PEP) in rabies-vaccinated dogs in some Asian countries. Instances of repeated administration of a complete five-vaccination PEP protocol within short periods of time following repeated bites from free-roaming dogs (in dogs that are already immune) may be considered unnecessary use of rabies vaccine that might better be used in vaccination of the free-roaming dog population. Application of the health check concept to Asian practice An important part of the global change in vaccination practice has been the move towards delivering vaccination as one part of an annual health check and promoting to clients that their annual veterinary visit is for a holistic assessment of the animal's health and wellbeing, rather than simply to receive a vaccine booster. The annual health check concept is rapidly gaining popularity in many countries of the world, where it has been proven to be advantageous for the business of veterinary practice. There is no reason why this concept should not be equally well received by the affluent urban clients of Asian veterinary practitioners and the VGG would encourage the national associations to provide education in, and endorsement for, the concept. Even in a less affluent rural community, the small animal practitioner should consider aspects of nutrition and ecto-and endoparasite control at the same time as deciding on a vaccination protocol for the individual pet animal. In some parts of Asia, it has been observed that a high proportion of pups and kittens carry high parasitic burdens and that it would be a sensible approach to deal with these before vaccination, in order to achieve the greatest possible protective immune response following administration of a vaccine. ## Acknowledgements The VGG gratefully acknowledges the time given by the large number of individuals who attended our meetings and contributed valuable data and local knowledge to the project. We are particularly grateful to the small animal associations and individuals who administered the questionnaire survey in the various countries, which was a demanding and time-consuming task. In particular, we thank Dr Louis Liu (Beijing Small Animal Veterinary Association), Dr Geoffrey Chen (Shanghai Small Animal Veterinary Association) and Dr Walasinee Moonarmart (Veterinary Practitioners Association of Thailand). The work of the VGG continues to be sponsored by MSD Animal Health. We are enormously grateful for the incredible logistical support provided by the national offices of MSD Animal Health in the four countries that we visited and for the oversight given by David Sutton (MSD Global) and Dr Raphael Zwijnenberg (MSD Asia-Pacific). ## Recommendations on vaccination for asian small animal practitioners ## Conflict of interest The VGG remains an independent committee of academic experts. Our meetings are not attended by our sponsors and our recommendations are made without the input of our sponsors. ## Recommendations on vaccination for asian small animal practitioners appendix 2: frequently asked questions Questions about vaccine products ## Are toxoplasma vaccines available in other countries? There are no commercial Toxoplasma vaccines available for use in cats anywhere in the world. ## Canine coronavirus infection is quite common in our area. we often get positive reactions with commercial test kits for coronavirus. what does the vgg think of the use of coronavirus vaccine? The VGG does not recommend the use of canine coronavirus vaccines as there is insufficient evidence that this vaccine is protective, or indeed that enteric coronavirus is a significant canine pathogen. Variant strains of this virus have been reported to cause disease in adult dogs and puppies in various parts of the world, but it is unclear that the available vaccines protect against these variants. The identification of coronavirus with a test kit does not necessarily mean it is the cause of disease. ## Is a monovalent vaccine better than a multi-valent vaccine? Vaccines with the fewest components possible enable practitioners to adhere to the WSAVA guidelines. Multi-component core MLV vaccines (e.g. for CDV, CAV-2 and CPV-2) are ideal for delivery of core vaccinations, but it is best to have individual vaccines for non-core antigens (e.g. Leptospira, canine infectious respiratory disease complex) so that these may be given only when risk-benefit analysis suggests that they will be of benefit. For Leptospira vaccines, multi-component products may provide the best protection if their formulation is based on scientific evidence that justifies the inclusion of multiple serovars in the vaccine. ## Will the number of different antigens in multi-valent vaccines adversely affect the efficacy of the vaccine? No. For a multi-valent vaccine to be licensed, the manufacturer must prove that each component of the vaccine can induce protective immunity, generally in challenge studies. ## Can you give all vaccinations at once to an adult dog presented with no previous history of vaccination? This is a similar question to that above. Yes, a dog should be able to respond to multiple antigens delivered simultaneously. However, you should never mix different vaccines in the same syringe unless specifically indicated by the datasheet. From first principles, it would be good practice to deliver the different vaccines to different anatomical sites so that different lymph nodes are involved in generating the adaptive immune response, but no studies have formally proven this. ## What are the quality differences between mlv vaccines and "genetic" vaccines? Genetic vaccines include virus vectored vaccines, genetically mutated (gene deleted) vaccines and naked DNA vaccines. These vaccines may theoretically be safer than certain MLV vaccines as there is no chance of "reversion to virulence". These vaccines are also designed to produce an optimum immune response. ## Can killed vaccines "break through" mda better than live? There is little evidence for this, but what is known is that some of the newer genetic vaccines appear to be able to generate immunity in the presence of MDA earlier than traditional MLV vaccines. ## Small breeds of dogs commonly suffer from adverse reactions. is it possible to reduce the dose of vaccine to avoid this? No. Vaccine doses are not calculated on a milligram per kilogram basis, as are drugs. The entire antigenic load is needed to stimulate immunity effectively. You should not split vaccine doses, nor give reduced volumes to small dogs. In the USA, a new product has been released that is designed for small dogs. This is formulated as a 0·5 mL dose, but contains much the same amount of antigen as does a conventional 1·0 mL vaccine. ## Why don't we have suitable combinations of core vaccines available to allow them to be used in accordance with the guidelines? Suitable products are available in some other countries. If you do not have them, then you and your national small animal veterinary association should lobby the manufacturers and government regulators to bring the suitable products to your marketplace. In many cases, industry would like to make new products available, but the block lies with the licensing authority. ## Why do we not have 3-year doi rabies vaccines? As above, this may be because the manufacturers have chosen not to bring you these products or because the licensing authority has not permitted their introduction of a 3-year labelling. In at least one Asian country, the only permitted rabies vaccine is a nationally produced product that only has a 1-year licensed DOI. ## Do canine core vaccines in asia have a doi of at least 7 years as stated by dr schultz? Many internationally marketed MLV vaccines that are quality assured have been independently tested by Dr Schultz, and shown to be protective, in a challenge study at 7 to 9 years (Schultz et al. 2010, Journal of Comparative Pathology, 142, S102-S108). The VGG does not know which of the nationally produced core vaccines may have similarly long DOI. ## A local 3-way leptospira vaccine is available in my country alongside the traditional bivalent products. which one should i use? If the local 3-way vaccine contains a combination of "relevant" Leptospira serovars that usefully extends the breadth of protection provided by vaccination under your local conditions, then it is likely to be more effective and preferable to a traditional bivalent product. ## Currently there are no bordetella vaccines available in japan. do the vgg think bordetella vaccines are important in japan? Vaccines against Bordetella bronchiseptica are non-core products. Bordetella is just one of numerous pathogens that can be involved in causing upper respiratory tract disease in dogs and cats. Bordetella bronchiseptica has been shown to be an important cause of canine respiratory disease in Japan, as in other countries, along with canine parainfluenza virus . Yes, the VGG suggests that vaccines against canine infectious respiratory disease could be very useful to Japanese practitioners and should be introduced. ## Some trivalent cat vaccines contain inactivated fpv and live fcv/fhv, can these still be used every 3 years? Yes, this is a core vaccine. Inactivated FPV will still provide protection for a minimum of 3 years. ## Is it better to use vaccines containing local strains rather than international vaccines? There is no evidence that international core vaccines are unable to provide good protection against CDV, CAV-1, CAV-2, CPV-2, FPV, FHV-1 and rabies virus, worldwide. In most instances, strain variation does not change the key protective antigens of the organism that are conserved between strains. In the case of Leptospira, inclusion of additional, locally important serovars or strains in a vaccine may lead to enhanced protection. ## A recent cpv outbreak in army dogs was shown to be caused by cpv-2c. there are recommendations that vaccines should contain the latest strains, what's the vgg view on this? Currently available international MLV vaccines contain CPV-2 (original strain), CPV-2a or CPV-2b. These vaccines are expected to confer substantial cross-protection against CPV-2c challenge, and indeed some have been shown to do so, shortly after vaccination. At present, there does not seem to be a pressing need to change the formulation of canine parvovirus vaccines. ## How do practices know that vaccines delivered to them have been stored correctly and that they are still potent? can vaccines be delivered with indicators to assure correct storage? We have asked this question to the manufacturers and suppliers of international vaccines during our Asian meetings and have been assured that there is continuation of the cold chain from importation to practice delivery. International manufacturers do utilise temperature indication systems during the bulk delivery stages. ## There is no national policy in india giving advice and recommendations on canine vaccination. when will we get a local policy? The WSAVA encourages all national small animal veterinary associations to develop national vaccination advice. This has already happened in many other countries. Some simply adopt and refer to the WSAVA guidelines, whereas others adapt the guidelines for the local situation. You should continue to lobby your national association to provide local guidance. ## How common is tetanus in dogs? should we vaccinate against it? In many parts of the world, tetanus is uncommon in dogs. There are no licensed vaccines for dogs, but in some areas deemed as being at high risk, veterinarians do use equine tetanus vaccine in dogs (off-label use). Given that tetanus is nowadays considerably more frequently observed than canine infectious hepatitis and canine distemper in many parts of the world, development of a canine tetanus vaccine may be justifiable and commercially viable. ## Does the vgg recommend which vaccine brand should be used? No. The VGG is an independent academic group that does not make product-specific recommendations. However, in the case of international vaccines, the VGG knows that all of these products have undergone rigorous assessment of quality, safety and efficacy that has permitted their licensing in many countries. The VGG does not recommend the use of some vaccines -but this is based on a lack of adequate scientific evidence (i.e. peerreviewed scientific literature) that the vaccine is necessary or efficacious. Recommendations are reviewed and adjusted as needed periodically. ## If one wants to use just the dhppi without the leptospira component of a vaccine, what should be used to reconstitute the dhppi? You should ask this question to the manufacturer or supplier of the particular vaccine, but a suitable diluent may be sterile normal saline or sterile water for injection. If not, the manufacturer should be able to provide you with the specific diluent required. ## What about the use of rabies vaccine in small mammals (e.g. rabbits and guinea pigs)? The VGG does not recommend rabies vaccination of these small mammals, except for ferrets. ## Should leptospira vaccine be used 6-monthly in high-risk areas? Yes, this is consistent with the VGG recommendations in the WSAVA guidelines. You should ideally have a good scientific evidence base for stating that your practice is in a high-risk area. ## What happens if a dog is bitten by a free-roaming dog after receiving the initial puppy rabies vaccine; should it receive pep? what if that dog receives pep and is then bitten again some weeks later, should it receive another course of pep? If the bitten puppy has been vaccinated properly, it should be protected against rabies. The VGG is aware that in India, PEP is used in this situation for the benefit of the puppy, and more importantly for the benefit of the human family. Repeated PEP is not justified. By that time the puppy will have received multiple vaccinations and further injections will provide no added benefit. ## Questions about vaccine delivery to puppies and kittens ## Is it ok to mix different manufacturer's products during the primary course? Core MLV vaccines from the different international suppliers are similar in composition and may be mixed during the primary course (e.g. if a puppy has an 8-to 9-week vaccine from one veterinarian and then moves to another veterinarian who uses a different product range). Manufacturers will not support this practice (and will advise against it) because they have not undertaken studies to prove compatibility of their products with those of other manufacturers. It may also be acceptable to use non-core vaccines from different manufacturers, with the exception of Leptospira vaccines where a first dose with a two-serovar product, and a second dose with a four-serovar product, would not induce immunity to the additional two serovars contained in the four-way vaccine. ## In a puppy that has received inoculations at 6 and 9 weeks with one vaccine brand, and is then presented to a practice that uses another vaccine brand at 6 months, what should be given? The second practice may give the international MLV core vaccine that they use routinely as described in the question above. If that puppy had not yet received a rabies vaccine, that should be given at 6 months as well (in a rabies endemic area). Remember that for puppies, some will not have responded to primary vaccination at either 6 or 9 weeks of age, and the VGG recommends a third vaccination at 16 weeks of age or greater. ## Often puppies or kittens are groomed before vaccination -is this ok? As long as the puppy or kitten is in good health and not overly stressed by the grooming procedure, there is no reason not to vaccinate after grooming. ## Can you give rabies and dhppi vaccine at the same time (concurrently)? Yes, but unless the vaccines have a specific concurrent use claim on the product label, then this may be considered "off-label" use. Ideally, the two vaccines used concurrently in this way should be given at different anatomical sites in order that vaccine antigens are carried to different lymph nodes in order to stimulate adaptive immunity at two distinct locations. ## Recommendations on vaccination for asian small animal practitioners ## Can one use rabies vaccine 1 week after dhppi? Yes, there is no problem in doing that. As discussed earlier, it would be sensible to inject this into a different location in order to stimulate immunity via a different lymph node. 30. If a puppy suckles for more than 1·5 months, do you need to start the vaccination protocol later? No. Remember that maternally derived antibody that interferes with puppy vaccination is only obtained from colostrum taken in during the first 24 to 48 hours of life. After that, entire antibody is not absorbed from the gastrointestinal tract. ## Why don't the vgg recommend rabies vaccination until after 12 weeks of age? This recommendation is consistent with the datasheets for the majority of international vaccines. ## Can we vaccinate puppies at less than 6 weeks of age? In general, no. Puppies at this age will have MDA that blocks the ability of MLV vaccines to prime the immune system. Moreover, vaccine datasheets do not support this practice and there may be safety issues with giving MLV vaccine to very young animals (i.e. <4 weeks of age). One exception is the use of intranasal vaccines against canine infectious respiratory disease. These can be used safely from a very young age. Check product datasheets. 33. There are some nationally manufactured rabies vaccines that are combined with DHPPi. Manufacturers recommend that these can be given from 8 weeks of age. How come these vaccine datasheets can say this? A datasheet recommendation should be based on proven safety and efficacy studies performed to the requirements of the licensing authority. One can only assume that such studies have been done and support this recommendation. If in doubt, inquire with the manufacturer or government authorities. ## 34. We have a core vaccine for puppies for which a final dose at 10 weeks is recommended. This seems contrary to the WSAVA guidelines. Such "early finish" vaccines were introduced in order to encourage the early socialisation of puppies, which is very important for their development. We believe that 25% of the puppies still have blocking levels of MDA (particularly against parvovirus) at 10 weeks of age (and 10% at 12 weeks of age) and so there is a risk that not all puppies will be fully protected until they receive a 12-month booster vaccine. The VGG recommends a final dose of puppy vaccine at 16 weeks of age or older. ## The 2010 wsava guidelines advise a 14-to 16-week final dose, but should this be 14, 15 or 16 weeks? We would recommend the final dose to be given at the 16-week end of this range and in the current document, we have used the phrase "at 16 weeks of age or older". For kittens, there are new studies that show persistence of MDA even beyond 16 weeks, and when we next revise the global WSAVA guidelines, we will consider this new evidence for kittens. ## In thailand, the legal requirement is that puppies be vaccinated against rabies at 2 months of age -is this correct immunologically? Most international canine rabies vaccines carry the recommendation for administration at 12 weeks of age, based on safety and efficacy studies. In this instance, the legal requirement would be in conflict with the datasheet recommendations if international vaccines are being used. Note that the WSAVA guidelines recommend a second vaccine be given (2 to 4 weeks later) in areas of high risk for rabies. ## If the pup has no mda, when should you start vaccination? In a practical setting, it would be difficult to prove that a pup had no MDA. This would necessitate knowing definitively that the pup did not take in colostrum. However, if this was known, then core vaccination may be given from 6 weeks of age. Certain MLV vaccines must not be given any earlier than 4 weeks of age as they may cause pathology in the pup. If this pup definitively had no MDA, it may respond adequately to a single dose of vaccine at 6 weeks of age; however, it may be pragmatic to give a second dose at 16 weeks of age. ## When can puppies go outside for proper socialisation? There is no doubt that ensuring early socialisation is an important part of responsible puppy ownership. Owners should be made aware of the risks -that not every puppy will be fully protected against lethal (core) diseases until after the 16-week vaccination (see Question 34). Owners should be advised about simple precautions; for example, only attending "puppy parties" where all of the dogs are vaccinated and attending such events on "clean territory" (e.g. not in the back room of the veterinary hospital). ## If the puppy sneezes after intranasal vaccination, is it necessary to vaccinate again? Sneezing, with loss of some of the vaccine, is commonly observed after the use of intranasal products. These vaccines have been designed to allow for partial loss of the product and so it should not be necessary to revaccinate, unless it is clear that none or very little of the product was delivered successfully. ## What do we do if the animal is presented late for vaccination? If this is a puppy, presented (for example) after 16 weeks of age, a single dose of international MLV core vaccine (CDV, CAV-2 and CPV-2) will be protective as will a single dose of rabies vaccine. Considering non-core vaccines, it is necessary to give two doses 2 to 4 weeks apart. If this is an adult dog, presented for revaccination (for example) at 4 years rather than 3 years since its last core vaccination, the same would apply for core vaccines and canine rabies. Any adult dog that does not receive annual Leptospira vaccination should be treated as a puppy and receive two injections 2 to 4 weeks apart and then an annual vaccine. Questions about vaccine delivery to adult animals ## Do you need to continue to vaccinate old dogs? For MLV core vaccines (CDV, CAV-2, CPV-2), current international recommendations are for revaccination of adult dogs no more frequently than every 3 years. Canine rabies vaccines should be given every 3 years where an international product is used (with a 3-year DOI) and that is consistent with local legal requirements. If non-core vaccines are chosen for use in an individual dog, they must be given at least annually. ## At what age can one stop vaccinating dogs? For core vaccines, the current recommendation is for lifelong revaccination no more frequently than every 3 years and if non-core vaccines are chosen for use, these are generally given annually. One can use serological testing in any adult dog to confirm protection and elect not to revaccinate that animal. Current advice is that serological assessment is performed every 3 years, but in dogs older than 10 years, this should be done annually. In many Asian countries, there is also a legal requirement to vaccinate (currently annually) against rabies. ## For an adult dog with no cdv antibody, what's the recommended vaccination protocol? An adult dog requires only one dose of international MLV core vaccine to generate a protective immune response. We would recommend vaccinating the dog and testing serologically 4 weeks later. An estimated 1 in every 5000 dogs may be a genetic non-responder to CDV and may never be able to respond to vaccination. ## What protocol is recommended for an unvaccinated adult dog? Core vaccination with a single dose of international MLV vaccine (CDV, CAV-2, CPV-2) plus rabies in endemic areas. Revaccination (or serological testing for CDV, CAV and CPV-2) no more frequently than every 3 years thereafter. Non-core vaccines should be selected based on a risk-benefit analysis for that individual animal. ## For an adult dog with an unknown leptospira vaccination history, what's the recommended vaccination protocol? is it still two doses 4 weeks apart as in puppies? Yes, this dog would require two doses of vaccine given 2 to 4 weeks apart and then annual revaccination thereafter. ## How is it best to vaccinate a pregnant bitch? is it best to give a booster vaccination before the pregnancy? Vaccines should not be given during pregnancy unless specifically indicated in the datasheet. The best approach is to ensure that breeding bitches are vaccinated (with core vaccines), but it is unnecessary to give additional core vaccines to breeding bitches immediately before pregnancy -their standard vaccination schedule (e.g. triennial core revaccination) will provide adequate protective immunity and colostral antibody for the puppies. ## If rabies vaccine is given multiple times during a period (6 months), is this safe? The international rabies vaccines are very safe, but there is no need to administer them to individual-owned pet dogs more frequently than every 3 years. The VGG is aware that in some Asian countries, the vaccine is used in a postexposure prophylaxis (PEP) protocol when a pet dog is bitten by a free-roaming dog. If the pet dog is vaccinated and already protected, this procedure should not be encouraged. ## What protocol is recommended for an unvaccinated adult cat? For an adult cat that has never been vaccinated, the VGG recommends core vaccination with two doses of international MLV vaccine (FPV, FCV, FHV-1) plus one dose of rabies vaccine in endemic areas. Revaccination (or serological testing for FPV) no more frequently than every 3 years thereafter. Noncore vaccines should be selected based on a risk-benefit analysis for that individual animal. ## A bitch that was initially vaccinated as a pup, but has not received booster vaccination since then was presented by the owners before breeding. should she be revaccinated? Yes. The bitch should receive one dose of international MLV core vaccine (CDV, CAV-2 and CPV-2) and in an endemic area also canine rabies vaccine. ## Questions about vaccine husbandry and general vaccination ## Is it ok to swab the vaccination site with spirit before vaccinating? No, alcohol or other disinfectant might inactivate modified live virus in core vaccines. ## Can you vaccinate and dose with anthelmintic at the same time? There is no reason not to do this. ## Should fiv-positive cats be vaccinated? It is suggested that FIV-positive cats may not be able to respond adequately to vaccination and may also be more susceptible to develop a vaccineinduced disease following MLV vaccination. The vaccination requirements of an FIV-positive cat should be considered carefully. Such animals would be best housed indoors away from other cats and not permitted outdoor access. If core vaccination is essential, then use of a killed rather than MLV core vaccine is recommended. ## Should a cat be vaccinated if it already has signs of upper respiratory disease? A cat with current clinical disease should not be vaccinated. Once it has recovered, the cat should have some natural immunity to FCV or FHV (or both if both agents were involved in causing the respiratory disease), but such immunity is never sterilising (even after vaccination). There is no indication NOT to vaccinate a cat that has recovered from a respiratory viral infection. A trivalent vaccine will protect against FPV and also against the respiratory virus (FHV-1 or FCV) that was not involved in causing the earlier respiratory disease. ## Should you vaccinate e. canis-infected dogs since these dogs can be immunosuppressed? There is no evidence that a dog with monocytic ehrlichiosis cannot respond adequately to vaccination or that protective antibody titres against core vaccine components diminish in E. canis-infected dogs. Ideally, the dog would be treated and any essential vaccination performed after the cessation of therapy. It may be a legal requirement to give rabies vaccine to such cases in any event. ## Should one vaccinate an animal that is diseased or stressed? No. This is contrary to good practice and the advice on most vaccine datasheets. ## How should dogs on medication for immune-mediated disease be vaccinated? Antineoplastic drugs, and some of the most potent drugs used to treat immune-mediated diseases, interfere with a dog's ability to respond immunologically to vaccination, but standard immunosuppressive doses of glucocorticoid have relatively little effect. Nevertheless, vaccines should not be administered to animals with significant disease and animals receiving high doses of glucocorticoid for immune-mediated disease fall into this category. Vaccination should be delayed until after the drugs have been tapered or stopped. Most dogs receiving such therapy will be adult animals that will already have acquired long-term immunological memory to core vaccine antigens and should be on a revaccination schedule of not more often than every 3 years for these core vaccines. ## Recommendations on vaccination for asian small animal practitioners ## Does vaccination at different subcutaneous sites have the same efficacy? This is an interesting question that has come about due to recommendations to vaccinate cats in locations other than the scruff of the neck in order to avoid the occurrence of a surgically challenging feline injection site sarcoma. In the USA, recommendations for vaccination of cats in the distal hindlimbs are made. The WSAVA vaccination guidelines propose vaccination into the skin of the lateral abdomen. In a recent pilot study, investigators vaccinated cats into the distal tail and actually addressed the question of efficacy by showing that such cats made protective serological responses to FPV and rabies virus . It has been suggested that further work is needed to ensure injection of heavily adjuvanted vaccines into the tails of cats is safe: it is feared that swelling in such a tight area may lead to development of "compartment syndrome" in some cats. However, this was not noted in the pilot study. 58. Power cuts are not uncommon in parts of our country and they can last for 2 to 3 days. What should one do as regards any vaccine in the fridge at the time -is it OK to use? MLV vaccine that has not been stored at appropriate temperature for 2 to 3 days should not be used. Some of the components of these vaccines (e.g. CDV) are temperature sensitive and there may have been inactivation of the virus. Questions about the use of serological testing ## How long after cpv-2/cdv vaccination should you wait before measuring protective antibody concentrations using in-clinic tests? This question is most relevant for puppies, because adult dogs are likely already to have serum antibodies present at the time of booster vaccination, regardless of how long an interval there has been since they were last vaccinated. If a puppy receives its final primary vaccine at 16 weeks of age, then it may be tested from 20 weeks of age onwards. Any antibody present at that stage cannot be of passive, maternal origin and therefore indicates that the puppy is actively protected. ## Why don't the vgg recommend that you do a rabies antibody test? For many Asian veterinarians, this question may be of little practical consequence, as regular rabies vaccination of dogs and cats is a legal requirement in many countries, irrespective of any titre results. Rabies antibody testing is only required in certain situations related to international pet travel. The international rabies vaccines are highly efficacious and it is generally considered that there is no need to demonstrate immunity post vaccination. ## Can we use antibody tests (cdv, cpv-2 and cav) to test the mda in order to decide the first vaccination time? Theoretically, this would be possible and years ago a "nomogram" was often used to estimate when pups might best respond to vaccination on the basis of the titre of antibody in the serum of the bitch. In practice, it would be very difficult and expensive to repeatedly sample and test young puppies in order to monitor the decline of MDA. ## What happens to the antibody titre over the 3-year period post vaccination? For CDV, CAV-2, CPV-2 and FPV, the antibody titre will be consistently present at similar titre. This has been shown in numerous field serological surveys of dogs last vaccinated up to 9 years previously and in experimental studies for dogs last vaccinated up to 14 years previously. For Leptospira, the titres will decline rapidly after vaccination and in any case are not well correlated with protection. Serum antibody titres are less relevant for FCV and FHV-1 where the most important type of immunity is mucosal and cell-mediated, respectively. ## 63. In an animal that has completed its puppy/kitten shots, is a higher antibody titre required to protect against heavy disease challenge? For CDV, CAV-2, CPV-2 and FPV, the answer is no. The presence of antibody (no matter what the titre) indicates that protective immunity and immunological memory is present in that animal. Giving more frequent vaccines to animals in an attempt to increase antibody titre is a pointless exercise. It is impossible to create "greater immunity" by attempting to increase an antibody titre. ## Can we test dogs as an alternative to annual vaccination? We are concerned about the advice to only boost every 3 years. Yes, certainly. There are now well-validated in-practice serological test kits that permit determination of the presence of protective serum antibody specific for CDV, CAV, CPV-2 and FPV. In other countries, these kits are used to confirm protection at 3-year intervals (instead of automatic revaccination for core diseases). You may perform serology annually, but if you collect and analyse the data that you generate within your practice, you will soon find that annual testing is not necessary. Questions about the annual health check ## In the annual health check, what tests/examinations should you do? The annual health check should focus on the basic physical examination (including body temperature, cardiac auscultation and palpation). An excellent history should be taken to understand the lifestyle and disease risks (e.g. travel, boarding, indoor versus outdoor exposure). The fundamentals of nutrition and parasite control should be discussed with the owners. ## Some owners may be reluctant to come back just for an annual health check. what advice can be provided to promote the health check concept in order to improve owner compliance? This is all a matter of education. Clients should realise that the health check examines all aspects of the health and wellbeing of their pet and may pick up the early stages of clinical problems. In terms of vaccination, the health check examination might include serology (every 3 years for core vaccine antigens) or the annual administration of non-core vaccine if such vaccines are required. ## The costs of an annual health check are far too high for my clients. The annual health check may be as simple as an excellent clinical history and physical examination -the costs for which are purely the professional time of the veterinarian. Fundamentally, the concept of an "annual health check" is a new way of delivering what most practitioners already offer as a "vaccination booster and physical examination". For more affluent clientele, the annual health check has proven a means of offering other veterinary services and increasing practice profitability. This is also an example of practicing better quality medicine and about redefining the veterinarian-client relationship. Questions about vaccine adverse effects 68. In case of a mild allergic reaction to a vaccine, can you use steroids to treat? Yes; reactions such as facial oedema and pruritus may be treated with anti-inflammatory (not immunosuppressive) doses of oral glucocorticoid (e.g. prednisolone) and/or with antihistamines. ## If an animal suffers an allergic reaction post vaccination, what should you do when the next vaccination is due? In this situation, there is a risk that revaccination will trigger the same allergic reaction. The answer to the question depends on the age of the dog and the stage of the vaccination programme, and the type of vaccine under consideration. For core vaccines, it is important that the animal receives one dose at 16 weeks or greater to induce protective immunity. An antihistamine or an anti-inflammatory dose of glucocorticoid may be administered to such animals in advance of vaccination, and they should be closely monitored immediately afterwards. Thereafter, such an animal might be serologically tested to demonstrate protective immunity rather than automatically revaccinated. If the reaction occurred in an adult dog, serological testing may be used instead of core revaccination. If the reaction is thought to have been triggered by a non-core vaccine, consideration should be given as to whether the animal really requires that vaccine in the future. ## Is there evidence that cutaneous vasculitis can be caused by vaccination? Yes, this is a very rare, but recognised, adverse reaction following vaccination, particularly rabies vaccination. ## What are adverse hypersensitivity reactions and how can these be differentiated clinically? The most common such reactions are facial oedema and cutaneous pruritus occurring within an hour (generally less) of vaccination. The temporal relationship suggests that the vaccine has triggered the reaction. ## Do we see signs of cutaneous allergic reactions in cats as in dogs? Yes. Cats may present with the same manifestations of type I hypersensitivity post vaccination as dogs (e.g. facial oedema and cutaneous pruritus). ## How do we know that a feline sarcoma was caused by a vaccine? how do we deal with this type of sarcoma? A feline injection site sarcoma (FISS) arises at an anatomical location into which injectable product has been delivered previously. It is suspected that a wide range of injectables, including vaccines, may potentially trigger these tumours. It is important to record the site of vaccination in cats in the medial record of the animal and the WSAVA guidelines give advice on suggested best locations for vaccinating cats. Unfortunately, these sarcomas are very aggressive. They infiltrate widely and around 20% may metastasise. They require significant surgical resection that is often best performed by a specialist. 74. Why are there more hypersensitivity cases caused by rabies vaccine than before? Why is this more common among toy poodle dogs? Hypersensitivity reactions may be caused by any type of vaccine, but killed adjuvanted products may be particularly associated with this type of reaction. We now know that a dominant antigen that causes these reactions is bovine serum albumin (BSA) that is incorporated into vaccines during their production. Manufacturers are now trying to reduce the concentration of BSA in animal vaccines. Such reactions are more common in many toy breeds, and in many countries, these breeds are now particularly popular. There is likely to be a genetic susceptibility, but this is poorly understood. ## Why do some dog breeding kennels continually have problems with dogs dying from cdv and cpv-2 infections? The most likely cause for this scenario is that the breeding stock is not adequately vaccinated. Outbreaks might occur among puppies that did not obtain sufficient MDA as the bitch was not effectively vaccinated. In contrast, where puppy vaccination is not performed according to WSAVA guidelines (i.e. with a final puppy vaccine at 16 weeks of age or older), there is a risk that some puppies may be unprotected if the bitch does have a high level of MDA. Finally, there are some breeds of dog (e.g. Rottweiler, Dobermann) that have a greater risk of being genetic non-responders to these vaccines. Good husbandry, hygiene and nutrition all play a role in minimising disease outbreaks in kennels. ## Can a modified live virus revert to virulence? will a dog be infected by an mlv vaccine? Yes, an MLV vaccine strain can theoretically revert to virulence, but this is exceedingly rare. Yes, MLV vaccines are called "infectious vaccines" because they work by inducing a low level of infection (and virus replication) in the dog, sufficient to induce immunity, but not disease. In the case of canine parvovirus, vaccinated dogs might shed the MLV vaccine strain of virus in the faeces for a short period after vaccination. This does not pose a risk to other dogs. 77. Some pups were vaccinated at 6 weeks of age with DHPPi and went down with infectious hepatitis at 7 weeks of age; why did this happen? The most common reason for this occurrence (i.e. infection in a vaccinated pup) is that the animal was already incubating infectious virus before it was vaccinated. It is possible that these pups might have been infected during the "window of susceptibility" when they no longer had sufficient MDA to fully protect them against virulent street virus, but the MDA that was present was still sufficient to interfere with their immune response to a recently administered vaccine. ## Apart from the (very small) risk of adverse reaction, what are the other risks of annual vaccination? The risks of adverse reaction following vaccination are indeed relatively small. For dogs and cats, this is in the order of 30 to 50 reactions for every 10,000 animals vaccinated, respectively, and the vast majority of these are non-serious reactions (e.g. transient pyrexia and lethargy, allergic reactions). However, if a serious reaction occurs in one of your client's animals -that is a difficult discussion to have. Adoption of new guidelines is not simply about minimising the risk of adverse reactions -it is about practicing better, evidence-based veterinary medicine and only performing a medical procedure (i.e. vaccination) when this is required. ## Some dogs are genetically poor responders (e.g. rottweilers). how should one vaccinate these breeds? The WSAVA guidelines contain a useful flow diagram that helps you identify non-responder dogs. All puppies should be vaccinated in the same way (with a final vaccination at 16 weeks of age or older) and if you are concerned about the breed and the potential for lack of response, you should serologically test at 20 weeks of age. Most non-responders will fail to seroconvert to just one of the core vaccine antigens (i.e. CDV, CAV or CPV-2). You may attempt to revaccinate and retest that dog, but a true non-responder (or low-responder) may still not respond to revaccination. Such animals simply lack the immunological ability to make an immune response to that particular antigen and will never respond to that vaccine component. Owners should be made aware that these dogs will be at risk, and ideally, they should not be used for breeding. [table] Table 1: Overview of vaccine-preventable canine infectious diseases seen in veterinary practice [/table] [table] Table 2: Overview of vaccine-preventable feline infectious diseases seen in veterinary practice [/table] [table] Table 4: An aspirational vaccination programme for Asian practitioners [/table] [table] Table 5: A pragmatic vaccination programme for Asian practitioners in 2014 [/table]	None	https://europepmc.org/articles/pmc7166337?pdf=render	EXECUTIVE SUMMARY In 2012 and 2013, the World Small Animal Veterinary Association (WSAVA) Vaccination Guidelines Group (VGG) undertook fact‐finding visits to several Asian countries, with a view to developing advice for small companion animal practitioners in Asia related to the administration of vaccines to dogs and cats. The VGG met with numerous first opinion practitioners, small animal association leaders, academic veterinarians, government regulators and industry representatives and gathered further information from a survey of almost 700 veterinarians in India, China, Japan and Thailand. Although there were substantial differences in the nature and magnitude of the challenges faced by veterinarians in each country, and also differences in the resources available to meet those challenges, overall, the VGG identified insufficient undergraduate and postgraduate training in small companion animal microbiology, immunology and vaccinology. In most of the countries, there has been little academic research into small animal infectious diseases. This, coupled with insufficient laboratory diagnostic support, has limited the growth of knowledge concerning the prevalence and circulating strains of key infectious agents in most of the countries visited. Asian practitioners continue to recognise clinical infections that are now considered uncommon or rare in western countries. In particular, canine rabies virus infection poses a continuing threat to animal and human health in this region. Both nationally manufactured and international dog and cat vaccines are variably available in the Asian countries, but the product ranges are small and dominated by multi‐component vaccines with a licensed duration of immunity (DOI) of only 1 year, or no description of DOI. Asian practitioners are largely unaware of current global trends in small animal vaccinology or of the WSAVA vaccination guidelines. Consequently, most practitioners continue to deliver annual revaccination with both core and non‐core vaccines to adult animals, with little understanding that “herd immunity” is more important than frequent revaccination of individual animals within the population. In this paper, the VGG presents the findings of this project and makes key recommendations for the Asian countries. The VGG recommends that (1) Asian veterinary schools review and increase as needed the amount of instruction in small animal vaccinology within their undergraduate curriculum and increase the availability of pertinent postgraduate education for practitioners; (2) national small animal veterinary associations, industry veterinarians and academic experts work together to improve the scientific evidence base concerning small animal infectious diseases and vaccination in their countries; (3) national small animal veterinary associations take leadership in providing advice to practitioners based on improved local knowledge and global vaccination guidelines; (4) licensing authorities use this enhanced evidence base to inform and support the registration of improved vaccine product ranges for use in their countries, ideally with DOI for core vaccines similar or equal to those of equivalent products available in western countries (i.e. 3 or 4 years). The VGG also endorses the efforts made by Asian governments, non‐governmental organisations and veterinary practitioners in working towards the goal of global elimination of canine rabies virus infection. In this paper, the VGG offers both a current pragmatic and future aspirational approach to small animal vaccination in Asia. As part of this project, the VGG delivered continuing education to over 800 Asian practitioners at seven events in four countries. Accompanying this document is a list of 80 frequently asked questions (with answers) that arose during these discussions. The VGG believes that this information will be of particular value to Asian veterinarians as they move towards implementing global trends in small companion animal vaccinology.
9b6e7145596c798d11c991c3e7ee1c0e626adcfc	pubmed	Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative	Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative Objective To develop evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral infl ammatory arthritis (UPIA). Methods 697 rheumatologists from 17 countries participated in the 3E ( E vidence, E xpertise, E xchange) Initiative of 2008-9 consisting of three separate rounds of discussions and modifi ed Delphi votes. In the fi rst round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007-2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results A total of 39 756 references were identifi ed, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the fi nal recommendation addressed monitoring of clinical disease activity in UPIA. Conclusions Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use. # Introduction In clinical practice, a large number of patients who present with recent-onset arthritis have undifferentiated peripheral infl ammatory arthritis (UPIA). In this context, patients' initial questions will focus on their likelihood of developing a well-defi ned rheumatic disease and on what the future holds for disease progression, persistence, functional impairment and quality of life. These are questions about future diagnosis and prognosis. The answers to these questions are vital for clinical decision making, including the choice of treatment. The 3E Initiative ( E vidence, E xpertise, E xchange) in rheumatology is a multinational effort aimed at promoting evidence-based medicine by formulating practical recommendations addressing clinical problems. The objective of the 3E Initiative of 2008-9 was to develop practical recommendations on how to investigate and follow-up undifferentiated peripheral infl ammatory arthritis by integrating systematically generated evidence and expert opinion of a broad panel of international rheumatologists. Although the term 'infl ammatory' in UPIA may seem redundant, the reason for its use was to clearly distinguish the target population from patients with degenerative joint disease, often called osteoarthritis or degenerative arthritis in the English medical literature. # Methods A total of 697 rheumatologists from 17 countries participated in the 3E Initiative of 2008-9. Each country was represented by a scientifi c committee consisting of one principal investigator and 5-13 members. The bibliographic team consisted of 10 international fellows (PM, IC, WK, RK, BK, MS, LS-F, KT, WV, EV) and fi ve mentors (DA, LC, RL, DvdH, CB), one of the mentors also being the scientifi c organiser (CB). The 17 national principal investigators were selected and invited by the 3E scientifi c organiser (CB) and each national chair was in charge of composing a national steering committee. The experts were all the members of Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral infl ammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative the 17 national steering committees who attended the multinational meetings for the 3E Initiative. During the fi rst international meeting (n=113 participants), 10 clinically relevant questions on how to investigate and follow-up UPIA were formulated and selected via a modifi ed Delphi vote. The areas addressed were fourfold: (1) the phase prior to establishing the operational diagnosis of UPIA-namely, which differential diagnosis should be considered in a patient presenting with (infl ammatory) arthritis and the minimal investigations necessary to consider a patient as having UPIA; (2) the diagnostic and prognostic value of clinical assessment and investigations in UPIA (history and physical examination, acute phase reactants, autoantibodies, x-rays, MRI, ultrasound (US), genetic markers and synovial biopsy); (3) the predictors of persistence (chronicity) in UPIA; and (4) the measures of clinical disease activity in UPIA. The clinical questions were structured using the PIO format (Patients, Participants or Problem; Intervention or Index test; Outcomes or target conditions).The patients included 'adults with UPIA'. Duration of symptoms was not an exclusion criterion. The defi nition of UPIA is controversial and there is no widely accepted classifi cation criterion for this condition. During the 2008-9 3E Initiative kick-off meeting, experts decided that only patients in whom clinically apparent joint swelling (synovial proliferation or synovial effusion) was observed by the rheumatologist should be included. For our review we systematically searched for studies of patients who did not fulfi l diagnostic/classifi cation criteria for any specifi c rheumatic disorder after initial assessment. Studies with mixed populations (eg, UPIA+arthralgia, UPIA+early rheumatoid arthritis (RA)) were also retained, as these could be useful for extrapolating results. The intervention or index test was defi ned according to each question (eg, erosions on x-rays, anti-citrullinated protein/peptide antibodies (ACPA) positivity) and the index test should have been assessed at baseline. The outcomes were defi ned as the development of well-defi ned rheumatic diseases (eg, RA, psoriatic arthritis) or relevant disease outcomes (eg, remission, radiographic progression). As diagnostic/classifi cation criteria we accepted either internationally validated criteria (eg, American College of Rheumatology criteria for RA 4 ) or the opinion of the treating physician/investigator. A systematic literature search for articles published up to February 2009 was carried out in Medline, Embase and Cochrane Library using comprehensive search strategies elaborated in collaboration with experienced librarians. The searches were limited to diagnostic and prognostic studies using a modifi cation of published sensitive search strategies. No language restrictions were used. Retrieved citations were screened for titles, abstracts and full text using predefi ned inclusion and exclusion criteria; full read papers and review articles were hand-searched for additional references. Retained articles were graded for their methodological quality according to the levels of evidence of the Oxford Centre for Evidence-Based Medicine (http://www. cebm.net/index.aspx?o=1025). Each question was addressed separately by independent searches. For each question, relevant data were extracted and appropriate statistics were calculated, including OR, sensitivity, specifi city, positive/negative predictive values and positive/ negative likelihood ratios. Details and results of the literature search for each question will be published separately, while the current article describes the merging process between the evidence found for each question and the interpretation of this by the experts, having the 10 recommendations as the result. In the second round, a national meeting was held in each country (total=697 participants) to discuss the generated evidence and propose a set of recommendations. In a third joint meeting the 17 scientifi c committees (n=94 participants) merged all propositions into 10 fi nal recommendations via discussion and modifi ed Delphi vote. The grade of recommendation according to the Oxford levels of evidence was attributed and the level of agreement was measured on a 10-point numerical rating scale (1=no agreement, 10=full agreement). [bib_ref] Evidence-based clinical guidelines: a new system to better determine true strength of..., Roddy [/bib_ref] Finally, the potential effect of each recommendation in clinical practice was assessed according to three impact statements voted by the rheumatologists. # Results A total of 39 756 references were identifi ed, of which 250 were systematically reviewed ( table 1 ). The 10 multinational key recommendations are listed in table 2 with the corresponding level of evidence and grade of recommendation. The mean level of agreement among the rheumatologists was 8.7 (range 7.4-9.1). The percentage of rheumatologists who indicated they would change their clinical practice according to each recommendation is shown in table 3 . Evidence for repeating investigations was not found for any of the questions, therefore all recommendations about this topic were based on expert opinion. Recommendation 1. All possible causes of arthritis (idiopathic, autoimmune, degenerative, infectious, malignancy, traumatic, metabolic) should be considered in the differential diagnosis. Complete history and thorough physical examination will determine the ranking order of possible differential diagnoses. Investigations should be based on the differential diagnosis of the patient. As UPIA is an operational diagnosis after excluding welldefi ned rheumatic diseases, the question about pre-UPIA differential diagnosis and investigations was analysed by looking at the diagnosis that was excluded in cohorts of patients with UPIA and by identifying the inclusion and exclusion criteria of these studies as well as the investigations performed before the UPIA cohort was established. RA was the most frequent diagnosis reported as exclusion criterion and there was no standard baseline investigation undertaken prior to inclusion as UPIA . Experts agreed that, when facing a new patient presenting with arthritis, every diagnosis needed to be kept in mind as UPIA is an exclusion diagnosis. Although the consensus was that it was impossible to name all possible diagnoses, it was felt useful to mention some major disease categories to make sure that these are considered. Experts also advised that UPIA should be constantly rethought, as patients may develop a disease that can be labelled with a specifi c diagnosis at any time. Moreover, this recommendation applies only if arthritis persists and not if it is self-limiting. Again, as the investigations will vary according to context and clinical presentation, experts felt that it would not be useful to make a list of recommended minimal investigations. ## Recommendation 2. to establish a specifi c diagnosis and prognosis following presentation of upia, a careful systematic history and physical examination should be performed with particular attention to age, gender, geographical area, functional status, duration of symptoms/ early morning stiffness, number plus pattern of tender/swollen joints, axial/entheseal involvement and extra-articular/systemic features. Although selected observational studies were of good quality, there was large heterogeneity with respect to the type of history and physical examination features described. [bib_ref] Prediction of diagnosis in acute and subacute oligoarthritis of unknown origin, Kvien [/bib_ref] Of the quantifi ed features, advanced age, female gender [bib_ref] A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis:..., Van Der Helm-Van Mil [/bib_ref] and greater morning stiffness were predictive of an eventual diagnosis of RA. A higher number of tender [bib_ref] A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis:..., Van Der Helm-Van Mil [/bib_ref] and swollen joints, [bib_ref] Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients..., Van Gaalen [/bib_ref] involvement of small joints of hands and feet, involvement of both the upper and lower extremities [bib_ref] A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis:..., Van Der Helm-Van Mil [/bib_ref] and symmetrical involvement [bib_ref] Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients..., Van Gaalen [/bib_ref] were also associated with progression to RA. Similar features were associated with disease persistence and development of erosions, [bib_ref] One year outcome of undifferentiated polyarthritis, Jansen [/bib_ref] while self-reported functional disability (Health Assessment Questionnaire (HAQ) score) and the presence of extraarticular features [bib_ref] One year followup variables predict disability 5 years after presentation with infl..., Wiles [/bib_ref] were uniquely predictive of future disability, along with advanced age, female gender [bib_ref] Recent onset arthritis in the elderly: a 5 year longitudinal observational study, Glennås [/bib_ref] and longer symptom duration. 67 Multinational recommendations on how to investigate and follow-up undifferentiated peripheral infl ammatory arthritis ## Recommendation (with level of evidence and grade of recommendation) Agreement mean (SD) 1. All possible causes of arthritis (idiopathic, autoimmune, degenerative, infectious, malignancy, traumatic, metabolic) should be considered in the differential diagnosis. Complete history and thorough physical examination will determine the ranking order of possible differential diagnoses . Investigations should be based on the differential diagnosis of the patient Experts recognised the importance of the abovementioned evidence-based features and, based on their clinical experience, also highlighted the contribution of the patient's geographical area of residence, the presence of axial/entheseal involvement and the presence of extra-articular/systemic features. However, the greater relevance given to features included in the recommendation does not preclude the need to perform a careful systematic history and physical examination in every patient with UPIA. ## Recommendation 3. erythrocyte sedimentation rate (esr) and c reactive protein (crp) should be performed at baseline in the investigation for diagnosis and prognosis of upia and repeated when clinically relevant. Elevated erythrocyte sedimentation rate (ESR) showed some diagnostic value for the development of RA but no prognostic value for persistence (chronicity) or structural damage. [bib_ref] Outcomes in patients with incipient undifferentiated arthritis, Morel [/bib_ref] C reactive protein (CRP) appeared to be a poor predictor of persistent arthritis, radiological progression and functional disability. However, there was some evidence for the usefulness of elevated CRP in predicting RA, especially when the CRP levels are higher. In one study, CRP did not have any diagnostic value with regard to spondylarthropathy. [bib_ref] Prediction of diagnosis in acute and subacute oligoarthritis of unknown origin, Kvien [/bib_ref] For other acute phase reactants, the evidence on diagnostic or prognostic value was scarce, negative or controversial. [bib_ref] A distinct multicytokine profi le is associated with anti-cyclical citrullinated peptide antibodies..., Hitchon [/bib_ref] also increased the probability of developing persistent synovitis or a worse radiographic outcome. [bib_ref] Prognostic factors in a large cohort of patients with early undifferentiated infl..., Quinn [/bib_ref] For anti-keratin antibodies (AKA) and anti-perinuclear factor, the evidence suggests diagnostic usefulness; AKA also appears to have some prognostic value. For all other markers including a variety of other autoantibodies as well as bone and cartilage biomarkers, the evidence for diagnostic or prognostic value is scarce, negative or controversial. [bib_ref] Low prevalence of antibodies to glucose-6-phosphate isomerase in patients with rheumatoid arthritis..., Matsumoto [/bib_ref] The same applies to disease outcomes different from those already mentioned. 59 [bib_ref] Predictive factors in early arthritis: long-term follow-up, Schumacher [/bib_ref] 76 81 93 100 116 127 128 The value of ACPA and RF in UPIA was recognised and, based on clinical experience, experts also advised consideration of additional autoantibody tests if non-RA systemic infl ammatory disorders are suspected. The use of the general term ACPA was preferred as the literature describes several tests for detecting antibodies to citrullinated peptides (such as anti-CCP1 and anti-CCP2) and newer generation tests are also expected to be used in the future. Recommendation 5. X-rays of affected joints should be performed at baseline. X-rays of hands, wrists and feet should be considered in the evaluation of UPIA as the presence of erosions is predictive for the development of RA and persistence of disease. These should be repeated within 1 year. Radiographic erosions 43 49 and Larsen grade 1 (in a population without erosions at baseline) [bib_ref] Magnetic resonance imaging and bone scintigraphy in the differential diagnosis of unclassifi..., Duer [/bib_ref] increased the probability of developing RA from UPIA. Moreover, when comparing mild versus progressive disease after 1 year follow-up, Sharp/van der Heijde scores at baseline were signifi cantly higher in the progressive disease group. [bib_ref] One year outcome of undifferentiated polyarthritis, Jansen [/bib_ref] In another study, [bib_ref] A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis:..., Van Der Helm-Van Mil [/bib_ref] erosions were found to be a predictor of RA in univariate but not in multivariate analysis. Overall, studies in mixed populations also provided some evidence for the usefulness of x-rays in predicting RA. [bib_ref] Validation of a prediction rule for development of rheumatoid arthritis in patients..., Kuriya [/bib_ref] In general, prognosis was worse when radiographic abnormalities at baseline were more severe. [bib_ref] How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive)..., Visser [/bib_ref] Experts recognised the clinical value of hand and feet x-rays in UPIA and, based on clinical experience, also recommended that x-rays of affected joints should be performed at baseline; Diagnosis reported as exclusion criteria and baseline investigations undertaken prior to inclusion as UPIA (ordered by the frequency of reporting in the retrieved literature), both in studies including patients exclusively with UPIA as well as in selected mixed populations that included a well-defi ned subset of patients with UPIA A. Reported differential diagnosis prior to establishing the operational diagnosis of UPIA -Rheumatoid arthritis -Osteoarthritis -Spondyloarthritis (reactive arthritis, psoriatic arthritis, ankylosing spondylitis and undifferentiated spondyloarthritis) -Crystal-related arthritis -Trauma -Connective tissue diseases (systemic lupus erythematosus, Sjögren syndrome and myositis) -Septic arthritis -Sarcoidosis -Soft tissue disorders -Polymyalgia rheumatica -Lyme disease -Vasculitis -Juvenile infl ammatory arthritis -Palindromic rheumatism -Fibromyalgia -Endocrinological origin -Malignancy-related arthritis -Viral aetiology B. Reported investigations prior to establishing the operational diagnosis of UPIA -History -Tender and swollen joint count -Rheumatoid factor -C reactive protein -Physical examination -Hands and feet x-rays -Full blood count -Antinuclear antibodies -Erythrocyte sedimentation rate -Biochemistry (liver function tests, glucose, urate and renal function) -HLA typing (HLA-B27 and HLA-DR) -Microbiological assessment -Anti-citrullinated protein/peptide antibodies -Radiography of the chest and/or of other affected joints -Urinalysis -Thyroid function tests -C3, C4 -Immunoglobulins -Antibodies to extractable nuclear antigens -Antibodies to double-stranded DNA -Specifi c serological assessment UPIA, undifferentiated peripheral infl ammatory arthritis. furthermore, experts advised that x-rays should be repeated within 1 year (in case of disease persistence). Moreover, although not voted to be included in the recommendation, some of the experts expressed their opinion that pelvic/sacroiliac joint x-rays should also be considered, particularly in RF-and ACPA-negative patients or if spondyloarthritis is suspected. There was a slightly lower agreement about this recommendation ( table 2 , 7.4 agreement), with a larger proportion of experts stating that they did not want to change their practice for this aspect ( table 3 , 35.7%). This lower concordance was mainly related to the inclusion of 'x-rays of affected joints at baseline' and about the advice to repeat x-rays 'within 1 year'. Recommendation 6. There is insuffi cient evidence to recommend the routine use of magnetic resonance imaging (MRI) and ultrasound (US) for diagnosis or prognosis in UPIA; in UPIA and suspicion of RA, MRI of hands and wrists could be considered for diagnosis. Bone oedema was found to be an independent predictor of the future development of RA from UPIA, [bib_ref] Anti-cyclic citrullinated peptide antibody and magnetic resonance imaging-detection of bone marrow oedema..., Tamai [/bib_ref] and the presence of a distinct MRI synovitis and erosion pattern with the involvement of several hand joints but not the fi rst carpometacarpal joint also increased the probability of developing RA. [bib_ref] Magnetic resonance imaging and bone scintigraphy in the differential diagnosis of unclassifi..., Duer [/bib_ref] The absence of the same MRI synovitis pattern decreased the probability of developing RA. [bib_ref] Magnetic resonance imaging and bone scintigraphy in the differential diagnosis of unclassifi..., Duer [/bib_ref] Overall, MRI studies in mixed populations provided some evidence for the usefulness of MRI (bone oedema, synovitis and erosions) in predicting RA. Regarding US, two mixed populations revealed US-power Doppler signal and US-gray scale synovitis as potential candidates for future studies in UPIA. Experts recognised that MRI of the hands and wrists has already been shown to be useful in predicting the development of RA from UPIA, while the value of US in UPIA is still to be determined. However, data are still too scarce to recommend the routine use of any of these imaging tools. This recommendation does not dispute the fact that, compared with physical examination and x-rays, both MRI and US may offer advantages through more sensitive depiction of infl ammatory and destructive disease manifestations. The current recommendation pertains only to the diagnostic and prognostic value of these imaging tools in UPIA. Recommendation 7. There is no genetic test that can be routinely recommended, however HLA-B27 testing may be helpful in specifi c clinical settings. There was a great heterogeneity among the genetic markers tested. [bib_ref] Prediction of diagnosis in acute and subacute oligoarthritis of unknown origin, Kvien [/bib_ref] The shared epitope (SE) was the most frequently studied marker. Eight studies tested its diagnostic utility and showed poor results. Only in one study was the positive likelihood ratio for RA relevant, but this result came from the study with the poorest quality and smallest sample size. [bib_ref] Outcomes in patients with incipient undifferentiated arthritis, Morel [/bib_ref] In isolation, no other genetic marker was informative of a future diagnosis in patients with UPIA. With regard to prognosis, the SE was weakly associated with a poor prognosis of arthritis in terms of development of erosions, mortality, disability and persistent synovitis. [bib_ref] Association of HLA alleles and clinical features in patients with synovitis of..., El-Gabalawy [/bib_ref] Other genes were not good predictors of erosions or other less studied outcomes. The experts acknowledged the current lack of evidence for the practical utility of genetics in UPIA. However, based on their clinical experience, experts chose to highlight that HLA-B27 may be helpful in the appropriate clinical setting-namely, when spondyloarthritis is suspected. Recommendation 8. Routine synovial biopsy is not recommended but can give information for differential diagnosis, especially in patients with persistent monoarthritis. Studies had signifi cant clinical and statistical heterogeneity. [bib_ref] Diagnostic classifi cation of spondylarthropathy and rheumatoid arthritis by synovial histopathology: a..., Baeten [/bib_ref] Three broad synovial features of interest were identifi ed in the literature: ACPA staining, immunohistochemistry and vascular patterns. In contrast to serological ACPA testing, ACPA staining was shown not to be highly specifi c for a diagnosis of RA. [bib_ref] The presence of citrullinated proteins is not specifi c for rheumatoid synovial..., Vossenaar [/bib_ref] In one study, synovial histopathology seemed to differentiate between RA and non-RA. [bib_ref] Immunohistological analysis of synovial tissue for differential diagnosis in early arthritis, Kraan [/bib_ref] The vascular pattern in undifferentiated arthritis was not specifi c enough to differentiate between spondyloarthritis and RA. The exact role of synovial biopsy in UPIA is yet to be determined and experts felt that it could not be recommended as a routine procedure. However, experts also highlighted the fact that synovial biopsy may give important diagnostic clues, especially in some selected cases (eg, persistent/chronic refractory monarthritis, suspicion of malignancy or suspicion of chronic infection such as tuberculosis). Recommendation 9. Predictors of persistent infl ammatory arthritis should be documented and include disease duration of ≥6 weeks, morning stiffness >30 min, functional impairment, involvement of small joints and/or knee, involvement of ≥3 joints, ACPA and/or RF positivity and presence of radiographic erosion. The question about chronicity was investigated by looking at prognostic studies that used multivariate analysis to identify independent predictors of persistence (chronicity). At baseline the following variables were found to be independent predictors of persistent (infl ammatory) arthritis: disease duration, [bib_ref] How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive)..., Visser [/bib_ref] duration of morning stiffness, [bib_ref] How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive)..., Visser [/bib_ref] change of functional status (measured by HAQ) in the fi rst 3 months, 82 failure to respond 2 weeks after local treatment with intra-articular corticosteroids, [bib_ref] Predictors of outcome in patients with oligoarthritis: results of a protocol of..., Green [/bib_ref] small joint involvement, [bib_ref] High anti-cyclic citrullinated peptide level is a stronger predictor than low level..., Mjaavatten [/bib_ref] knee involvement, [bib_ref] Differentiating persistent from self-limiting symmetrical synovitis in an early arthritis clinic, Tunn [/bib_ref] presence of RF, presence and level of ACPA, [bib_ref] How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive)..., Visser [/bib_ref] functional status (HAQ), [bib_ref] Clinical characteristics of patients presenting with oligoarthritis in a very early arthritis..., Mjaavatten [/bib_ref] arthritis of at least three joints, 75 proximal interphalangeal joint involvement, [bib_ref] Clinical characteristics of patients presenting with oligoarthritis in a very early arthritis..., Mjaavatten [/bib_ref] metatarsophalangeal joint involvement [bib_ref] How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive)..., Visser [/bib_ref] and radiographic erosion at the hands and feet. [bib_ref] How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive)..., Visser [/bib_ref] The magnitude of the association in the same predictor was diverse among the studies depending on the patient characteristics (namely, if the population was purely UPIA or not), the study design and the variables used to adjust for in the models. Recommendation 10. Disease activity should be monitored, however no specifi c tool can be recommended. Five studies evaluated the validation of different clinical measures in patients with UPIA. Validation aspects of four questionnaires (WHO Disability Assessment Schedule, [bib_ref] The clinimetric properties of the World Health Organization Disability Assessment Schedule II..., Baron [/bib_ref] London Handicap Scale, Disease Repercussion Profi le and the HAQ 171 ) and three physical measures (RA Disease Activity Index, [bib_ref] Validity of the RADAI in early rheumatoid arthritis, Bykerk [/bib_ref] McGill Range of Motion Index 173 and NOAR Damage Joint Count 174 ) were partially assessed in these studies but none of the instruments of disease activity was fully validated for its use in UPIA. Although no instrument of disease activity has been fully validated for its use in UPIA, experts felt that it was important to recommend that there should be a conscious effort to record disease activity. # Discussion Ten multinational recommendations on how to investigate and follow-up UPIA in the clinical setting were developed, which are practical, evidence-based and supported by a large panel of international rheumatologists in the 3E Initiative. We followed an established group decision method. A representative expert panel of 697 academic and community rheumatologists from 17 countries selected relevant questions that refl ect the challenges of approaching a patient with UPIA. They openly discussed the evidence from the literature followed by a silent voting process. We used the touch pad methodology with prespecifi ed cut-off levels of agreement to generate the fi nal recommendations. Several rounds of rewording and revoting were sometimes required to reach the specifi ed cut-off for agreement. This process highlights the international dimension of this collaboration and strengthens the current recommendations. It ensured that the fi nal recommendations were evidence-driven as well as clinically relevant. Furthermore, the broad participation increases external validity and enhances future dissemination and implementation into rheumatological practice worldwide. Another main feature of the 3E Initiative was the promotion of epidemiology and systematic literature research, all participants having been updated on how to appraise published evidence. There is widespread interest in predictive medicine. Following a strict methodology, we aimed to fi nd all available evidence regarding each question which resulted in a large number of reviewed articles. However, the evidence in truly UPIA populations is scarce, exposing the need to create a research agenda addressing this topic. In particular, future studies should clearly distinguish between individuals with early well-defi ned rheumatic diseases, individuals with UPIA and individuals with infl ammatory joint symptoms but no obvious joint swelling. All these populations can be studied for predictive algorithms and results may be different depending on the study population. The defi nition of UPIA is controversial and much of the literature is skewed towards early RA. The diffi culty in defi ning UPIA is underlined by the continuous changing face of different categories of patients, which can be well illustrated by the recent new ACR/EULAR criteria for RA, [bib_ref] Rheumatoid arthritis classifi cation criteria. An American College of Rheumatology/European League Against..., Aletaha [/bib_ref] as several of the patients we now describe as having UPIA will likely be labelled as having RA. Nevertheless, despite the infl uence that this changing may have on research and daily practice, the recommendations presented in this article are based on currently available evidence. They may help the clinician in the effective management of patients with UPIA and can be adjusted if future studies or clinical experience reveal new insights. In summary, multinational recommendations for the investigation and follow-up of patients with undifferentiated arthritis in daily clinical practice were developed, integrating systematic literature review and expert opinion with the aim of promoting evidence-based medicine and ultimately improving patient care. [table] Table 1: Results of the systematic literature search for each recommendation topic [/table] [table] Table 3: Percentage of rheumatologists in the 3E Initiative who indicated for each recommendation if it would change their clinical practice [/table] [table] 42: 48 79 80 90 -95 Based on sparse evidence and on personal experience regarding acute phase reactants, experts recommended that only ESR and CRP should be performed at baseline and repeated according to the clinical setting.Recommendation 4. Testing of rheumatoid factor (RF) and/or ACPA should be performed in the evaluation of patients with UPIA, as these factors are predictive of RA diagnosis and prognosis; negative tests do not exclude progression to RA. If a connective tissue disease/systemic infl ammatory disorder is suspected, additional autoantibody tests should be considered.96 -110 with a diagnosis of RA at follow-up was compelling in the retrieved literature. The absence of ACPA or RF was diagnostically less helpful. The presence of ACPA or RF75 106 -109 111 -115 [/table]	None	https://ard.bmj.com/content/annrheumdis/70/1/15.full.pdf	Objective To develop evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis (UPIA). Methods 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2008–9 consisting of three separate rounds of discussions and modified Delphi votes. In the first round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007–2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results A total of 39 756 references were identified, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the final recommendation addressed monitoring of clinical disease activity in UPIA. Conclusions Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use.
ab5a6ce27e1f1cf8359a25d045b1eab29c1bb3f0	pubmed	Quality Improvement Guidelines for Transjugular Intrahepatic Portosystemic Shunt (TIPS)	Quality Improvement Guidelines for Transjugular Intrahepatic Portosystemic Shunt (TIPS) # Introduction In Europe and in North America, portal hypertension accompanies cirrhosis of the liver in over 90 % of the cases. Cirrhosis of the liver is caused by alcohol abuse in about half of the cases; a third is due to chronic viral hepatitis B and C; and the remainder is the result of various metabolic or idiopathic disorders of the liver. Transjugular intrahepatic portosystemic shunting, as a percutaneous alternative to surgical portosystemic shunts for decompression of symptomatic portal hypertension, was conceived and its technique developed in animal experiments in the late 1960s by Rösch et al. [bib_ref] Transjugular portal venography and radiologic portacaval shunt: an experimental study, Rösch [/bib_ref]. ## Definitions Portal hypertension is a syndrome caused by increased resistance in the portohepatic circulation and an increase in the splanchnic vein blood supply. In the normal liver, the difference between pressures in the portal vein and the free hepatic veins or right atrium usually does not exceed 5 mm Hg. Portal hypertension is defined as a gradient larger than 6 mm Hg, but clinical complications seem to occur only when the pressure gradient exceeds 10-12 mm Hg. Wedged hepatic pressure measurement has two components. The portal component is the pressure transmitted from the hepatic sinusoids, and the systemic component is the blood pressure transmitted from the central veins. It is the portal component that causes the development of portal systemic collaterals. The term corrected sinusoidal pressure includes only the portal component and is calculated by subtracting the mean right atrial or inferior vena cava pressure from the wedged hepatic venous pressure. Wedged hepatic pressure is obtained through an end-hole catheter that is advanced into a hepatic vein until it can go no further. Alternatively, pressure can be measured through the wire channel of a double lumen balloon catheter inflated in a more central vein. Transjugular intrahepatic portosystemic shunt (TIPS) is the percutaneous method of creating a portosystemic shunt to decrease or treat portal hypertension. TIPS is a side-toside shunt of a determined diameter designed to function as a partial shunt that preserves a portion of portal flow to the liver [bib_ref] AASLD practice guidelines: the role of transjugular intrahepatic portosystemic shunt (TIPS) in..., Boyer [/bib_ref]. Flow through the completed shunt is assessed by comparing the degree of preferential filling of the shunt to the that of the portal vein branches and portosystemic collaterals (mainly in the gastric veins). The identification of hepatofugal (reversed) blood flow in portal vein branches (total shunting) is a sign of good flow through the shunt. Technical success is defined as a decrease of the portosystemic pressure gradient to 12 mm Hg or less, or a reduction of at least 20 %. Clinical success is defined as cessation of variceal bleeding, decrease of ascites, and conversion into diureticsensitive ascites, as well as improvement of liver function in patients referred for massive thrombosis of hepatic veins. Hepatic encephalopathy is defined as the complex of all cerebral dysfunctions that can occur during the course of serious liver disease. Clinical symptomatology, which as a rule is potentially reversible, ranges from disorientation, somnolence, and lethargy to sopor and coma. Hepatic encephalopathy has three forms: type A, associated with acute liver failure; type B, associated with portosystemic bypass without liver disease; and type C, or chronic, associated with liver cirrhosis. ## Pretreatment imaging Ultrasonography should verify portal and hepatic vein patency; exclude intrahepatic tumor or cyst; determine maximum blood flow velocities in the portal vein; measure diameters and the congestion index of the main portal, superior mesenteric, and splenic veins; evaluate splenic size; and document the presence and extent of portosystemic collaterals and ascites. This evaluation is the baseline for comparisons to be made during follow-up. Computed tomography (CT) should identify distortion of liver anatomy including lobar atrophy and size of the liver, and evaluate the spatial relationships of the liver and the right kidney, hepatic veins, and portal vein branches. Patency of the portal vein and its tributaries, focal liver lesions, and amount of ascites are also identified by CT. Magnetic resonance imaging measures hepatic flows using a phase contrast technique and provides the most specific imaging diagnosis of the hepatocellular carcinoma using liver cell-specific contrast agent [bib_ref] MR-based visualization and quantification of three-dimensional flow characteristics in the portal venous..., Stankovic [/bib_ref]. ## Indications for treatment and contraindications ## Refractory ascites Refractory ascites is the most frequent indication for TIPS. Refractory ascites is defined as an abdominal fluid collection that cannot be mobilized or the early recurrence of abdominal fluid that cannot adequately be prevented by medical therapy [bib_ref] AASLD practice guidelines: the role of transjugular intrahepatic portosystemic shunt (TIPS) in..., Boyer [/bib_ref]. The term refractory ascites has two different meanings: diuretic-resistant ascites and diuretic-intractable ascites. Diuretic-resistant ascites does not respond to an intensified diuretic treatment of up to 400 mg/day spironolactone, up to 160 mg/day of furosemide, and sodium restriction to a maximum intake of 5.2 g of salt/day. Diuretic-intractable ascites cannot be mobilized or their early recurrence cannot be prevented because of the development of diuretic-induced complications that preclude the use of an effective diuretic dosage. Two important complications occur in patients with cirrhotic ascites: spontaneous bacterial peritonitis and hepatorenal syndrome [bib_ref] Management of adult patients with ascites due to cirrhosis: an update, Runyon [/bib_ref] [bib_ref] Predictors of early mortality after transjugular intrahepatic portosystemic shunt creation for the..., Harrod-Kim [/bib_ref]. Hepatic hydrothorax occurs in patients with ascites when there is direct communication between the peritoneal and pleural cavities. In most patients, the defect is in the diaphragm that overlies the dome of the liver. Hepatic hydrothorax is due to an accumulation of ascitic fluid migrating through the diaphragmatic defect [bib_ref] Hepatic hydrothorax, Strauss [/bib_ref]. ## Variceal bleeding The causes of gastrointestinal hemorrhage in a patient with portal hypertension may be variceal rupture, portal hypertension gastropathy, postsclerotherapy ulcers, peptic ulcer disease, hemorrhagic gastritis, and Mallory-Weiss tear. TIPS is generally accepted as a second-line therapy after failure of endoscopic and medical therapy of bleeding from gastroesophageal varices. ## Massive thrombosis of the hepatic veins TIPS is indicated when medical therapy fails. TIPS is technically feasible in most patients with thrombosis of the hepatic veins. A direct puncture from the intrahepatic inferior vena cava into the liver parenchyma is possible in patients without a remaining hepatic vein stump. The rationale of the use of TIPS is to decompress the liver from venous congestion using the portal vein and TIPS as an outflow tract. ## Portal vein thrombosis TIPS should be considered in patients with portal vein thrombosis with or without cavernomatous transformation. TIPS can be technically feasible when intrahepatic portal branches are patent. The procedure should be referred to centers with extensive experience [bib_ref] Transjugular intrahepatic portosystemic shunt (TIPS), the preferred therapeutic option for Budd Chiari..., Senzolo [/bib_ref]. ## Portosystemic collaterals embolization There are three main indications for occluding large portosystemic collaterals. The most frequent is embolization of the left and short gastric veins in a patient with a recent history of acute variceal bleeding, especially if the bleeding source was gastric varices. Another indication is closure of large collaterals with continuing competitive flow after TIPS. In addition, patients with a history of portosystemic encephalopathy or patients at high risk for that condition may benefit from embolization of large portosystemic collaterals performed during calibrated TIPS. ## Tips contraindications TIPS is absolutely contraindicated in cases of unproved portal hypertension (either clinically or anatomically). TIPS should be carefully considered in the following circumstances: APACHE II score [20, especially in Child C patients, and irreversible phase of hemorrhagic shock; Child-Pugh score [12 and MELD score [18; right-sided heart failure with elevation of the central venous pressure (mean right atrium pressure [15 mm Hg); hepatic encephalopathy poorly controlled by lactulose, especially in patients older than 60, patients with diabetes, and patients receiving hemodialysis; chronic occlusion of the portal vein with periportal collaterals, hypervascular hepatic tumors, polycystic liver disease; and active infection, either intrahepatic or systemic. To provide TIPS for variceal bleeding, the following laboratory values are required: total bilirubin \60 lmol/L (3.5 mg/dl), especially in Child C patients; and corrected international normalized ratio (INR) of \1.8. To provide TIPS for refractory ascites, the following laboratory values are required: total bilirubin \50 lmol/L (3 mg/dl); and serum creatinine of \180 lmol/L (2.1 mg/dl), except in cases of hepatorenal syndrome. Elevated total serum bilirubin level can also be due to biliary obstruction, hemobilia, hemolysis, or primary biliary cirrhosis. In such cases, values of [60 lmol (3.5 mg/dl) are not a contraindication for TIPS. The encephalopathy test and the anatomic ultrasound and CT studies can be excluded when a patient is acutely bleeding and cannot undergo endoscopic therapy. ## Patient preparation Laboratory tests are performed to reveal coagulopathy, liver and renal failure, and systemic infection, as well as to establish Child-Pugh classification (i.e., prothrombin time/ INR, partial thromboplastin time, creatinine, urea, electrolytes, bilirubin, total protein, complete blood count, transaminases). The operator should know at least these values to assess and minimize potential risks arising from iodinated agent administration, structural liver injuries, and overshunting of the portosystemic blood flow [bib_ref] Transjugular intrahepatic portosystemic shunt for cirrhosis and ascites: effects in patients with..., Michl [/bib_ref]. Subclinical hepatic encephalopathy is revealed using a number connecting test. The patient's signature should be documented in the chart every day. To improve the patient's clinical state, hematocrit, protein, coagulation deficit (fresh frozen plasma if INR is [1.8, platelet infusion if count is \50,000 9 10 9 /L, or according to the center's standards) should be corrected. The acutely bleeding patient has to be hemodynamically stabilized during the procedure. Cardiologic evaluation should reveal preexisting cardiac dysfunction. Silent cirrhotic cardiomyopathy may be unmasked after TIPS insertion [bib_ref] Transjugular intrahepatic shunt worsens the hyperdynamic circulatory state of the cirrhotic patient:..., Azoulay [/bib_ref]. Prophylactic broad-spectrum antibiotics should be administered. With a potentially limited effect on hepatic metabolism, antibiotics are initiated on the day of procedure and continued for at least two additional days. (Antibiotic therapy should be included in the therapy of variceal bleeding.) Two cross-matched blood units should be available. Draining of tense ascites can be performed to decrease the angle between the hepatic veins and the inferior vena cava and have better fluoroscopic imaging. Clinicians should be aware of hepatorenal syndrome. Monitored ascites drainage can improve respiratory comfort during the procedure. It should be determined whether patients have an allergy to contrast media. In patients with a history of idiosyncratic reaction to iodinated contrast media, a reaction rate of 16-44 % (i.e., 4-8 times more that of the general population) has been reported upon reexposure. Pretreatment with corticosteroids at least 12 h before the administration of contrast medium is recommended to prevent adverse reaction. Patients should be instructed to restrict their oral intake for at least 6-8 h before the procedure. Placement of a reliable intravenous line should be possible. Informed consent-a comprehensive description and an explanation of the reasons for this therapy, including potential consequences-must be provided to the patient or patient's family. Alternative therapies should be mentioned. ## Equipment specifications Monoplane digital subtraction angiography equipment that is capable of performing standard projections, including lateral view, should be available. This equipment should provide high-quality fluoroscopy with zooming and reference imaging. The catheterization laboratory should be equipped with ultrasonography to navigate puncture of the jugular and portal veins. Transcatheter blood pressure measurement should be available during the procedure. There are two TIPS needle-set designs. The first is a relatively simple set, consisting of a 15-to 16-gauge, 55-cm-long, curved steel needle and teflon catheter. The needle has a sharp, reversed bevel at its distal tip. The puncture is made by advancing the entire device through a liver parenchyma. Correct portal vein access is verified by blood return upon aspiration by a 10 ml syringe filled with contrast medium. The contrast medium is used for immediate opacification of the portal vein (excluding accidental puncture of the hepatic artery or biliary duct). Once the portal vein branch is filled with good distal flow, a 180-cmlong stiff guide wire is introduced through the stiff curved cannula. A modification of this set is available that consists of a blunt outer cannula and sharp inner mandril. The second type of needle set consists of a 14-gauge metal cannula covered with thin-walled teflon catheter. Inside this long cannula is a needle covered with 5F teflon tapered tip catheter. The cannula secures the wedged position of the set inside the hepatic vein, and its curved tip controls the direction of the puncture. The cannula itself does not cross the parenchyma during each needle pass. Instead, the puncture is made by a forceful push of the 0.038 inch needle toward the portal vein branch while the metal cannula is held in wedged position in the hepatic vein. When this sheathed needle is used, the diameter of the puncture hole is approximately 1.7 mm (i.e., 5F). Also available is a pediatric TIPS set, which includes a 0.018 inch guide wire instrumentarium. ## Procedure After entry into the internal jugular vein, a catheter is introduced and guided through the superior vena cava, right atrium, and inferior vena cava into a hepatic vein-usually the right hepatic vein. Wedge hepatic pressure measurement follows. The use of the proximal portion of the hepatic vein has two purposes. The first is to utilize, for shunt creation, the largest diameter of the hepatic vein to potentially prevent or delay any outflow shunt stenosis. The second is to be sure that one begins cephalad to the desired portal vein entry site. A needle inserted through the catheter is then used to puncture the liver from a central portion of the hepatic vein and enter the main portal branch, usually the right portal vein. In the right hepatic vein, the cannula is rotated approximately 90°anteriorly and then advanced and maintained with continual caudal pressure such that it is wedged against the wall of the hepatic vein. When in the middle hepatic vein, the cannula is rotated posteriorly in the some way. Carbon dioxide wedged hepatic venography is used to identify the portal vein [bib_ref] The use of carbon dioxide wedged hepatic venography to identify the portal..., Maleux [/bib_ref]. The puncture can be also navigated with ultrasonography. Depending on the anatomy, it might by possible to use a tract from the right hepatic vein to the left portal branch, and vice versa. The needle tract is then dilated by a balloon catheter, establishing a connection between the portal and systemic circulation directly inside the liver parenchyma. The parenchymal tract is kept open by insertion of an expandable metallic stent. A dedicated TIPS stent graft was designed to extend the covered portion to the orifice of the hepatic vein at the inferior vena cava. The only noncovered part of the stent graft, which is 2 cm long, is that part which protrudes into the portal vein. This both anchors the device and allows blood to flow through the interstices of the noncovered portion to the peripheral (parenchymal) portal vein branches. From the early TIPS experience, the alternative to the dedicated stent graft has been a self-expandable stent used for bridging portal and hepatic veins in a similar way. The bare stents are used for patients at high risk of hepatic encephalopathy or for recanalization of the portal vein. The shunt diameter is finalized by balloon dilatation of the deployed stent graft or stent. Depending on the diameter of the expandable stent or stent graft used for TIPS creation, various amounts of portal blood are diverted into the systemic circulation, resulting in the decompression of portal hypertension. The size of the balloon catheter is usually 8 mm. Depending on the pressure gradient measured between the portal vein and right atrium after stent or stent graft placement, the larger angioplasty balloon catheter can be used to achieve adequate stepwise decompression. For patients who are liver transplant candidates, precise positioning of both ends of the stent or stent graft is critical. The needle may exit the liver and lacerate the liver capsule or enter the hepatic artery. Embolization of the parenchymal tract is the first-line treatment to prevent hemoperitoneum. The TIPS tract must be intraparenchymal, or dilatation of the extrahepatic portion of the portal vein results in fast exsanguination. The frequency of this complication is about 1 %. Entry into the right or left portal vein branch should be at least 1 to 2 cm from the portal vein bifurcation. The direct injection into the dilated tract should be done as soon as possible to reveal potential extravasation. If it is positive, the balloon is again inflated and the stent graft placed to tamponade the extrahepatic leak. According the patient's blood pressure, fluid volume resuscitation is immediately initiated and the anesthesiologist is called. The final step of the TIPS procedure is placement of pigtail catheter over the portal vein guide wire for followup portography and pressure measurement. The post-TIPS blood pressure is measured within the main portal vein. Once the value is stabilized and recorded, the tip of the sheath or pigtail catheter is moved to the hepatic vein or the suprahepatic inferior vena cava, and the blood pressure is again recorded. Thus, at the completion of the TIPS procedure, at least four pressure values will have been obtained: those in the portal vein and hepatic vein (or inferior vena cava) before and after shunt placement. ## Monitoring patients during tips The TIPS procedure can be performed with conscious sedation in most patients, although children, critically ill or uncooperative patients, and those on artificial ventilation may require general anesthesia. The routine use of general anesthesia is preferred in some centers. Conscious sedation requires careful patient monitoring and the assistance of a nurse. Midazolam and fentanyl are routinely used with the administration of supplemental oxygen through nasal prongs or a face mask under continuous oxygen saturation monitoring with a pulse oximetry probe and regular blood pressure measurement. These medications are provided in addition to local skin anesthesia to alleviate the considerable pain that accompanies dilatation of the shunt tract. The intensity of pain varies from patient to patient. Continuous electrocardiogram monitoring is also required, especially while maneuvering the entry guide wire from the right atrium into the inferior vena cava during inadvertent catheter or wire passage into the right ventricle. The contact of catheters or wires with the inner walls of the right atrium or ventricle can cause severe arrhythmias. ## Postprocedural follow-up All TIPS patients are followed by serial duplex ultrasonography at 24 h, 1, 3, and 6 months after the TIPS placement, then every 6 months thereafter [bib_ref] Value of Doppler sonography in revealing transjugular intrahepatic portosystemic shunt malfunction: a..., Zizka [/bib_ref] [bib_ref] Role of ultrasound surveillance of transjugular intrahepatic portosystemic shunts in the covered..., Carr [/bib_ref]. An upper endoscopy is scheduled at 6 months in patients treated for gastrointestinal bleeding as a complementary assessment. The patients are continually followed by a hepatologist. Anticoagulation is not routinely recommended except in patients treated for massive thrombosis of the hepatic veins (Budd-Chiari syndrome). In these cases, strict anticoagulation is mandatory to keep the INR above 2. Occurrence of hepatic encephalopathy or its worsening is revealed by direct question of the patient, or by obtaining information by asking family members. Specific questions are asked regarding changes in personality, working capacity, sleep behaviors, and power of concentration. There are psychometric tests for the early detection of subclinical encephalopathy, including study of a handwriting specimen, a number-connection test, and a line-tracing test. When a polytetrafluoroethylene-covered stent graft is used, hepatic encephalopathy may be frequent; unlike bare stents, its occurrence tends to be constant during follow-up. Refractory hepatic encephalopathy can be managed by reducing the shunt diameter via various stenosing devices [bib_ref] Rifaximin treatment in hepatic encephalopathy, Bass [/bib_ref] [bib_ref] Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic..., Riggio [/bib_ref]. ## Outcome Unpredictable shunt patency remains the greatest problem with this method. With conventional bare metal stents, the probabilities of shunt dysfunction after the primary procedure are *25 and 50 % after 6 and 12 months, respectively. Creation of a TIPS with the use of expanded polytetrafluoroethylene (ePTFE)-covered stent grafts has been reported to reduce the incidence of shunt dysfunction to 13 % at 6 months and 15-20 % at 1 year. The use of ePTFE-covered stent grafts has dealt with the main problem of primary TIPS dysfunction [bib_ref] Role of ultrasound surveillance of transjugular intrahepatic portosystemic shunts in the covered..., Carr [/bib_ref]. Similarly, ePTFE-covered stent grafts also have a place in the secondary prevention of TIPS dysfunction and can improve long-term patency [bib_ref] Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic..., Riggio [/bib_ref] [bib_ref] Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized..., Bureau [/bib_ref] [bib_ref] The use of a polytetrafluoroethylene-covered stent graft for transjugular intrahepatic portosystemic shunt..., Rössle [/bib_ref] [bib_ref] Emerging issues in the use of transjugular intrahepatic portosystemic shunt (TIPS) for..., Riggio [/bib_ref] [bib_ref] Influence of the secondary deployment of expanded polytetrafluoroethylene-covered stent grafts of maintenance..., Jirkovsky [/bib_ref]. Multiple trials and meta-analyses report much better control of refractory ascites with TIPS than with largevolume paracenteses. TIPS may convert diuretic-resistant ascites into diuretic-sensitive ascites. However, survival and transplant-free survival are similar with the two techniques. Encephalopathy occurs more often in patients treated with TIPS than patients with large-volume paracenteses [bib_ref] A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with..., Rössle [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient..., Salerno [/bib_ref]. TIPS results in improvement of renal function, as indicated by a decrease in serum creatinine and blood urea nitrogen levels [bib_ref] Advanced hemodynamic monitoring before and after transjugular intrahepatic portosystemic shunt: implication for..., Saugel [/bib_ref]. TIPS is effective in controlling acute bleeding from varices refractory to medicamentous therapy, and TIPS should be used in preference to surgery. TIPS should be performed only if pharmacologic and endoscopic therapy have failed in the prevention of variceal rebleeding or when rebleeding occurs after sclerotherapy, and in high-risk patients after the first bleeding attack (hepatic venous pressure gradient [20 mm Hg, or Child-Pugh class B and C with active bleeding during endoscopy) [bib_ref] Early use of TIPS in patients with cirrhosis and variceal bleeding, Garcia-Pagan [/bib_ref]. TIPS should be used in the management of patients with massive thrombosis of hepatic veins whose condition fails to improve with anticoagulation. A large retrospective study revealed 1 and 10 year transplant-free survival to be 88 and 69 %, respectively. TIPS patency in this group of patients, who have hypercoagulopathy, was best in those who received a dedicated covered stent [bib_ref] TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients, Garcia-Pagan [/bib_ref]. ## Complications The procedure-related morbidity and mortality of TIPS are much lower than for conventional surgical shunts. The reported rate of fatal complications is 1.7 % (range 0.6-4.3 %). This rate has been found to be inversely related to the number of TIPS procedures performed [bib_ref] TIPS: short-and longterm results: a survey of 1750 patients, Barton [/bib_ref]. Fatal periprocedural complications include intraperitoneal hemorrhage as a result of extrahepatic rupture of the portal vein, laceration of the hepatic artery, and transcapsular puncture with the transjugular needle. Postprocedural complications and adverse effects include impairment of liver function, indicated by an increase in serum bilirubin concentration; occurrence of hepatic encephalopathy; and cardiac volume overload, which might result in deterioration of circulatory function in patients with cirrhosis and with preexisting heart insufficiency. # Conclusions Technical and medical advances have been introduced in TIPS practice to improve shunt patency and to increase the effectiveness of hepatic encephalopathy treatment. These advances will expand the indications for TIPS in the future. Conflict of interest The authors declare that they have no conflict of interest. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.	None	https://link.springer.com/content/pdf/10.1007/s00270-012-0493-y.pdf	None
908fa3e3fff84ffd32bdd901c0d81a24ed66212b	pubmed	Diagnosis and management of the drug hypersensitivity reactions in Coronavirus disease 19: An EAACI Position Paper	Diagnosis and management of the drug hypersensitivity reactions in Coronavirus disease 19: An EAACI Position Paper Coronavirus disease 2019 (COVID-19), a respiratory tract infection caused by a novel human coronavirus, the severe acute respiratory syndrome coronavirus 2, leads to a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Given the huge influence caused by the overwhelming COVID-19 pandemic affecting over three million people worldwide, a wide spectrum of drugs is considered for the treatment in the concept of repurposing and off-label use. There is no knowledge about the diagnosis and clinical management of the drug hypersensitivity reactions that can potentially occur during the disease. This review brings together all the published information about the diagnosis and management of drug hypersensitivity reactions due to current and candidate off-label drugs and highlights relevant recommendations. Furthermore, it gathers all the dermatologic manifestations reported during the disease for guiding the clinicians to establish a better differential diagnosis of drug hypersensitivity reactions in the course of the disease.K E Y W O R D S ## \| introduc ti on Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a novel member of human coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 1 It causes a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild, uncomplicated illness and severe cases, with or without pneumonia. 2 Hospitalization and oxygen support, and admission to an intensive care unit are required in 14% and 5% of the patients, respectively. 1 Gastrointestinal symptoms and positive viral nucleic acid testing on rectal swabs are considered as indicators of infection in digestive system and fecal-oral transmission of COVID-19. [bib_ref] Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral..., Xu [/bib_ref] Moreover, skin symptoms, including exanthems, may appear during the evolution of the disease leading to differential diagnosis with drug hypersensitivity reactions (DHRs). [bib_ref] Cutaneous manifestations in COVID-19: a first perspective, Recalcati [/bib_ref] In critically ill patients, COVID-19 can be complicated by acute respiratory distress syndrome (ARDS), septic shock, and multi-organ dysfunction syndrome. In such patients, in response to viral infection, the excessive activation and expansion of T lymphocytes and macrophages lead to an overproduction of cytokines, which causes a cytokine storm and a hyperinflammatory state. [bib_ref] Continuous intravenous Anakinra infusion to calm the cytokine storm in macrophage activation..., Monteagudo [/bib_ref] [bib_ref] The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R)..., Zhang [/bib_ref] Acute hyperinflammation may activate coagulation cascade and inhibit fibrinolytic reaction, thus promoting thrombosis. Coagulopathy and thrombocytopenia are serious complications which increase the risk of hemorrhage and thrombosis and progress to disseminated intravascular coagulation (DIC). [bib_ref] Coronavirus disease 2019 (COVID-19): a clinical update, Zhou [/bib_ref] The periodically updated World Health Organisation interim guidance allows reliable comparison of investigational therapeutic interventions as part of randomized controlled trials, provides recommendations for the management, and forms the basis of many institutional or national protocols. Unfortunately, none of the drugs used for COVID- [bib_ref] General considerations on rapid desensitization for drug hypersensitivity -a consensus statement, Cernadas [/bib_ref] have been proven to be truly effective yet; besides, no specific antiviral drugs have been approved for COVID-19 by health authorities. [bib_ref] Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review, Sanders [/bib_ref] [bib_ref] Favipiravir: pharmacokinetics and Concerns about clinical trials for 2019-nCoV infection, Du [/bib_ref] At the moment, there is no specific treatment for COVID-19, and standard practice of care focuses on treating the clinical symptoms with supportive care. In this review, diagnosis and management of DHRs, which are expected to be caused by current or candidate repurposed and off-label drugs used for COVID-19 treatment mostly based on prior knowledge, are discussed. [bib_ref] Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review, Sanders [/bib_ref] Drugs in this review are classified into four groups according to their potential roles in different phases of the disease as antiviral drugs, antiviral and/or immunomodulatory drugs used in viral pneumonia; anti-cytokine and anti-inflammatory drugs considered during macrophage activation syndrome (MAS) and cytokine storm; anti-inflammatory drugs in ARDS; and anti-aggregant and anti-coagulant drugs in coagulopathy . Information of DHRs due to the use of additional drugs for various purposes can be found in the relevant European Academy of Allergy and Clinical Immunology (EAACI) resources. [bib_ref] An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions, Garvey [/bib_ref] [bib_ref] Towards a more precise diagnosis of hypersensitivity to beta-lactams -an EAACI position..., Romano [/bib_ref] [bib_ref] Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations, Aberer [/bib_ref] [bib_ref] EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity, Brockow [/bib_ref] [bib_ref] Drug hypersensitivity in children: report from the pediatric task force of the..., Gomes [/bib_ref] [bib_ref] Skin test concentrations for systemically administered drugs -an ENDA/EAACI Drug Allergy Interest..., Brockow [/bib_ref] [bib_ref] In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest..., Mayorga [/bib_ref] [bib_ref] General considerations on rapid desensitization for drug hypersensitivity -a consensus statement, Cernadas [/bib_ref] [bib_ref] Desensitization in delayed drug hypersensitivity reactions -an EAACI position paper of the..., Scherer [/bib_ref] Since emerging recent findings are dynamically changing the clinical interventions, it is expected that the list of drugs determined according to current knowledge may change with upcoming recommendations in future. F I G U R E 1 Currently investigated drugs in COVID-19 grouped according to their clinical use ## \| s k in manife s tati on s induced by cov i d -19 There have been increasing reports of dermatologic manifestations associated with COVID-19 . It is knowledge, although in progress, rapidly evolving as evidenced by most publications being ahead of print and available only in an electronic version or reported in networks. According to pathogenetic mechanisms, skin manifestations reported so far can be divided into (1) skin manifestations similar to those in other viral infections and (2) skin manifestations related to thrombovascular events and vascular pathologies. ## \| skin manifestations similar to those in other viral infections During the COVID-19 outbreak in China, it was not a focus to document skin manifestations. Consequently, skin rash has only been reported in 2 out of 1.099 infected patients (0.2%). [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan [/bib_ref] In contrast, a study by dermatologists from Italy reported skin manifestations in 18/88 patients (20.4%) with COVID-19. [bib_ref] Cutaneous manifestations in COVID-19: a first perspective, Recalcati [/bib_ref] Cutaneous manifestations seen were either erythematous rash (n = 14), widespread urticaria (n = 3), or chickenpox-like vesicular rash (n = 1). In Spain, among 375 patients with suspected or confirmed COVID-19, maculopapular eruptions (MPEs), sometimes similar to pityriasis rosea, were observed in 47% of the cases, urticarial lesions in 19%, and vesicular eruptions of the trunk in 9%. [bib_ref] Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus..., Casas [/bib_ref] Another case of urticaria was presented in France [bib_ref] Urticarial eruption in COVID-19 infection, Henry [/bib_ref] and patients with morbilliform exanthem in the USA . [bib_ref] A case of COVID-19 pneumonia in a young male with full body..., Hunt [/bib_ref] Varicella-like lesions predominantly on the trunk were described in 22 patients with proven COVID-19 infection in Italy. [bib_ref] Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of..., Marzano [/bib_ref] Predominance of vesicles was reported in 54.5% and generally mild itching in nine (40.9%) patients. The vesiculopapular exanthem appears to develop early in the course of the disease . [bib_ref] Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus..., Casas [/bib_ref] ,An outbreak of severe Kawasaki-like disease has been reported at epicenters of COVID-19 infection also associated with a polymorphic rash in 30%-50% of affected children. [bib_ref] An outbreak of severe Kawasakilike disease at the Italian epicentre of the..., Verdoni [/bib_ref] one case, picture of a urticaria-like rash in a 6-month-old child with Kawasaki-like disease associated with COVID-19 infection is shown . [bib_ref] COVID-19 and Kawasaki disease: novel virus and novel case, Jones [/bib_ref] Two patients with bilateral flexural exanthems resembling systemic drug-related intertriginous exanthems (SDRIFE), one with axillary purpuric lesions associated with thrombocytopenia, have been published . [bib_ref] COVID-19 can present with a rash and be mistaken for Dengue": Petechial..., Jimenez-Cauhe [/bib_ref] A prospective study from ## \| skin manifestations associated with thrombovascular events and vascular pathologies COVID-19 exanthems have also been reported with petechiae and low platelet count resembling dengue. [bib_ref] COVID-19 can present with a rash and be mistaken for dengue, Joob [/bib_ref] In two patients, unilateral lesions on the thigh resembling livedo reticularis or erythema ab igne have been described with microthromboses discussed as possible etiology . [bib_ref] A dermatologic manifestation of COVID-19: transient livedo reticularis, Manalo [/bib_ref] Chilblain-like skin lesions have been frequently reported to be associated with COVID-19 22,35-37 . [bib_ref] COVID-19) infection-induced chilblains: a case report with histopathological findings, Kolivras [/bib_ref] They appear in up to 19% of patients, typically in mildly affected ones, and late in the evolution of the disease. [bib_ref] Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus..., Casas [/bib_ref] ## \| antivir al ag ents us ed for vir al pneumonia ## \| clinical use in covid-19 Most antiviral agents used for COVID-19 act either by inhibiting hydroxychloroquine. [bib_ref] The epidemiology, diagnosis and treatment of COVID-19, Zhai [/bib_ref] [bib_ref] Therapeutic options for the 2019 novel coronavirus (2019-nCoV), Li [/bib_ref] [bib_ref] Treatment options for COVID-19: The reality and challenges, Jean [/bib_ref] [bib_ref] SARS-CoV-2: recent reports on antiviral therapies based on lopinavir/ritonavir, darunavir/ umifenovir, hydroxychloroquine,..., Costanzo [/bib_ref] Oseltamivir is recommended for concomitant influenza infection. [bib_ref] Oseltamivir for influenza in adults and children: systematic review of clinical study..., Jefferson [/bib_ref] Darunavir or LPV/r can be concomitantly administered with chloroquine or hydroxychloroquine. [bib_ref] SARS-CoV-2: recent reports on antiviral therapies based on lopinavir/ritonavir, darunavir/ umifenovir, hydroxychloroquine,..., Costanzo [/bib_ref] ## \| hypersensitivity reactions Drug hypersensitivity reactions to ribavirin, darunavir, LPV/r, remdesivir, and oseltamivir are rarely reported, whereas no DHRs to favipiravir and umifenovir are known at present [bib_ref] Cochrane systematic review: pegylated interferon plus ribavirin vs. interferon plus ribavirin for..., Simin [/bib_ref] [bib_ref] A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe COVID-19, Cao [/bib_ref] [bib_ref] Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48..., Madruga [/bib_ref] [bib_ref] Oseltamivir induced Stevens-Johnson syndrome/toxic epidermal necrolysis-case report, Zuo [/bib_ref] [bib_ref] Oseltamivir-induced toxic epidermal necrolysis in a patient with Cushing's disease, Gonzalez-Ramos [/bib_ref] [bib_ref] Compassionate use of remdesivir for patients with severe COVID-19, Grein [/bib_ref]. ## \| ribavirin Ribavirin is used in combination with pegylated-interferon α2a (peg-IFN-α2a) for treating chronic hepatitis C, and both have been associated with several cutaneous DHRs. [bib_ref] Ribavirin for chronic hepatitis C: and the mystery goes on, Brillanti [/bib_ref]. The etiological diagnosis is difficult in case of combination therapy. A drug provocation test (DPT) confirmed the diagnosis of ribavirin hypersensitivity in a patient having MPE due to combined use of peg-IFN-α2a and ribavirin. [bib_ref] Delayed hypersensitivity to ribavirin confirmed by provocation test, Barreira [/bib_ref] In another case, an erythema multiforme-type drug eruption occurred with peg-IFN-α2a, ribavirin, and/or fluvastatin sodium therapy and a positive lymphocyte transformation test (LTT) confirmed the diagnosis of ribavirin hypersensitivity. [bib_ref] Adverse skin reactions due to ribavirin in hepatitis C combination therapy with..., Shindo [/bib_ref] Successful desensitization protocols were reported [bib_ref] Successful desensitization to ribavirin in a patient with chronic hepatitis C, Ladd [/bib_ref] [bib_ref] Ribavirin desensitization in chronic hepatitis C, Toker [/bib_ref]. ## \| lopinavir/ritonavir (lpv/r) Lopinavir/ritonavir, either alone or in combination, has been rarely reported to be associated with DHRs. In human immunodeficiency virus (HIV)-infected patients who received LPV/r combination, MPE rate was reported as 2%-4%.Acute generalized exanthematous pustulosis (AGEP) was described in two cases receiving LPV/r 61. In a multicentre randomized study that evaluated the long-term efficacy and safety of the combination of efavirenz or LPV/r plus abacavir/lamivudine, 2/63 patients in the LPV/r group discontinued the study because of a DHR.In a recent cohort of 199 severe COVID-19-infected patients who received LPV/r combination, only two (1%) experienced self-limited skin eruptions. [bib_ref] A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe COVID-19, Cao [/bib_ref] A recent study evaluating 217 patients from China revealed that most of the adverse drug reactions (ADRs) were associated with LPV/r and umifenovir with 63.8% and 18.1%, respectively, and history of a drug allergy was higher in these patients (8.5%) comparing with the ones without ADRs (2.2% vs, P < .044). 63 ## \| darunavir Darunavir can induce a variety of delayed skin eruptions from mild MPE in most cases, to severe bullous cutaneous reactions in HIVinfected patients. [bib_ref] Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48..., Madruga [/bib_ref] [bib_ref] Safety and efficacy of darunavir (TMC114) with low-dose ritonavir in treatment-experienced patients:..., Molina [/bib_ref] A phase III randomized clinical trial performed in 604 patients treated with darunavir/r or LPV/r showed that the percentage of patients experiencing rash was higher in those receiving darunavir/r compared with others (16% vs 7%). Two patients receiving darunavir/r required treatment cessation due to a severe rash. [bib_ref] Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48..., Madruga [/bib_ref] Darunavir contains a sulfonamide moiety and should be used with caution in patients with a known sulfonamide allergy. [bib_ref] Cross-reactivity between darunavir and trimethoprim-sulfamethoxazole in HIV-infected patients, Buijs [/bib_ref] Desensitization was reported to be successful in patients with nonimmediate hypersensitivity reactions (NIHRs) to darunavir [bib_ref] Hypersensitivity reaction to darunavir and desensitization protocol, Bravo [/bib_ref] [bib_ref] Hypersensitivity and desensitization to darunavir in a case of HIV infection with..., Lorber [/bib_ref]. ## \| oseltamivir Oseltamivir, used in influenza, causes rare hypersensitivity reactions although close monitoring of patients is important as two cases with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) have been reported, [bib_ref] Oseltamivir induced Stevens-Johnson syndrome/toxic epidermal necrolysis-case report, Zuo [/bib_ref] [bib_ref] Oseltamivir-induced toxic epidermal necrolysis in a patient with Cushing's disease, Gonzalez-Ramos [/bib_ref] with only one being confirmed by LTT. [bib_ref] Oseltamivir-induced toxic epidermal necrolysis in a patient with Cushing's disease, Gonzalez-Ramos [/bib_ref] Another case report revealed anaphylaxis due to oseltamivir confirmed by a skin prick test (SPT) [bib_ref] Anaphylaxis after Oseltamivir (Tamiflu) therapy in a patient with sensitization to star..., Hirschfeld [/bib_ref]. ## \| remdesivir A recent multicentre study showed that only one (1.6%) out of 61 patients with COVID-19, experienced MPE during remdesivir treatment and therefore discontinued it prematurely 51. ## \| antivir al and/or immunomodul atory drug s us ed for vir al pneumonia ## \| azithromycin ## \| clinical use in covid-19 Azithromycin interferes with virus internalization process in influenza infection [bib_ref] Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering..., Tran [/bib_ref] and has shown clinical effects in COVID-19infected patients, although its mechanism against SARS-CoV-2 remains unclear. 70 ## \| hypersensitivity reactions Regarding immediate hypersensitivity reactions (IHRs), urticaria is the most frequent manifestation [bib_ref] Macrolides allergy, Araujo [/bib_ref] ; furthermore, anaphylaxis can occur. [bib_ref] Azithromycin anaphylaxis in children, Mori [/bib_ref] Concerning NIHRs, MPE is described to occur independently 73 or only in the presence of a concurrent infection. [bib_ref] Azithromycin eruption in infectious mononucleosis: a proposed mechanism of interaction, Schissel [/bib_ref] Azithromycin has been implicated in contact dermatitis in occupational 75 and nonoccupational settings. [bib_ref] Non-occupational allergic contact dermatitis caused by azithromycin in an eye solution, Mendes-Bastos [/bib_ref]. Diagnosis is complex as skin testing is not validated, presenting discrepancies in nonirritating dilutions for SPT and intradermal test (IDT). [bib_ref] Nonirritating intradermal skin test concentrations for commonly prescribed antibiotics, Empedrad [/bib_ref] [bib_ref] Determination of nonirritating concentrations of antibiotics for intradermal skin tests in Korean..., Won [/bib_ref] For NIHRs, positive responses to patch tests (PTs)were described. [bib_ref] Occupational allergic contact dermatitis from azithromycin in pharmaceutical workers: a case series, Milkovic-Kraus [/bib_ref] In addition, no validated in vitro tests are available. [bib_ref] Suspicion of macrolide allergy after treatment of infectious diseases including Helicobacter pylori:..., Seitz [/bib_ref] Oral DPT remains as the gold standard for diagnosis. [bib_ref] Diagnostic value of oral challenge testing in the diagnosis of macrolide hypersensitivity, Unal [/bib_ref] A successful desensitization protocol was reported in a case of mast cell activation syndrome 88. ## \| hydroxychloroquine/chloroquine ## \| clinical use in covid-19 Hydroxychloroquine/chloroquine have in vitro antiviral effects against SARS-Cov-2 by preventing virus/cell fusion, and immunomodulatory effects by inhibiting production of inflammatory cytokines. 89 ## \| hypersensitivity reactions Dermatologic ADRs are difficult to be distinguished as a side effect of or an allergic reaction to these drugs or a flare of the underlying dermatological disease. [bib_ref] Cutaneous adverse drug reactions with antimalarials and allergological skin tests, Soria [/bib_ref] [bib_ref] Early cutaneous eruptions after oral hydroxychloroquine in a lupus erythematosus patient: A..., Matsuda [/bib_ref] The most common manifestation is mild pruritic MPEs within initial 4 weeks of treatment. [bib_ref] Cutaneous adverse drug reactions with antimalarials and allergological skin tests, Soria [/bib_ref] Recently, a 5-hour desensitization protocol for nonimmediate urticaria was successfully administered 108. Two cases of IHR were reported [bib_ref] Successful desensitization for hydroxychloroquine anaphylaxis, Donado [/bib_ref] [bib_ref] Short desensitization in an adolescent with hydroxychloroquine anaphylaxis, Perez-Sanchez [/bib_ref] and one was confirmed by SPTs 109 ; however, there are no available data for in vitro diagnosis. A hydroxychloroquine desensitization procedure that enables the turning of positive SPTs into negative was published. [bib_ref] Successful desensitization for hydroxychloroquine anaphylaxis, Donado [/bib_ref] In a case of anaphylaxis, a 7 day-desensitization procedure was successfully performed with premedication 110. ## \| auranofin ## \| clinical use in covid-19 Auranofin is an anti-inflammatory compound that can possibly inhibit the replication of SARS-CoV-2 in cell culture and reduce the expression of cytokines caused by SARS-CoV-2 and the associated lung damage. 111 ## \| hypersensitivity reactions There are no reported hypersensitivity reactions due to auranofin. ## \| interferons ## \| clinical use in covid-19 Type ## \| hypersensitivity reactions Cutaneous eruptions induced by IFNs are common, with an incidence of 13%-23%. [bib_ref] Eczema-like lesions and disruption of therapy in patients treated with interferon-alfa and..., Vazquez-Lopez [/bib_ref] ## \| ivermectin ## \| clinical use in covid-19 Ivermectin is an antiparasitic drug also shown to have an in vitro activity against SARS-CoV-2 by inhibition of viral replication. 128 ## \| hypersensitivity reactions Rare case reports of multiple FDEs, [bib_ref] Ivermectin-induced fixed drug eruption in an elderly Cameroonian: a case report, Ngwasiri [/bib_ref] confirmed DRESS by skin biopsy and blood eosinophilia, [bib_ref] Ivermectininduced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Kerneuzet [/bib_ref] confirmed SJS 131 and TEN 132 by skin biopsy were published ( ## \| nitazoxanide ## \| clinical use in covid-19 Nitazoxanide is an antiparasitic agent which also has antiviral activities. Combined with hydroxychloroquine or azithromycin, a synergistic effect has been suggested as hydroxychloroquine and azithromycin inhibit viral entry and fusion, while nitazoxanide upregulates innate immune response to prevent ongoing viral replication in COVID-19. 133 ## \| hypersensitivity reactions No DHRs to nitazoxanide are reported. ## \| anti -c y tok ine/anti -infl ammatory drug s us ed for ma s/ c y tokine s torm/ards ## \| tocilizumab ## \| clinical use in covid-19 Tocilizumab, an anti-IL-6 receptor humanized monoclonal antibody, is under investigation for treatment of COVID-19 and has shown promising results in cytokine storm. 6 ## \| hypersensitivity reactions The rate of all ADRs to tocilizumab is reported to be around 8%, among them 0.1%-0.7% are DHRs. [bib_ref] Hypersensitivity to biological agents-Updated diagnosis, management and treatment, Regnier Galvao [/bib_ref] revealed that STs have a low negative predictive value in NIHR. [bib_ref] Management of hypersensitivity reactions to Tocilizumab, Tetu [/bib_ref] Desensitization to tocilizumab in NIHRs was effectively applied in a weekly scheme with premedication in one case. [bib_ref] Effective desensitization to tocilizumab in delayed hypersensitivity reaction, Cortellini [/bib_ref] Rapid drug desensitization is successfully and routinely used for IHRs [bib_ref] General considerations on rapid desensitization for drug hypersensitivity -a consensus statement, Cernadas [/bib_ref] [bib_ref] Hypersensitivity to biological agents-Updated diagnosis, management and treatment, Regnier Galvao [/bib_ref]. ## \| anakinra ## \| clinical use in covid-19 Anakinra, a recombinant IL-1 receptor antagonist, is under investigation for the treatment of cytokine storm seen during COVID-19. 5 ## \| hypersensitivity reactions Anakinra causes ADRs in 75% of patients. Many of them are related to injection site reactions within the first weeks of application and can present either as an IHR or NIHR. [bib_ref] Observational study on efficacy, safety, and drug survival of anakinra in rheumatoid..., Den Broeder [/bib_ref] [bib_ref] Injection-site reactions upon Kineret (anakinra) administration: experiences and explanations, Kaiser [/bib_ref] Systemic IHRs such as urticaria, angioedema, anaphylaxis, [bib_ref] Successful desensitization with anakinra in a case with immediate hypersensitivity reaction, Soyyigit [/bib_ref] [bib_ref] Anaphylactic reaction to anakinra in a rheumatoid arthritis patient intolerant to multiple..., Desai [/bib_ref] [bib_ref] Successful rapid subcutaneous desensitization to anakinra in a case with a severe..., Yılmaz [/bib_ref] and NIHRs 152 as infiltrating erythematous skin plaques were rarely reported as single cases. IHR after a first dose of anakinra was reported in a case possibly due to components that are able to induce a direct mast cell degranulation [bib_ref] Successful rapid subcutaneous desensitization to anakinra in a case with a severe..., Yılmaz [/bib_ref] [bib_ref] Cutaneous mast cell degranulation in rats receiving injections of recombinant human interleukin-1..., Bendele [/bib_ref]. For evaluating IHRs to anakinra, SPTs and IDTs were performed with the undiluted drug. [bib_ref] Anaphylactic reaction to anakinra in a rheumatoid arthritis patient intolerant to multiple..., Desai [/bib_ref] [bib_ref] Successful rapid subcutaneous desensitization to anakinra in a case with a severe..., Yılmaz [/bib_ref] For both IHRs [bib_ref] Successful desensitization with anakinra in a case with immediate hypersensitivity reaction, Soyyigit [/bib_ref] [bib_ref] Successful rapid subcutaneous desensitization to anakinra in a case with a severe..., Yılmaz [/bib_ref] and NIHRs, [bib_ref] Rapid desensitization to anakinra-related delayed reaction: Need for a standardized protocol, Emmi [/bib_ref] successful desensitization protocols were reported . ## \| sarilumab ## \| clinical use in covid-19 Sarilumab, another IL-6 receptor antagonist, is under investigation in a phase II/III clinical trial in patients with severe COVID-19 infection. 154 ## \| hypersensitivity reactions It is generally a well-tolerated drug; however, it can cause local reactions on injection site. In an open-label study, in 3% of the patients it caused a pruritic generalized rash which did not affect the treatment [bib_ref] Immunogenicity of sarilumab monotherapy in patients with rheumatoid arthritis who were inadequate..., Wells [/bib_ref]. ## \| canakinumab ## \| clinical use in covid-19 Canakinumab, a high-affinity human anti-IL-1β monoclonal antibody, is considered as a candidate in treatment of severe COVID-19. 156 ## \| hypersensitivity reactions This anti-IL-1 agent is normally well tolerated and indicated as an alternative in cases with an anaphylactic reaction to anakinra. [bib_ref] Drug reactions in children with rheumatic diseases receiving parenteral therapies: 9 years'..., Koc [/bib_ref] However, there is a recently reported case who developed immediate diffuse urticaria after the tenth canakinumab administration and was prevented from further reactions with cetirizine premedication 137 . ## \| janus kinase (jak) inhibitors (baricitinib, ruxolitinib, tofacitinib) ## \| clinical use in covid-19 Janus kinase inhibitors are under investigation for their potential role in regulating the overactive signaling in the JAK-STAT pathway seen during cytokine storm in critically ill COVID-19-infected patients. Baricitinib with its potential to inhibit clathrin-mediated endocytosis, and its ability to ameliorate associated chronic inflammation in interferonopathies is expected to show promising results in ongoing clinical trials of COVID-19. 157,158 ## \| hypersensitivity reactions Few cases were reported: one with a morbiliform eruption and exfoliative dermatitis due to ruxolitinib, [bib_ref] Drug-associated skin lesions in a patient with myelofibrosis receiving ruxolitinib, Fournier [/bib_ref] another one with palmoplantar pustulosis due to baricitinib, [bib_ref] Palmoplantar pustulosis-like eruption induced by baricitinib for treatment of rheumatoid athritis, Koumaki [/bib_ref] and cases of acute urticaria [bib_ref] An urticarial drug eruption caused by tofacitinib for alopecia universalis, Doohan [/bib_ref] and palmoplantar pustulosis 162 due to tofacitinib . ## \| cyclosporine ## \| clinical use in covid-19 Cyclosporine A prevents the transcription of genes encoding cytokines like IL-2 and inhibits the replication of diverse coronaviruses at noncytotoxic, low-micromolar concentrations in vitro. [bib_ref] Cyclosporin A inhibits the replication of diverse coronaviruses, De Wilde [/bib_ref] ## \| hypersensitivity reactions Rare cases of pruritus, urticaria, angioedema, and anaphylaxis were reported. [bib_ref] Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and..., Volcheck [/bib_ref] [bib_ref] Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?, Kang [/bib_ref] [bib_ref] IgE-mediated anaphylaxis after first intravenous infusion of cyclosporine, Ebo [/bib_ref] The possible mechanisms can be both immunologic and nonimmunologic, which seems to depend on the administration route and formulation. [bib_ref] Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and..., Volcheck [/bib_ref] In some cases, DHRs have been attributed to the additives such as castor oil [bib_ref] Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?, Kang [/bib_ref] or Cremophor EL. [bib_ref] IgE-mediated anaphylaxis after first intravenous infusion of cyclosporine, Ebo [/bib_ref] SPTs and IDTs or basophil activation test (BAT) can be used for the diagnosis of cyclosporine-and additive-induced IgE-mediated IHRs [bib_ref] In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest..., Mayorga [/bib_ref] [bib_ref] Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and..., Volcheck [/bib_ref] [bib_ref] IgE-mediated anaphylaxis after first intravenous infusion of cyclosporine, Ebo [/bib_ref]. ## \| colchicine ## \| clinical use in covid-19 It is a nonselective inhibitor of NLRP3 inflammasome which is thought to be a major pathophysiologic component of ARDS and/or acute lung injury seen in COVID-19. 167 ## \| hypersensitivity reactions Rare cases of anaphylaxis, [bib_ref] Successful rapid subcutaneous desensitization to anakinra in a case with a severe..., Yılmaz [/bib_ref] confirmed FDE with DPT 168 and successfully desensitized MPE [bib_ref] Reporting a desensitization protocol for colchicine treatment, Levinger [/bib_ref] were reported. For PTs, it is recommended to dilute colchicine to 1% in petrolatum [bib_ref] Relevance of skin tests with drugs in investigating cutaneous adverse drug reactions, Barbaud [/bib_ref]. ## \| eculizumab ## \| clinical use in covid-19 Eculizumab, a humanized anti-C5 monoclonal antibody, is under investigation as a candidate drug to play a role in the thrombotic microvascular injury mediated by complement activation causing lung injury either due to severe pneumonia or ARDS in severe COVID-19. 21,36,171 ## \| hypersensitivity reactions Immediate hypersensitivity reactions or infusion reactions due to eculizumab are very rare. [bib_ref] Safety and efficacy of eculizumab in Guillain-Barre syndrome: a multicentre, double-blind, randomised..., Misawa [/bib_ref] [bib_ref] Eculizumab safety: five-year experience from the global atypical hemolytic uremic syndrome registry, Rondeau [/bib_ref] A case of anaphylaxis diagnosed with STs was successfully desensitized with a rapid protocol 174 . ## \| glucocorticoids ## \| clinical use in covid-19 In COVID-19-infected patients, the use of glucocorticoids (GCs) is rather controversial. [bib_ref] Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury, Russell [/bib_ref] [bib_ref] Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia, Zhou [/bib_ref] Early start of GCs could be helpful for patients who have an overly exuberant inflammatory response or are at high risk of developing ARDS, whereas the benefit of GCs as rescue treatment remains doubtful. 177 ## \| hypersensitivity reactions IHRs to GCs are overall rare and mostly IgE-mediated. [bib_ref] Cross-reactivity in cell-mediated and IgE-mediated hypersensitivity to glucocorticoids, Ventura [/bib_ref] [bib_ref] Allergic hypersensitivity to topical and systemic corticosteroids: a review, Baeck [/bib_ref] [bib_ref] Skin testing for immediate hypersensitivity to corticosteroids: a case series and literature..., Baker [/bib_ref] [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] IgE-mediated hypersensitivity reactions to methylprednisolone, Aranda [/bib_ref] [bib_ref] Immediate hypersensitivity to corticosteroids, Venturini [/bib_ref] In a review of the literature from 2004 to 2014, anaphylaxis was the most common manifestation reported (60.8%, 73/120 reactions) followed by urticaria and/or angioedema (26.7%). Methylprednisolone was implicated in 41% of reactions, followed by prednisolone (20%), triamcinolone (14%), and hydrocortisone (10%). [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] In most subjects with IHRs, it is possible to identify the culprit and safe alternative GCs by performing immediate-reading STs. [bib_ref] Cross-reactivity in cell-mediated and IgE-mediated hypersensitivity to glucocorticoids, Ventura [/bib_ref] [bib_ref] Allergic hypersensitivity to topical and systemic corticosteroids: a review, Baeck [/bib_ref] [bib_ref] Skin testing for immediate hypersensitivity to corticosteroids: a case series and literature..., Baker [/bib_ref] [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] IgE-mediated hypersensitivity reactions to methylprednisolone, Aranda [/bib_ref] [bib_ref] Immediate hypersensitivity to corticosteroids, Venturini [/bib_ref] [bib_ref] Hypersensitivity to systemic corticosteroids: an infrequent but potentially life-threatening condition, Rachid [/bib_ref] [bib_ref] Steroid allergy: clinical features and the importance of excipient testing in a..., Li [/bib_ref] In the aforementioned review, 74.1% of 112 STs carried out with GCs suspected of being responsible for reactions were positive. [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] In some subjects, positive STs were associated with positive serum-specific IgE assays and BATs [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] IgE-mediated hypersensitivity reactions to methylprednisolone, Aranda [/bib_ref]. Immediate hypersensitivity reactions to medication components other than the GC itself, such as succinate ester used to enhance the solubility in parenteral preparations, have been described. [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] Steroid allergy: clinical features and the importance of excipient testing in a..., Li [/bib_ref] Hence, when evaluating a reaction to an esterified GC, it is advisable to include in STs the suspected GC and the same GC without the ester component, or with a different ester. Immediate hypersensitivity reactions to excipients or preservatives in GC preparations, such as lactose, carboxymethylcellulose, polyethylene glycol, and hexylene glycol, have also been reported. [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] Steroid allergy: clinical features and the importance of excipient testing in a..., Li [/bib_ref] Therefore, testing should be performed with a preservative free GC, in addition to preservative testing per se if needed 185 . A study proposed a comprehensive diagnostic algorithm to evaluate hypersensitivity reactions to GCs, as well as to their components and preservatives. [bib_ref] Steroid allergy: clinical features and the importance of excipient testing in a..., Li [/bib_ref] This algorithm included STs with Carmellose ® eye drops in subjects who had reacted to carboxymethylcellulose-containing GCs and with cow's milk proteins in those who had reacted to lactose-containing GCs. In the allergy workup, negative results in STs should be confirmed with DPTs. [bib_ref] Skin testing for immediate hypersensitivity to corticosteroids: a case series and literature..., Baker [/bib_ref] [bib_ref] Immediate hypersensitivity reactions to corticosteroids, Patel [/bib_ref] [bib_ref] IgE-mediated hypersensitivity reactions to methylprednisolone, Aranda [/bib_ref] [bib_ref] Immediate hypersensitivity to corticosteroids, Venturini [/bib_ref] [bib_ref] Hypersensitivity to systemic corticosteroids: an infrequent but potentially life-threatening condition, Rachid [/bib_ref] [bib_ref] Steroid allergy: clinical features and the importance of excipient testing in a..., Li [/bib_ref] DPTs are also recommended to ensure tolerance of alternative preparations. [bib_ref] Hypersensitivity to systemic corticosteroids: an infrequent but potentially life-threatening condition, Rachid [/bib_ref] Cross-reactivity patterns based on structural characteristics have not been clearly established for IHRs as they have been for allergic contact dermatitis. [bib_ref] Allergic hypersensitivity to topical and systemic corticosteroids: a review, Baeck [/bib_ref] DPTs have shown that patients often tolerate alternative GCs belonging to the same chemical group as the responsible GC. [bib_ref] IgE-mediated hypersensitivity reactions to methylprednisolone, Aranda [/bib_ref] [bib_ref] Immediate hypersensitivity to corticosteroids, Venturini [/bib_ref] Desensitization to methylprednisolone has been successfully performed [bib_ref] Successful rapid desensitization to methylprednisolone sodium hemisuccinate: a case report, Angel-Pereira [/bib_ref] [bib_ref] Successful methylprednisolone desensitization in a pediatric patient, Guvenir [/bib_ref]. Nonimmediate hypersensitivity reactions following systemic administration of GCs have been more rarely reported than IHRs; most reports concerned isolated cases of eczematous or exanthematous skin eruptions [bib_ref] Cross-reactivity in cell-mediated and IgE-mediated hypersensitivity to glucocorticoids, Ventura [/bib_ref] [bib_ref] Allergic hypersensitivity to topical and systemic corticosteroids: a review, Baeck [/bib_ref] [bib_ref] High rate of skin complications due to low-molecular-weight heparins in pregnant women, Bank [/bib_ref] [bib_ref] Non-immediate heparin and heparinoid cutaneous allergic reactions: a role for fondaparinux, Tan [/bib_ref] If the treatment is continued regardless of a local reaction, the patient may develop generalized eczema or exanthem. [bib_ref] Enoxaparin-induced generalized exanthem, Kim [/bib_ref] [bib_ref] Management of allergy to heparins in postoperative care: subcutaneous allergy and intravenous..., Seitz [/bib_ref] Patients with a NIHR to UFH or LMWH at injection site usually tolerate intravenous administration of UFH. [bib_ref] Heparin allergy: delayed-type non-IgE-mediated allergic hypersensitivity to subcutaneous heparin injection, Trautmann [/bib_ref] Cross-reactivity among LMWHs has been reported in NIHRs. [bib_ref] Clinical patterns of heparin allergy: cross-reactivity between low-molecular-weight heparins and unfractionated heparins, Rodriguez-Fernandez [/bib_ref] However, fondaparinux is generally well tolerated in patients who react to LMWHs. [bib_ref] Non-immediate heparin and heparinoid cutaneous allergic reactions: a role for fondaparinux, Tan [/bib_ref] Heparin may induce DRESS Immune-mediated heparin-induced thrombocytopenia (HIT) is induced by IgG antibodies against complex of heparin and platelet-factor 4 tetramers. [bib_ref] Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin..., Greinacher [/bib_ref] HIT manifests as a more than 50% decrease in the platelet count in 5-10 days after the onset of treatment. [bib_ref] Heparin-Induced Thrombocytopenia, Greinacher [/bib_ref] The risk of HIT is increased exclusively with UFH. [bib_ref] Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis, Martel [/bib_ref] Treatment includes the discontinuation of heparin and the introduction of an alternative anti-coagulant such as argatroban, fondaparinux, danaparoid, or bivalirudin. [bib_ref] Heparin-induced recurrent anaphylaxis, Berkun [/bib_ref] The IgE-mediated reactions to heparin manifesting as urticaria, angioedema, and anaphylaxis are rare. [bib_ref] Clinical patterns of heparin allergy: cross-reactivity between low-molecular-weight heparins and unfractionated heparins, Rodriguez-Fernandez [/bib_ref] [bib_ref] Heparin-induced recurrent anaphylaxis, Berkun [/bib_ref] [bib_ref] Allergic anaphylaxis due to subcutaneously injected heparin, Anders [/bib_ref] Positive STs with UFH and LMWHs have been reported [bib_ref] Clinical patterns of heparin allergy: cross-reactivity between low-molecular-weight heparins and unfractionated heparins, Rodriguez-Fernandez [/bib_ref] [bib_ref] Heparin-induced recurrent anaphylaxis, Berkun [/bib_ref] [bib_ref] Allergic anaphylaxis due to subcutaneously injected heparin, Anders [/bib_ref] [bib_ref] Immediate type hypersensitivity to Heparins: two case reports and a review of..., Cesana [/bib_ref]. Crossreactivity in IHRs has been reported between UFH and LMWH and among LMWHs. [bib_ref] Immediate type hypersensitivity to Heparins: two case reports and a review of..., Cesana [/bib_ref] For IHRs with heparins, diagnostic approach primarily consists of SPTs and IDTs. [bib_ref] Skin test concentrations for systemically administered drugs -an ENDA/EAACI Drug Allergy Interest..., Brockow [/bib_ref] The results of BAT with UFH and LMWH are controversial. [bib_ref] Allergic anaphylaxis due to subcutaneously injected heparin, Anders [/bib_ref] [bib_ref] Recurrent anaphylaxis due to enoxaparin, Leguisamo [/bib_ref] [bib_ref] Allergy to heparin: a new in vitro diagnostic technique, Caballero [/bib_ref] Heparin itself may cause a release of histamine, leading to a false-positive ST. Further serial dilutions of heparin (1:100, 1:1000, 1:10 000) might be needed. [bib_ref] Allergic anaphylaxis due to subcutaneously injected heparin, Anders [/bib_ref] IDTs and PTs with the culprit and alternative heparin are performed in NIHRs. [bib_ref] Skin test concentrations for systemically administered drugs -an ENDA/EAACI Drug Allergy Interest..., Brockow [/bib_ref] PTs, with tape stripping, are less sensitive but may be positive [bib_ref] Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options, Bircher [/bib_ref]. Drug provocation test is considered when the diagnosis is obscure, tissue pathology is unavailable, or an alternative anti-coagulant needs to be determined. [bib_ref] Heparin-induced skin lesions, Schindewolf [/bib_ref] been established yet and published as case reports [bib_ref] Heparin allergy: successful desensitization for cardiopulmonary bypass, Parekh [/bib_ref] [bib_ref] Rush desensitization in heparin hypersensitivity: a case report, Patriarca [/bib_ref]. ## \| dipyridamole ## \| clinical use in covid-19 Dipyridamole is an inhibitor of phosphodiesterase 3 and 5; thereby, it increases intracellular cAMP and/or cGMP in platelets and inhibits platelet aggregation. [bib_ref] Anti-platelet therapy: phosphodiesterase inhibitors, Gresele [/bib_ref] ## \| hypersensitivity reactions Drug hypersensitivity reactions related to dipyridamole are extremely rare. An adult patient with delayed eczematous lesions revealed positive PT results. [bib_ref] Dipyridamole-induced eczematous drug eruption with positive patch test reaction, Salava [/bib_ref] Anaphylaxis or anaphylaxis like reactions were described in two cases; however, they lack diagnostic tests [bib_ref] Acute reaction to dipyridamole during myocardial scintigraphy, Angelides [/bib_ref] [bib_ref] Anaphylaxis-like reaction induced by dipyridamole during myocardial scintigraphy, Weinmann [/bib_ref]. ## \| d iag nos is , d ifferential d iag nos is , and manag ement of dhr s due to drug s inve s ti g ated for the tre atment of covid -19 Considering the severity of the disease and the emergent need for Our recommendations for the diagnosis and management of DHRs due to drugs administered during COVID-19 are listed in Box 1. This review also highlights the presence of two different groups of disease-related exanthems as an important cause of differential diagnosis of DHRs expected during the treatment of the disease. We think that it is extremely important to distinguish these disease-related eruptions from true DHR-related skin manifestations considering that the majority of the drugs used are more associated with drug-related nonimmediate skin reactions. ## \| con clus ion In near future, further data from ongoing clinical studies and registries established in different countries will enlighten the obscure parts of our understanding on DHRs due to the drugs used in the treatment of COVID-19 and will possibly enable us to establish accurate diagnostic and treatment approaches for these reactions. ## Co n fli c t o f i nte r e s t None of the authors declare conflict of interest. ## O rci d ## Box 1 recommendations for diagnosis and management of dhrs in covid-19 - No equivalent alternatives for the currently off-label repurposed drugs or novel drugs used in COVID-19 do exist. - We should extrapolate our knowledge on DHRs from other clinical situations to COVID-19 considering the scarce experience for the DHRs during the disease. - Various drugs being used in different phases of the disease seem to cause rare but potentially severe DHRs, mostly nonimmediate cutaneous hypersensitivity reactions based on data from limited number of case reports. - The most important differential diagnosis of these DHRs is disease-related exanthems, which can further be classified into the ones similar to those in other viral infections and the others related to thrombovascular events and vascular pathologies seen during COVID-19. - Experience of diagnostic and management methods for DHRs due to the drugs used in COVID-19 depend mostly on few case reports or series. - Knowledge of DHRs is urgently needed from pharmacovigilance registries and data from ongoing clinical trials ofCOVID-19. - Quick diagnostic and therapeutic decisions in case of DHRs during COVID-19 are mandatory. - Clinical diagnosis of DHRs during COVID-19 might mostly rely on clinical observations and basic laboratory findings regarding the need of urgent treatment of COVID-19. - If the risks of a DHR outweigh the benefits obtained from the drug administration, the offending drug should be discontinued. - When introducing an alternative drug, a DPT may be preferred in order to reduce the risk of a possible DHR. - If an alternative drug cannot be replaced, the offending drug can be administered via desensitization with published or tailored protocols when there are no contraindications. - "Treating through" concept, the continued administration of a drug despite a suspected allergic hypersensitivity reaction, can also be considered under strict surveillance measures if the underlying DHR is mild and self-limiting, and an alternative drug does not exist. [fig] France: reported a prevalence of 5/103 (4.9%) and confirmed association of pruritic erythematous rash (n = 2) and urticaria (n = 2) with COVID-19 infections 31 ; they additionally observed one oral herpes simplex virus type 1 reactivation. The histopathological picture of exanthematic skin lesions generally resembles that of viral exanthems. However, in individual patients, early microthrombi and an interface dermatitis with necrotic keratinocytes surrounded by lymphocytes have been reported.32 [/fig] [fig] F I G U R E 3 E 2: Skin manifestations associated with thrombovascular events and vascular pathologies. A, Transient unilateral livedo reticularis (erythema ab igne), 34 B, COVID-19-induced chilblains, 35 C, Acro-ischemia with cyanosis, skin bulla, and dry gangrene in critically ill patient 38 Hypersensitivity reactions due to drugs with antiviral properties investigated for the treatment of COVID-19 in clinical trials or in vitro studies Drug groups Drugs Purpose of use in COVID-19 [/fig] [table] Table 2: No data about STs, in vitro tests, or DPT are available. In addition, no cases of desensitization were reported. [/table]	None	https://www.authorea.com/doi/pdf/10.22541/au.158896330.05120330	Coronavirus disease 2019 (COVID‐19), a respiratory tract infection caused by a novel human coronavirus, the severe acute respiratory syndrome coronavirus 2, leads to a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Given the huge influence caused by the overwhelming COVID‐19 pandemic affecting over three million people worldwide, a wide spectrum of drugs is considered for the treatment in the concept of repurposing and off‐label use. There is no knowledge about the diagnosis and clinical management of the drug hypersensitivity reactions that can potentially occur during the disease. This review brings together all the published information about the diagnosis and management of drug hypersensitivity reactions due to current and candidate off‐label drugs and highlights relevant recommendations. Furthermore, it gathers all the dermatologic manifestations reported during the disease for guiding the clinicians to establish a better differential diagnosis of drug hypersensitivity reactions in the course of the disease.
42c15a65ec740b84cd1f0db1a89d4130e5b03814	pubmed	Management of neck metastases in head and neck cancer: United Kingdom National Multidisciplinary Guidelines	Management of neck metastases 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. A rational plan to manage the neck is necessary for all head and neck primaries. With the emergence of new level 1 evidence across several domains of neck metastases, this guideline will identify the evidence-based recommendations for management.Recommendations- Computed tomographic or magnetic resonance imaging is mandatory for staging neck disease, with choice of modality dependant on imaging modality used for the primary site, local availability and expertise. (R) - Patients with a clinically N0 neck, with more than 15-20 per cent risk of occult nodal metastases, should be offered prophylactic treatment of the neck. (R) - The treatment choice of for the N0 and N+ neck should be guided by the treatment to the primary site. (G) - If observation is planned for the N0 neck, this should be supplemented by regular ultrasonograms to ensure early detection. (R) - All patients with T1 and T2 oral cavity cancer and N0 neck should receive prophylactic neck treatment. (R) - Selective neck dissection (SND) is as effective as modified radical neck dissection for controlling regional disease in N0 necks for all primary sites. (R) - SND alone is adequate treatment for pN1 neck disease without adverse histological features. (R) - Post-operative radiation for adverse histologic features following SND confers control rates comparable with more extensive procedures. (R) - Adjuvant radiation following surgery for patients with adverse histological features improves regional control rates. (R) - Post-operative chemoradiation improves regional control in patients with extracapsular spread and/or microscopically involved surgical margins. (R) - Following chemoradiation therapy, complete responders who do not show evidence of active disease on co-registered positron emission tomography-computed tomography (PET-CT) scans performed at 10-12 weeks, do not need salvage neck dissection. (R) - Salvage surgery should be considered for those with incomplete or equivocal response of nodal disease on PET-CT. (R) of disease. Controversy surrounds the management of the neck in head and neck squamous cell cancer. This is primarily due to the paucity of high-level evidence for many treatment paradigms, but this trend may be reversing with randomised controlled trials and systematic reviews published recently and a few # Introduction The presence, site and size of metastatic neck disease are important prognostic factors in head and neck squamous cell cancer. Head and neck tumours have a propensity to metastasise to neck nodes and several factors control the natural history and spread more in progress. This section discusses the management of neck metastases at initial presentation and for residual or recurrent neck disease. It outlines major clinical controversies regarding the management of occult and overt metastatic squamous cell carcinoma (SCC) to the neck nodes. ## Assessment and staging For the purpose of assessment and documentation, the neck is described in six anatomical levels, . Level VII is relevant for some head and neck tumours and is included in the table for completeness. ## Clinical palpation Clinical palpation is regarded as inaccurate (sensitivity and specificity 70-80 per cent) due to factors including inter-operator variability, shape of neck, absence or presence of significant subcutaneous fat and varying size of involved cervical nodes. Computed tomographic (CT) and magnetic resonance imaging (MRI) scanning These techniques have similar sensitivity (81 per cent) in detecting metastatic disease, with CT demonstrating better specificity. [bib_ref] Detection of lymph node metastases in head and neck cancer: a meta-analysis..., De Bondt [/bib_ref] Co-registered positron emission tomography-computed tomography scanning (PET-CT) has been shown to alter initial staging in up to one-third of patients, but the value of this is unclear. This technique has higher sensitivity in picking up clinically occult primaries, synchronous second primaries and distant metastases. PET-CT has demonstrated high negative predictive values in the assessment of neck disease after organ preservation regimes. ## Ultrasound (us) scanning and us-guided fine needle aspiration cytology (fnac) Ultrasound has been demonstrated to have consistently high sensitivity (87 per cent) in diagnosing metastatic neck disease. Ultrasound-guided FNAC requires both expertise and experience, and has very high specificity rates (98 per cent) in diagnosis. It should be noted that there are no absolute ultrasound characteristics for differentiating benign from malignant disease. ## Sentinel node biopsy The aim of this technique is to identify and excise the echelon nodes using radioscintigraphy, which are then tested for occult disease. Patients with no occult disease in the sentinel nodes receive no further treatment for the neck. Meta-analyses suggest that sentinel node biopsy has sensitivity rates exceeding 90 per cent. 2,3 A recent prospective multicentre study that recruited 415 patients with 0.5-4 cm transorally resectable SCC and an N0 neck, showed that sentinel node biopsy had a sensitivity, negative predictive value and false negative rate of 86, 95 and 14 per cent, respectively. [bib_ref] Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in..., Schilling [/bib_ref] [fig_ref] TABLE III CLASSIFICATION: OF NECK DISSECTION TECHNIQUES [/fig_ref]. There is an increasing trend to divide neck dissections into two broad types with subdivisions: comprehensive (removal of levels I-V) and selective (less than five levels). The need for less extensive surgery in the chemoradiation era, with neck dissection procedures that cannot be classified under the existing systems has led to calls for revision of this system. [bib_ref] Proposal for a rational classification of neck dissections, Ferlito [/bib_ref] It is recommended that the levels or sublevels removed during selective neck dissection (SND) be precisely stated in the operation notes. In order to minimise confusion within labelling the levels during processing, the neck dissection specimen should be divided according to the levels in the operating room and sent to the laboratory in different containers. An alternative is to orientate the neck dissection specimen on a suitable base and label the levels with a marking pen, with or without a photograph, and send it to the laboratory. There is good evidence for reduced longterm morbidity with SND compared with the comprehensive types, namely modified radical neck dissection (MRND) and radical neck dissection (RND). Surgical therapy must be delivered within accredited multidisciplinary teams, by members regularly involved in caring for head and neck cancer patients. ## Radiotherapy Radiotherapy (RT) should be delivered within an accredited department using megavoltage photons typically from a linear accelerator (typical energy 6 MV). Similar principles should be used for selecting the nodes for RT as are described above for surgery. The probability of microscopic involvement of other nodal groups rises with increasing T-stage and this leads to larger volumes of tissue-requiring irradiation. Radiotherapy to the neck requires adequate immobilisation and a five-point fixation shell is recommended. Computed tomography scanning in the treatment position provides the anatomical and electron density information required for RT planning. Conventional and three-dimensional conformal RT often require the use of multiple phases of treatment using photons and electrons of appropriate energy. These techniques have now been superseded by intensity modulated radiotherapy (IMRT), particularly where bilateral nodal irradiation is indicated, where it has been shown to be associated with a reduced risk of late xerostomia and has become the standard of care. There is now increasing use of concomitant chemoradiotherapy following publication of level 1 studies, suggesting that use of chemoradiotherapy improves overall and progression free survival in advanced head and neck cancer both in the primary and post-operative settings. Altered fractionation regimes have also been shown to offer some advantage over standard fractionation. ## Management strategies for the various neck nodal stages Treatment of cervical lymph nodes is either elective (in the clinically negative neck) or therapeutic (in the clinically positive neck). Management of the clinically node negative neck (N0) New primary. Clinical and radiological examinations are unable to detect microscopic disease in lymph nodes. Several large retrospective series have reported the incidence of metastases found on histological examination after RNDs in patients with clinically node negative (N0) necks. These figures are useful in identifying the risk of occult metastases in N0 necks and are used to guide clinicians when deciding whether prophylactic treatment of the neck is appropriate . A study of risk-benefit analysis made in the 1990s using data from retrospective series, when RND was the only procedure widely used for elective neck treatment, suggested that prophylactic treatment of the neck was required if the risk of occult nodal metastases rose above 20 per cent. Given the low morbidity of either available treatment modality, there is support for elective treatment for lesser risk (5-15 per cent). Primary sites with greater than 15 per cent risk of occult metastatic disease in the neck would include almost all squamous cancers of the upper aerodigestive tract except T1 and T2 cancers of the glottis and selected T1 cancers of the oral cavity. A recent randomised controlled trial (RCT) reported on 500 patients with lateralised stage T1 or T2 oral SCCs randomised to elective neck dissection (n = 245) or observation and intervention (n = 255), with a median follow up period of 39 months. [bib_ref] Elective versus therapeutic neck dissection in nodenegative oral cancer, D'cruz [/bib_ref] At three years, elective node dissection resulted in an improved rate of overall survival (80.0 per cent; 95 per cent confidence interval (CI), 74.1 to 85.8), as compared with therapeutic dissection (67.5 per cent; 95 per cent CI, 61.0 to 73.9), with a hazard ratio for death of 0.64 in the elective-surgery group (95 per cent CI, 0.45 to 0.92; p = 0.01 by the log-rank test). Patients in the elective-surgery group also had a higher rate of disease-free survival than those in the therapeutic-surgery group (69.5 per cent vs 45.9 per TABLE II TUMOUR-NODE-METASTASIS CLASSIFICATION OF REGIONAL NODES N x Regional lymph nodes cannot be assessed N 0 No regional lymph node metastases N 1 Metastasis in a single ipsilateral lymph node 3 cm or less in greatest dimension N 2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes none more than 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N 2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension N 2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension N 2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N 3 Metastasis in a lymph node more than 6 cm in greatest dimension Note: Midline nodes are considered to be ipsilateral nodes ## S164 cent, p < 0.001). A meta-analysis of all previously published RCTs including data on 283 patients showed that elective neck dissection reduced the risk of disease-specific death (fixed-effects model relative risk = 0.57, 95 per cent CI 0.36-0.89, p = 0.014; random-effects model relative risk = 0.59, 95 per cent CI 0.37-0.96, p = 0.034) compared with observation. [bib_ref] A meta-analysis of the randomized controlled trials on elective neck dissection versus..., Fasunla [/bib_ref] The classical RND has no role to play in elective treatment of the N0 neck. [bib_ref] Management of metastatic neck disease -summary of the 11th Evidence Based Management..., O'hara [/bib_ref] The choice lies between an MRND and an SND. Prospective studies suggest SND is as effective as MRND for most primary sites with minimal morbidity. [fig_ref] TABLE IV RECOMMENDED: NECK LEVELS TO BE DISSECTED FOR OCCULT NECK DISEASE BASED ON PRIMARY... [/fig_ref] shows the suggested neck levels that should be addressed for various primary sites, with the recommendations based on a recent analysis of the evidence base. [bib_ref] Management of metastatic neck disease -summary of the 11th Evidence Based Management..., O'hara [/bib_ref] For oral cavity tumours, SND of levels I to III should be performed. Due to the possibility of skip lesions in level IV, especially in tongue tumours, some studies recommend including level IV. In oropharyngeal, laryngeal and hypopharyngeal tumours, SND of levels II-IV should be performed. Level IIb dissection may not be necessary for the majority of patients, as the incidence of isolated metastasis at this site is less than 2 per cent. [bib_ref] Dissection of the submuscular recess (sublevel IIb) in squamous cell cancer of..., Paleri [/bib_ref] Elective neck irradiation is as effective as elective neck dissection in controlling subclinical regional disease, with control rates reported to be around 90 per cent. When the primary tumour is treated with RT, first echelon lymph nodes, which are at the greatest risk of harbouring occult disease, are usually included in the high dose or radical RT treatment volume. A large retrospective series comparing elective neck dissection and elective neck irradiation in patients with oral cavity, oropharyngeal and laryngeal cancer reported no statistically significant difference in local control at five years. In patients with hypopharyngeal cancers, local control was significantly better with RT compared with surgery. The consensus guidelines drawn up by experts from clinical research organizations within Europe, Asia, Australia/New Zealand and North America, published in 2014, should be followed for delineation of lymph nodal levels in the node negative neck. [bib_ref] Delineation of the neck node levels for head and neck tumors: a..., Gregoire [/bib_ref] Large retrospective series have reported on the risk of contralateral nodal involvement by each anatomic tumour subsite. As in ipsilateral N0 necks, the contralateral neck should be treated if the estimated risk of occult spread exceeds 15-20 per cent, as occurs with tumours encroaching or crossing the midline. Elective nodal irradiation may be preferred to surgery when both sides of the neck are to be treated. In long-term follow-up of the untreated N0 neck, consideration should be given where available to ultrasound surveillance and ultrasound-guided aspiration cytology as a method of detecting and treating early disease before it becomes clinically palpable. [bib_ref] Prospective randomized study of selective neck dissection versus observation for N0 neck..., Yuen [/bib_ref] Recurrent primary cancer. Occult metastatic rates are low (5-10 per cent) in the setting of radiorecurrent cancer if the neck has been included in the radiation field. As neck dissection (ND) in the salvage setting is associated with more complications with no reported benefit, if access to the neck vessels is not needed for primary resection or reconstruction, routine elective neck dissection may not be needed during salvage surgery for locally recurrent primary cancers. Management of the clinically node positive neck When there is clinical or radiological evidence of disease in neck lymph nodes, active treatment is required. Level 1 studies exist to guide the treatment of metastatic neck disease in specific scenarios [fig_ref] FIG. 3: Algorithm for management of the N+ neck when chemoradiation is the primary... [/fig_ref]. The risk of occult metastases in other apparently uninvolved levels of the neck is high, and depending on the primary site, treatment of these nodes is also required. Level V is least likely to be involved, with between 3 and 7 per cent of patients undergoing RND having positive nodes at level V. The treatment choice of the N+ neck should be guided by the treatment to the primary site, and there is long-term data to support this premise. 13 N1 neck disease. Prospective data from large cancer databases suggest that single modality therapy is sufficient to deal with ipsilateral, single nodes of less than 3 cm in size. If surgery is the chosen modality, SND may be appropriate. As approximately 50 per cent of clinically N1 necks are upstaged after pathological assessment, many patients subsequently require post-operative radiation. Prospective studies have shown that in the absence of bulky disease (N1, N2b), appropriate SND in combination with ## Recommendations ## S166 postoperative RT result in neck control rates equivalent to those achieved by comprehensive neck dissection. [bib_ref] Management of metastatic neck disease -summary of the 11th Evidence Based Management..., O'hara [/bib_ref] Complete response rates are much higher in patients with nodes of less than 3 cm in size and regional control rates following RT alone are best in patients with nodes less than 2 cm in size. N2 and N3 neck disease. If the primary modality is surgery for this stage of neck disease, MRND and RND result in equivalent rates of disease control in the neck when performed in appropriately selected patients. [bib_ref] Management of metastatic neck disease -summary of the 11th Evidence Based Management..., O'hara [/bib_ref] Retrospective and prospective studies suggest that adding irradiation post-operatively increases regional control, [bib_ref] Chemotherapy added to locoregional treatment for head and neck squamouscell carcinoma: three..., Pignon [/bib_ref] especially in the presence of adverse features such as extracapsular nodal spread, positive margins, pT3 or pT4 primary, pN2 or pN3 nodal disease, nodal disease in levels IV or V, perineural invasion and vascular invasion. Randomised controlled trials from the EORTC and RTOG have shown improved control with chemoradiotherapy in the post-operative setting, especially in the presence of extracapsular spread and/or microscopically involved surgical margins. [bib_ref] Defining risk levels in locally advanced head and neck cancers: a comparative..., Bernier [/bib_ref] Patients with two or more histopathologically involved lymph nodes without extracapsular spread as their only risk factor did not benefit from the addition of chemotherapy. Morbidity of neck irradiation is higher in patients who have undergone an RND. If the primary site is suitable for non-surgical treatment, the neck should be treated at the same time. For neck disease staged N2 and above, this will usually involve chemoradiotherapy. The PET-Neck phase III randomised trial compared PET-CT-guided active surveillance with planned neck dissection for neck disease staged N2 or N3 treated by chemoradiotherapy. The study recruited 282 patients into each arm and showed that the survival outcomes were similar with a minimum follow up of two years. A post treatment PET-CT surveillance strategy led to fewer neck dissections, fewer complications, was cost effective (per person cost saving of £1415) and provided 0.07 additional quality adjusted life years compared with planned neck dissection. Based on the results of the PET-Neck trial, there is no role for planned neck dissection after primary chemoradiotherapy. [bib_ref] PET-NECK -a multi-centre randomized phase III controlled trial (RCT) comparing PETCT guided..., Mehanna [/bib_ref] The current standard of care should be a CT-PET scan between 10 and 12 weeks following chemoradiotherapy, with ND being offered to those who show incomplete or equivocal response of nodal disease. Complete responders may need no further intervention. [bib_ref] Diagnostic performance of post-treatment FDG PET or FDG PET/CT imaging in head..., Gupta [/bib_ref] The extent of the salvage neck dissection can be based on local protocols, with the recognition that there is an increasing trend to perform a limited neck clearance in these individuals, with removal of the involved level alone or an adjacent level. In patients with fixed and unresectable nodal disease, RT or chemoradiotherapy will be the only options available, but a low likelihood of curative outcome should be recognised. If the primary tumour is small but sited where resection is not feasible, and associated with advanced neck disease, resection of the nodal disease followed by treatment of the primary tumour by RT (± chemotherapy) plus post-operative RT to the involved neck could potentially be considered but this will be associated with a significant delay in the management of the primary disease which may result in interval primary disease progression. ## Recommendations - The treatment choice to the N+ neck should be guided by the treatment to the primary site (G) - Selective neck dissection alone is adequate treatment for pN1 neck disease without adverse histological features (R) - Post-operative radiation for adverse histologic features following SND confers control rates comparable to more extensive procedures (R) - Adjuvant radiation following surgery for patients with adverse histological features improves regional control rates (R) - Post-operative chemoradiation improves regional control in patients with extracapsular spread and/or microscopically involved surgical margins (R) Assessing treatment response Neck node size and fixity predict response rate and local control with RT alone. In patients with clinical N2 or N3 disease, there is poor correlation between clinical and pathological response following chemoradiotherapy. As discussed above, the PET-Neck trial demonstrated equivalent survival rates to planned neck dissection, with a lower morbidity and a higher overall cost-effectiveness. Co-registered PET-CT scans, performed at least 10 weeks after treatment is now considered the standard of care. A negative PET-CT scan following treatment portends a high disease free survival. [bib_ref] Long-term results of positron emission tomography-directed management of the neck in node-positive..., Sjovall [/bib_ref] High standard uptake values are associated with residual disease and this can be used to decide the need for neck dissection following primary chemoradiotherapy. [bib_ref] Diagnostic performance of post-treatment FDG PET or FDG PET/CT imaging in head..., Gupta [/bib_ref] [bib_ref] Management of the neck after chemoradiotherapy for head and neck cancers in..., Wee [/bib_ref] [bib_ref] A systematic review and meta-analysis of the role of positron emission tomography..., Isles [/bib_ref] Recommendations - Following chemoradiation therapy, complete responders who do not show evidence of active disease on co-registered PET-CT scans performed at 10-12 weeks, do not need salvage neck dissection (R) - Salvage surgery should be considered for those with incomplete or equivocal response of nodal disease on PET-CT (R) ## Management of recurrent neck disease Prior to planning salvage treatment, the patient should be meticulously evaluated for distant metastases. This group is likely to benefit from PET-CT scans to look for distant metastases. If the recurrence has occurred following RT or chemoradiotherapy and is surgically resectable, surgery should be offered but acknowledge the higher risk of complications. In patients who present with unresectable disease, re-irradiation with or without chemotherapy should be considered, particularly in those who present more than two years since their previous treatment. Evidence of partial repair of RTinduced spinal cord subclinical damage and newer RT delivery techniques (IMRT, Tomotherapy ® , protons) that allow better sparing of neurological, vascular and soft tissue at risk make this a realistic option in a larger number of patients. In patients who recur after previous surgical treatment, options include re-resection followed by adjuvant radiation, or primary RT or chemoradiotherapy. ## Palliative care Patients who have incurable nodal recurrence present a significant challenge, particularly when distant metastases are not present as people can then live with recurrent disease for many months or longer. Fungating neck nodes have a significant effect on psychosocial function. The impact on speech and swallowing needs careful discussion with dieticians and speech and language therapists so that the potential benefits of tube feeding can be weighed against the risk of over-medicalising terminal care. Specialist palliative care teams should ideally be involved in these discussions before such complications develop. There may be occasions where palliative RT, chemotherapy or surgery have the potential to improve quality of life (QoL) in this situation. The overall expected prognosis, patient perspective and goals, morbidity of treatment and likely benefits need to be openly discussed to ensure that there is a reasonable expectation that any intervention will improve QoL for a given individual. ## Ongoing research Current portfolio studies open to recruitment and relevant to neck metastases include: the role of SND in patients with early oral SCC (1-3 cm primary size) and no clinical evidence of lymph node metastases in the neck (SEND trial). ## Key points - The neck stage is the single most important tumour prognostic factor - Prognosis is affected by number of involved nodes, the anatomic level in the neck, tumour load, the presence of extracapsular spread, perineural and vascular invasion, previous treatment by surgery or radiotherapy and resectability - A large number of malignant nodes will measure less than 10 mm in diameter and extracapsular spread will occur in a substantial percentage of smaller nodes, as small as 2 mm. These may not be identified on conventional (CT and magnetic resonance) imaging - Incidence of nodal metastases depends on site and size of the primary tumour. This figure may be as low as 1 per cent for early glottic tumours or as high as 80 per cent for nasopharyngeal carcinomas - The majority of tumours will metastasise in a predictable manner to certain nodal groups but it should be remembered that tumours can metastasise to more remote sites (i.e. nasopharyngeal cancers to level V, tongue cancers to level IV) and that the pattern of spread will be disrupted by previous surgery or radiotherapy - The possibility of bilateral nodal disease should be considered especially when the primary site involves the tongue base, nasopharynx or supraglottic larynx or when the primary site crosses midline - Neck dissections should be documented as per the accepted classification system - Radiotherapy target delineation should follow the internationally recognised consensus guidelines - Standardised reporting of neck dissection specimens according to the Royal College of Pathologists data set is essential - Issues of function and quality of life have to be considered in the management of metastatic neck disease. [fig] S: Left anterior belly of digastric P (L): Right anterior belly of digastric Nodes above the level of lower body of hyoid bone, below mylohyoid muscles and anterior to a transverse line drawn through the posterior edge of submandibular gland on an axial image Ib ubmandibular triangle : Body of mandible I: Posterior belly of digastric A (M): Anterior belly of digastric P (L): tylohyoid muscle IIa Upper jugular : Lower level of bony margin of jugular fossa I: Level of lower body of hyoid bone A (M): tylohyoid muscle P (L): Vertical plane defined by accessory nerve uperior and inferior limits as described under surgical boundaries Nodes posterior to a transverse plane defined by the posterior surface of submandibular gland and anterior to a transverse line drawn along the posterior border of the sternomastoid. NOTE: Nodes lying medial to the carotids are retropharyngeal and not level II IIb Upper jugular : Lower level of bony margin of jugular fossa I: Level of lower body of hyoid bone A (M): Vertical plane defined by accessory nerve P (L): Posterior border of sternomastoid muscle III Mid Jugular : Level of lower body of hyoid bone I: Horizontal plane along inferior border of anterior cricoid arch A (M): Lateral border of sternohyoid muscle P (L): Posterior border of sternocleidomastoid muscle or sensory branches of the cervical plexus uperior and inferior limits as described under surgical boundaries Nodes anterior to a transverse line drawn on each axial scan through the posterior edge of the CM and lateral to the medial margin of the common carotid arteries IV Lower jugular : Horizontal plane along inferior border of anterior cricoid arch I: Clavicle A (M): Lateral border of sternohyoid muscle P (L): Posterior border of sternocleidomastoid muscle or sensory branches of the cervical plexus uperior and inferior limits as described under surgical boundaries Nodes anterior to a transverse line drawn on each axial scan through the posterior edge of the CM and lateral to the medial margin of the common carotid arteries Va Posterior triangle : Convergence of CM and trapezius muscles I: Horizontal plane along inferior border of anterior cricoid arch A (M): Posterior border of sternocleidomastoid muscle or sensory branches of the cervical plexus P (L): Anterior border of trapezius muscle Nodes posterior to a transverse line drawn on each axial scan through the posterior edge of the = superior; I = inferior, A = anterior; P = posterior, L = lateral; M = medial; CM = sternocleidomastoid NECK METATAE IN HEAD AND NECK CANCER: UK GUIDELINE 163 [/fig] [fig] FIG. 3: Algorithm for management of the N+ neck when chemoradiation is the primary modality.FIG. 2 Algorithm for management of the N+ neck when surgery is the primary modality. V PALERI, T G URBANO, H MEHANNA et al. [/fig] [table] TABLE IV RECOMMENDED: NECK LEVELS TO BE DISSECTED FOR OCCULT NECK DISEASE BASED ON PRIMARY SITE [/table]	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/4F1FD1691DD9BE23CA80DCA0BCBBCBF4/S002221511600058Xa.pdf/div-class-title-management-of-neck-metastases-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. A rational plan to manage the neck is necessary for all head and neck primaries. With the emergence of new level 1 evidence across several domains of neck metastases, this guideline will identify the evidence-based recommendations for management. Recommendations • Computed tomographic or magnetic resonance imaging is mandatory for staging neck disease, with choice of modality dependant on imaging modality used for the primary site, local availability and expertise. (R) • Patients with a clinically N0 neck, with more than 15–20 per cent risk of occult nodal metastases, should be offered prophylactic treatment of the neck. (R) • The treatment choice of for the N0 and N+ neck should be guided by the treatment to the primary site. (G) • If observation is planned for the N0 neck, this should be supplemented by regular ultrasonograms to ensure early detection. (R) • All patients with T1 and T2 oral cavity cancer and N0 neck should receive prophylactic neck treatment. (R) • Selective neck dissection (SND) is as effective as modified radical neck dissection for controlling regional disease in N0 necks for all primary sites. (R) • SND alone is adequate treatment for pN1 neck disease without adverse histological features. (R) • Post-operative radiation for adverse histologic features following SND confers control rates comparable with more extensive procedures. (R) • Adjuvant radiation following surgery for patients with adverse histological features improves regional control rates. (R) • Post-operative chemoradiation improves regional control in patients with extracapsular spread and/or microscopically involved surgical margins. (R) • Following chemoradiation therapy, complete responders who do not show evidence of active disease on co-registered positron emission tomography–computed tomography (PET–CT) scans performed at 10–12 weeks, do not need salvage neck dissection. (R) • Salvage surgery should be considered for those with incomplete or equivocal response of nodal disease on PET–CT. (R)
fbb033341776a438f2bb48d8e7b5044fe0984bad	pubmed	Serum neurofilament light as a biomarker in progressive multiple sclerosis	Serum neurofilament light as a biomarker in progressive multiple sclerosis There is an unmet need in multiple sclerosis (MS) therapy for treatments to stop progressive disability. The development of treatments may be accelerated if novel biomarkers are developed to overcome the limitations of traditional imaging outcomes revealed in early phase trials. In January 2019, the International Progressive MS Alliance convened a standing expert panel to consider potential tissue fluid biomarkers in MS in general and in progressive MS specifically. The panel focused their attention on neurofilament light chain (NfL) in serum or plasma, examining data from both relapsing and progressive MS. Here, we report the initial conclusions of the panel and its recommendations for further research. Serum NfL (sNfL) is a plausible marker of neurodegeneration that can be measured accurately, sensitively, and reproducibly, but standard procedures for sample processing and analysis should be established. Findings from relapsing and progressive cohorts concur and indicate that sNfL concentrations correlate with imaging and disability measures, predict the future course of the disease, and can predict response to treatment. Importantly, disease activity from active inflammation (i.e., new T2 and gadolinium-enhancing lesions) is a large contributor to sNfL, so teasing apart disease activity from the disease progression that drives insidious disability progression in progressive MS will be challenging. More data are required on the effects of age and comorbidities, as well as the relative contributions of inflammatory activity and other disease processes. The International Progressive MS Alliance is well positioned to advance these initiatives by connecting and supporting relevant stakeholders in progressive MS. Treatment to prevent gradual progression of disability remains a major unmet medical need in multiple sclerosis and was a driving force for initiation of the International Progressive MS Alliance ("the Alliance") in 2012. The specific mission of the Alliance is to accelerate the development of effective disease-modifying and symptom management therapies for persons with progressive forms of MS. [bib_ref] Setting a research agenda for progressive multiple sclerosis: the International Collaborative on..., Fox [/bib_ref] The Alliance acknowledges that a central aspect to success of its mission is to accelerate proof-of-concept clinical trials of new therapies in progressive MS, thereby encouraging drug development [bib_ref] Progressive MS: from pathophysiology to drug discovery, Salvetti [/bib_ref] and stimulating further investment from industry. Ideally, early-stage trials depend on treatment response biomarkers, which predict clinical benefits and allow treatment effects to be detected more quickly and with smaller sample sizes than trials using clinical measures as primary outcomes. For relapsing MS, this requirement has been met by lesion activity on conventional MRI. [bib_ref] MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis..., Sormani [/bib_ref] Numerous pathologic mechanisms are purported to contribute to the progression of disability in progressive forms of MS, but no dominant mechanism has been identified. [bib_ref] Progressive MS: from pathophysiology to drug discovery, Salvetti [/bib_ref] Therefore, biomarkers of specific pathologic mechanisms are unlikely to be informative for proof-of-concept trials of therapies with varying modes of action. Instead, the focus has been to identify biomarkers of neurodegeneration, which integrates the end-stage consequences of combined pathologies. Sample size calculations from longitudinal studies have enabled the adoption of brain atrophy, measured using MRI, as a biomarker of progressive MS and used as the primary outcome in phase 2 trials. [bib_ref] Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple..., Altmann [/bib_ref] [bib_ref] Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled,..., Kapoor [/bib_ref] [bib_ref] Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive..., Chataway [/bib_ref] [bib_ref] Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical..., Fox [/bib_ref] Despite its intuitive association with loss of neural tissue, brain atrophy has a number of limitations as a treatment response biomarker. Loss of volume is not pathologically specific, depends on many factors such as tissue hydration, and thus follows a complicated trajectory after starting treatment. [bib_ref] Is multiple sclerosis a lengthdependent central axonopathy? The case for therapeutic lag..., Giovannoni [/bib_ref] Thus, additional biomarkers, in particular those related specifically to neuronal structure and function, are required to monitor progressive MS. Body fluid biomarkers have the potential to be more pathologically specific than imaging biomarkers, may reflect ongoing pathology over the entire CNS, and may be more responsive to the effects of treatment. Through 2017, the Alliance considered a number of biomarkers and decided at its Future Strategies Meeting in Dublin, Ireland, in July 2018 to focus on neurofilament light chain (NfL) as a test candidate. This decision followed recent methodological developments that allow ultra-sensitive measurements of serum NfL (sNfL) concentrations, which avoids the need to sample CSF, [bib_ref] Plasma concentration of the neurofilament light protein (NFL) is a biomarker of..., Gisslen [/bib_ref] [bib_ref] Comparison of three analytical platforms for quantification of the neurofilament light chain..., Kuhle [/bib_ref] thus offering more convenient testing and increased acceptability of sampling by patients. Modeling suggests that NfL as a biomarker may have comparable sensitivity to imaging outcomes for testing efficacy in phase 2 trials of relapsing MS. [bib_ref] Blood neurofilament light as a potential endpoint in phase 2 studies in..., Sormani [/bib_ref] Consequently, the Alliance convened an expert panel to discuss the current state of research on NfL as a biomarker in MS in general and progressive MS specifically, with a view to mobilizing the MS community toward filling key gaps in knowledge and understanding. Because much of the initial NfL data were collected in relapsing MS and provided important insights regarding its use and relevance in MS, we have included it here as foundational studies. Here, we summarize the outcome of the group's meeting in Washington DC in January 2019 and its subsequent discussions. Based on published regulatory guidance, [bib_ref] BEST (Biomarkers E, and Other Tools) Resource. Silver Spring: Food and Drug..., Fda-Nih Biomarker Working [/bib_ref] 2 potential Contexts of Use were agreed upon as the basis for further work: 1. sNfL as a pharmacodynamic/treatment response biomarker, to be used as an end point/outcome monitor in clinical trials in progressive MS 2. sNfL as a prognostic biomarker that can predict disease progression, to be used for the selection of patients with progressive MS into trials ## Plausibility and analytical validity Neurofilaments are plausible biomarkers of neurodegeneration because they are cytoskeletal proteins confined to the neuroaxonal compartment. [bib_ref] Neurofilaments as biomarkers in neurological disorders, Khalil [/bib_ref] Their concentrations are elevated across a wide range of neurologic diseases, consistent with release on axonal damage from multiple causes. [bib_ref] Neurofilaments as biomarkers in neurological disorders, Khalil [/bib_ref] Although the most widely used monoclonal antibodies for NfL [bib_ref] Monoclonal antibodies selective for low molecular weight neurofilaments, Norgren [/bib_ref] have been highly specific in NfL knock-out animal experiments, [bib_ref] Neurofilament light chain in blood and CSF as marker of disease progression..., Bacioglu [/bib_ref] the extent to which intact NfL and its degradation products contribute to the immunoassay signal is unclear. This limits the interpretation of NfL kinetics in individual patients. Currently, the most widely used assay for measuring serum or plasma concentrations of NfL is the Quanterix platform, which uses single molecule array (Simoa) technology and is available commercially.Technical validation of this assay indicates good analytical accuracy. A recent multicenter study analyzing identical serum samples across different sites reported excellent interassay and intersite coefficients of variation (<10%). [bib_ref] International multi-site analytical validation of the Simoa NF-light assay in human serum..., Kuhle [/bib_ref] Further work is still required to establish interbatch and within-batch assay variability. [bib_ref] Strategic platform selection and validation of biomarker assays to measure serum neurofilament..., Sharma [/bib_ref] Glossary MS = multiple sclerosis; NfL = neurofilament light chain; Simoa = single molecule array; sNfL = serum NfL; T25FW = Timed 25-Foot Walk time; 9HPT = 9-Hole Peg Test time. A correlation between NfL levels in the serum or plasma and levels in the CSF has been demonstrated for various neurologic diseases and suggests that measures of ongoing neuroaxonal injury can be obtained from blood NfL levels without the need to obtain CSF by lumbar puncture. [bib_ref] Neurofilaments as biomarkers in neurological disorders, Khalil [/bib_ref] These results are consistent with small studies in progressive MS indicating a modest correlation between NfL concentrations in serum/ plasma and CSF. For example, analysis of the progressive MS patient subset from Disanto et al. [bib_ref] Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis, Disanto [/bib_ref] indicated an r of 0.7 (n = 18), although other studies showed a weaker correlation. [bib_ref] NfL levels in CSF, serum, and plasma of RRMS and patients in..., Harp [/bib_ref] Larger studies are needed to better understand the relationship between blood and CSF levels of NfL. NfL concentrations are approximately 20% higher when measured in serum compared with plasma, which indicates that serum and plasma levels are not interchangeable within the same study. A few studies have assessed the stability of NfL. There appears to be minimal effect of freezing and thawing on NfL concentrations, [bib_ref] Increased neurofilament light chain blood levels in neurodegenerative neurological diseases, Gaiottino [/bib_ref] [bib_ref] A comparative study of CSF neurofilament light and heavy chain protein in..., Kuhle [/bib_ref] and sNfL concentrations are stable in samples stored for 1 week at either room temperature or at 4°C 21 (also Teunissen, unpublished). NfL appears to remain stable in samples stored under standard biobanking conditions over many years. [bib_ref] Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis, Disanto [/bib_ref] Despite these encouraging findings, standard protocols are needed to define the acceptable parameters for type of collection tube, delay in processing, and processing methods. Apart from Simoa, other high-sensitivity platforms apply similar reagents, such as the Olink proximity ligation protein analysis neuropanel. Novel automated systems include the Cobas Elecsys system by Roche and the ADVIA immunoassay system by Siemens. Although the increasing availability of multiple systems is likely to facilitate widespread implementation in research and clinical care, reference methods and materials are needed to ensure data comparability across different systems. ## Clinical validity NfL is a highly sensitive marker of neuronal injury, irrespective of the cause of that injury. However, NfL concentrations are typically far lower in MS than in many rapidly progressive primary neurodegenerative diseases, which show a faster rate of neuronal loss than MS. [bib_ref] Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic..., Bridel [/bib_ref] Average serum or plasma NfL concentrations are higher in relapsing and progressive MS than in controls, [bib_ref] Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis, Disanto [/bib_ref] [bib_ref] Blood neurofilament light chain as a biomarker of MS disease activity and..., Kuhle [/bib_ref] [bib_ref] Serum neurofilament as a predictor of disease worsening and brain and spinal..., Barro [/bib_ref] although the concentration ranges in MS overlap with controls to an extent that makes it difficult to define a pathologic cutoff at the individual patient level. This problem is further complicated by the fact that blood concentrations of NfL increase by an average 2.2% per year between ages 18 and 70 years in healthy controls. [bib_ref] Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis, Disanto [/bib_ref] [bib_ref] Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic..., Bridel [/bib_ref] The reasons for this age-dependent increase are not well understood. The parallel increase in CSF and blood suggests that it is due mainly to physiologic age-dependent neuronal loss, but metabolic factors may also contribute, similar to the agedependent increase of the CSF/serum albumin quotient. [bib_ref] Evidence for sex difference in the CSF/plasma albumin ratio in ;20 000..., Parrado-Fernández [/bib_ref] Hence, establishing reference values (e.g., a normative database) over a wide range of ages and evaluating the effects of comorbidities (i.e., cerebrovascular disease, diabetes, and smoking status) on serum concentrations are critical next steps for developing NfL as a tool for personalized medicine in MS, especially for patients with progressive MS. For the use of NfL concentration as a biomarker in clinical trials, the effects of age and comorbidities can be controlled on relative grounds by both covariate adjustment and randomization, although these confounding variables may limit precision, interpretation, and strength of association with outcomes. Hence, a normative database of NfL is an indispensable tool to address this limitation. Such a database would also enable quantitative modeling of disease progression, which has been a valuable tool for parsing relevant covariates such as age that significantly influence relevant clinical trial outcomes. A normative database could help enable application of NfL measurement to individual patient monitoring and therapeutic decision making. Such models have been developed for other relevant outcome measures, reviewed by regulators, and made available for clinical trial optimization in diseases such as Alzheimer disease, [bib_ref] The future is now: model-based clinical trial design for Alzheimer's disease, Romero [/bib_ref] Parkinson disease, [bib_ref] Dopamine transporter neuroimaging as an enrichment biomarker in early Parkinson's disease clinical..., Conrado [/bib_ref] and autosomal dominant polycystic kidney disease. [bib_ref] A drug development tool for trial enrichment in patients with autosomal dominant..., Perrone [/bib_ref] Comparisons with imaging and disability measures Numerous retrospective academic cohort studies [bib_ref] Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis, Disanto [/bib_ref] [bib_ref] Serum neurofilament as a predictor of disease worsening and brain and spinal..., Barro [/bib_ref] [bib_ref] Association between serum neurofilament light chain levels and long-term disease course among..., Canto [/bib_ref] [bib_ref] Plasma neurofilament light chain levels in patients with MS switching from injectable..., Piehl [/bib_ref] [bib_ref] Monitoring disease activity in multiple sclerosis using serum neurofilament light protein, Novakova [/bib_ref] and analyses of large phase 3 trials in relapsing MS [bib_ref] Blood neurofilament light chain as a biomarker of MS disease activity and..., Kuhle [/bib_ref] [bib_ref] Serum neurofilament light (NfL) for disease prognosis and treatment monitoring in multiple..., Calabresi [/bib_ref] suggest that the concentration of NfL in serum, plasma, and CSF is a promising biomarker in MS. Applications include (1) acute disease activity (including correlations with baseline T2 lesion volume and the number of enhancing T1 lesions) and (2) prediction of subsequent MRI lesion activity, brain volume loss, relapse rate, and worsening of disability. In patients with Alzheimer disease and amyotrophic lateral sclerosis, increasing mean serum concentrations occur months or years before the emergence of the first clinical manifestations. [bib_ref] Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease, Preische [/bib_ref] [bib_ref] Neurofilament light: a candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion, Benatar [/bib_ref] Similarly, an increased CSF NfL concentration in radiologically isolated syndrome is a risk factor for later transition to clinically definite MS. [bib_ref] Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated..., Matute-Blanch [/bib_ref] [bib_ref] Neurofilament-light chain levels are predictive of on-going disease activity in radiologically isolated..., Thouvenot [/bib_ref] Recent results from clinical trials in progressive MS accord with those in relapsing-remitting disease (table 1) and suggest that the concentration of NfL is associated with concurrent disease activity and long-term disease outcome in all forms of MS. In placebo-controlled phase 3 trials of fingolimod and siponimod, baseline plasma NfL concentrations were higher in patients with Gd+ lesions at baseline compared with those without Gd+ lesions. [bib_ref] Neurofilament light levels in the blood of patients with secondary progressive MS..., Kuhle [/bib_ref] In both trials, a high NfL concentration at baseline was associated with greater brain volume loss at 1-2 years and a higher likelihood of confirmed disability worsening. These associations were independent of treatment assignment or the presence of contrast-enhancing lesions at baseline. From these data, it was also estimated that a 1-year placebo-controlled trial would require a tentative sample size of 94 participants with secondary progressive MS per arm to detect a 20% reduction of NfL concentration with 80% power. [bib_ref] Neurofilament light levels in the blood of patients with secondary progressive MS..., Kuhle [/bib_ref] Similarly, in a phase 3 trial of natalizumab, baseline sNfL concentration was associated with (1) baseline disease activity and disability measures, including the number of Gd+ lesions, T2 lesion volume, Timed 25-Foot Walk time (T25FW), and 9-Hole Peg Test time (9HPT), and (2) brain atrophy over 96 weeks. sNfL concentration at week 96 was also significantly higher in participants who progressed during the study (defined using the Expanded Disability Status Scale, T25FW, or 9HPT) compared with those who did not. [bib_ref] Natalizumab reduces serum concentrations of neurofilament light chain in secondary progressive multiple..., Kapoor [/bib_ref] When considered with the results in relapsing-remitting MS, these similar and more recent findings in progressive MS support the prognostic Context of Use for NfL defined earlier.However, these findings are at a group level and require deeper analysis of the existing trial data and further longitudinal studies to interpret NfL concentrations at an individual level and to build a disease model that might support trial enrichment. These studies should clarify (1) ## Responsiveness to treatment Results from a number of clinical trials in relapsing MS indicate that serum and plasma NfL concentrations respond consistently within 3-6 months of the start of antiinflammatory therapies, that changes in NfL can be associated with changes in clinical and imaging outcomes, and that the response of NfL to higher-efficacy therapies such as alemtuzumab and fingolimod is larger than the response to interferon-beta. [bib_ref] Blood neurofilament light chain as a biomarker of MS disease activity and..., Kuhle [/bib_ref] [bib_ref] Association between serum neurofilament light chain levels and long-term disease course among..., Canto [/bib_ref] Previously, 2 small studies reported positive treatment effects on CSF concentrations of NfL in progressive MS [fig_ref] Table 2: Response of neurofilament light concentrations to treatment in progressive MS [/fig_ref]. [bib_ref] Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis, Axelsson [/bib_ref] [bib_ref] Natalizumab in progressive MS: results of an open-label, phase 2A, proof-of-concept trial, Christensen [/bib_ref] Lower concentrations were observed after treatment for 12-24 months with either mitoxantrone or rituximab in patients with primary progressive MS compared with baseline and with a small group of age-matched controls (table 2). The difference was most prominent in those patients with evidence of ongoing inflammatory activity. [bib_ref] Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis, Axelsson [/bib_ref] Treatment with natalizumab for 60 weeks was also associated with lower CSF NfL concentrations in a single-arm, open-label study in a progressive cohort. [bib_ref] Natalizumab in progressive MS: results of an open-label, phase 2A, proof-of-concept trial, Christensen [/bib_ref] Furthermore, changes in CSF NfL correlated with clinical changes during treatment with natalizumab or monthly methylprednisolone. [bib_ref] CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual..., Christensen [/bib_ref] [bib_ref] Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis, Ratzer [/bib_ref] Recently, the initial analyses of peripheral blood NfL concentrations were communicated from the phase 3 trials of fingolimod and ocrelizumab in primary progressive MS (INFORMS and ORATORIO, respectively) and of siponimod and natalizumab in secondary progressive MS (EXPAND and ASCEND, respectively) [fig_ref] Table 2: Response of neurofilament light concentrations to treatment in progressive MS [/fig_ref]. [bib_ref] Neurofilament light levels in the blood of patients with secondary progressive MS..., Kuhle [/bib_ref] [bib_ref] Natalizumab reduces serum concentrations of neurofilament light chain in secondary progressive multiple..., Kapoor [/bib_ref] [bib_ref] Siponimod reduces neurofilament light chain blood levels in secondary progressive multiple sclerosis..., Kuhle [/bib_ref] [bib_ref] Blood neurofilament light levels are lowered to a healthy donor range in..., Bar-Or [/bib_ref] Treatment was associated with lower NfL concentrations compared with placebo in all 4 trials. A significant NfL response was apparent with or without the presence of observed inflammatory activity in both the siponimod and natalizumab trials, but the effect sizes were smaller in the progressive inactive subgroups. [bib_ref] Natalizumab reduces serum concentrations of neurofilament light chain in secondary progressive multiple..., Kapoor [/bib_ref] [bib_ref] Siponimod reduces neurofilament light chain blood levels in secondary progressive multiple sclerosis..., Kuhle [/bib_ref] In the ASCEND and INFORMS trials, a robust reduction in NfL was observed despite an absence of clinical benefit. [bib_ref] Neurofilament light levels in the blood of patients with secondary progressive MS..., Kuhle [/bib_ref] [bib_ref] Natalizumab reduces serum concentrations of neurofilament light chain in secondary progressive multiple..., Kapoor [/bib_ref] Ibudilast, which appears to act on noninflammatory processes to slow whole-brain atrophy without affecting relapse rate or lesion activity, 51 has been reported on initial analysis of the SPRINT-MS phase 2 trial to have no effect on the concentration of NfL in either serum or CSF. [bib_ref] Effect of ibudilast on neurofilament-light chain in progressive MS: analysis from a..., Fox [/bib_ref] Background immune modulating therapy in this trial was only injectable therapies (or none), and ongoing inflammatory activity may have obscured the ability to detect an ibudilast-related reduction in NfL. Further studies of NfL using legacy trial biobanks and ongoing trials will help to clarify the relationship of changes in NfL concentrations with disability measures, including the time course of NfL changes and their clinical meaningfulness. Importantly, clinical studies indicate that disease activity as measured by clinical relapses and MRI (either gadolinium-enhancing or new T2 lesions) is associated with increased NfL. Thus, measurement of NfL in progressive MS trials that target disease progression may be confounded by intercurrent disease activity, as may have occurred in the SPRINT-MS trial of ibudilast described above. Further analyses of clinical trial data sets with particular attention to disease activity will help clarify the appropriate use and utility of NfL in clinical trials. # Limitations of nfl In addition to the technical challenges mentioned earlier, there are several limitations in the application of NfL to individual patients with MS and the evaluation of MS therapies. NfL is a cytoskeletal protein that can be released as a result of almost any type of brain injury. NfL is not specific to MS, and thus, any neurologic disease or injury can confound efforts to use NfL to characterize MS and response to MS therapies. NfL release can arise from infiltrative inflammation seen in relapsing MS (and less frequently in progressive MS), but also the various different pathologies associated with progressive MS. This confounding may limit the ability of NfL to measure the neurodegenerative aspects of progressive MS and potential impact of putative neuroprotective therapies. Understanding the impact of different comorbid conditions such as cerebrovascular disease, diabetes, and smoking status on serum concentrations is a critical next step in developing NfL as a tool for personalized medicine in MS, especially for patients with progressive MS. The utility of NfL monitoring for individual patient management is not yet defined and might require integrating more clinical, biological, and imaging features in the future. Standardize sample collection and assay methods to align results across multiple assay platforms. - Review standard operating procedures currently in use - Establish standards for sample collection and storage - Analyze nonstandard sample collection and storage to understand tolerance for variance in sample collection and storage - Compare different assay methods to understand comparability and commutability 54 Establish a normative database of NfL concentrations in healthy volunteers to establish the effects of age and comorbidities and then develop disease models to support trial design and clinical validity. - Establish key parameters for a normative database - Clarify types of data, necessary number of samples, appropriate control groups, and specific potential confounders Analyze legacy trial biobanks for NfL to determine the predictive value of NfL, how NfL responds to different therapies and clarify its relationship to clinical and imaging outcomes. A particular issue is the relative extent to which inflammatory activity and underlying disease progression contribute to changes in the concentration of NfL. - Conduct a landscape analysis to ensure that all legacy data sets are captured - Check availability of biological samples for further analysis - Outline statistical analysis plans and harmonize across data sets Abbreviations: NfL = neurofilament light chain; sNfL = serum NfL. ## Ongoing studies There are many ongoing studies that will further characterize NfL and understand its relevance to MS in general and in progressive MS specifically. Many clinical trials that biobanked serum or plasma samples are analyzing NfL. A US NIH-funded study (1U01NS111678-01A1) funded in 2020 will evaluate NfL as a prognostic and monitoring biomarker in over 5,700 individuals with MS. A study funded by the US National MS Society will evaluate sNfL from the US National Health and Nutrition Examination Survey of healthy adults to assess the effects of demographics, lifestyle factors, and comorbidities on sNfL levels and establish demographicspecific reference ranges of sNfL. A study funded by the Swiss National Science Foundation will investigate the relationship between sNfL and MRI characteristics, treatment response, and quality of life and characterize NfL turnover in the blood. NfL is being studied in other neurologic diseases too. The Biomarkers Consortium of the Foundation of the NIH aims to establish whether NfL in blood provides a prognostic marker that can accelerate the development of diseasemodifying therapeutics in familial frontotemporal dementia. Other initiatives focus on the standardization of measurements to prepare for the use of blood biomarkers in both clinical trials and routine clinical practice. For example, the International Federation of Clinical Chemistry Working Group performs a round robin/commutability study of NfL in plasma and serum to study the correlation between the different assays and identify candidate Reference Materials. Future Certified Reference Materials can be used to align measurements across analytical platforms. The Standardization of Alzheimer Blood Based Biomarkers Working Group of the Alzheimer Association Global Biomarkers Standardization Consortium develops standard operating procedures for blood collection and processing for a broad range of potential markers, including NfL. These and other efforts will help further our understanding of the role of NfL in identifying new therapies and managing the disease in people living with MS. # Conclusions Our review of existing data suggests that sNfL may provide a plausible biomarker of progressive MS, addressing some of the limitations of current imaging biomarkers to accelerate drug development through the proposed Contexts of Use. However, significant gaps remain in our understanding of NfL and must be addressed before NfL can be accepted as a biomarker by the progressive MS community and, potentially, by regulatory agencies. These gaps include the following: 1. Sample collection and assay methods should be standardized to align results across current (and future) assay platforms, which will support analytical validity across the globe. 2. A normative database of sNfL concentrations in healthy volunteers is required. This database should include the effects of age and comorbidities, which will allow the development of disease models to support trial design and clinical validation. 3. A deeper analysis of legacy clinical trial data sets will help clarify the predictive value of baseline concentrations of sNfL, define how sNfL responds to different types of therapies, and clarify the relationship between NfL levels and clinical and imaging outcomes. A particular issue is the relative extent to which inflammatory activity including activated microglia and other disease processes contribute to changes in NfL. [table] Table 1: Associations between baseline NfL concentrations and activity of progressive MS Abbreviations: EDSS = Expanded Disability Status Scale; MS = multiple sclerosis; NfL = neurofilament light chain; RCT = randomized controlled trial; SDMT = Symbol Digit Modalities Test; T25FW = Timed 25-Foot Walk time; 9HPT = 9-Hole Peg Test time. [/table] [table] Table 2: Response of neurofilament light concentrations to treatment in progressive MS [/table] [table] Table 3: Next steps needed to increase understanding of sNfL [/table]	None	https://n.neurology.org/content/neurology/95/10/436.full.pdf	There is an unmet need in multiple sclerosis (MS) therapy for treatments to stop progressive disability. The development of treatments may be accelerated if novel biomarkers are developed to overcome the limitations of traditional imaging outcomes revealed in early phase trials. In January 2019, the International Progressive MS Alliance convened a standing expert panel to consider potential tissue fluid biomarkers in MS in general and in progressive MS specifically. The panel focused their attention on neurofilament light chain (NfL) in serum or plasma, examining data from both relapsing and progressive MS. Here, we report the initial conclusions of the panel and its recommendations for further research. Serum NfL (sNfL) is a plausible marker of neurodegeneration that can be measured accurately, sensitively, and reproducibly, but standard procedures for sample processing and analysis should be established. Findings from relapsing and progressive cohorts concur and indicate that sNfL concentrations correlate with imaging and disability measures, predict the future course of the disease, and can predict response to treatment. Importantly, disease activity from active inflammation (i.e., new T2 and gadolinium-enhancing lesions) is a large contributor to sNfL, so teasing apart disease activity from the disease progression that drives insidious disability progression in progressive MS will be challenging. More data are required on the effects of age and comorbidities, as well as the relative contributions of inflammatory activity and other disease processes. The International Progressive MS Alliance is well positioned to advance these initiatives by connecting and supporting relevant stakeholders in progressive MS.
17e67fb3ec9eb041eb53803bc8e8cedce4c96250	pubmed	The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours	The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists 90 Y-DOTATOC ([ 90 Y-DOTA 0 ,Tyr 3 ]-octreotide) or 177 Lu-DOTATATE ([ 177 Lu-DOTA 0 ,Tyr 3 ,Thr 8 ]-octreotide or [ 177 Lu-DOTA 0 ,Tyr 3 ]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving 177 Lu-DOTATATE or 90 Y-DOTA-TOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts' opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency. Keywords Peptide receptor radionuclide therapy . PRRNT . PRRNT, neuroendocrine tumours, guideline/s, renal protection Purpose This guidance document is aimed at assisting and guiding nuclear medicine specialists in: 1. Assessing patients with neuroendocrine tumours for their eligibility to undergo treatment with [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y-or Lu-radiolabelled somatostatin analogues. 2. Providing guidance on performing peptide receptor radionuclide therapy (PRRNT) and implementing this treatment in a safe and effective manner. 3. Understanding and evaluating the outcome of PRRNT, namely treatment results and possible side effects including both renal and haematological toxicities. A committee of international experts was assembled under the auspices of the International Atomic Energy Agency (IAEA), in cooperation with the EANM Therapy, Oncology and Dosimetry Committees and with the Society of Nuclear Medicine and Molecular Imaging. They worked together to create this guidance document on the use of somatostatin analogue-based PRRNT. This guidance document was compiled taking into account recent literature and experts' opinion. ## Regulatory issues Applicable in all countries Clinicians involved in unsealed source therapy must be knowledgeable about and compliant with all applicable national and local legislation and regulations. Applicable in the USA The radiopharmaceuticals used for the diagnostic and therapeutic procedures addressed in this guidance document are not approved by the Food and Drug Administration (FDA) in the USA. Therefore in the USA these procedures should be performed only by physicians enrolled in an investigational protocol pursuant to a valid Investigational New Drug application or Radioactive Drug Research Committee approval and under the purview of an appropriate institutional review board. ## Background information and definitions ## Definitions prrnt PRRNT (or PRRT) involves the systemic administration of a specific well-defined radiopharmaceutical composed of a βemitting radionuclide chelated to a peptide for the purpose of delivering cytotoxic radiation to a tumour. The oligopeptides are designed to target cellular proteins, commonly cell surface receptors, such as the somatostatin receptor (sstr) subtype 2 (sstr2) that is overexpressed on the cell surface of NETs in a tumour-specific fashion, thereby ensuring a high level of specificity in the delivery of the radiation to the tumour. Hence, PRRNT is a molecularly targeted radiation therapy, and thus is distinct from external beam radiation therapy. Somatostatin The naturally occurring somatostatin molecule is an oligopeptide comprising either 14 or 28 amino acids with a limited half-life in blood due to rapid enzymatic degradation. Somatostatin exerts an antisecretory endocrine and exocrine effect in addition to tumour cell-growth inhibition. Stabilized analogues of somatostatin (SSA) show prolonged duration of action. ## Somatostatin receptors In humans five sstr subtypes have been identified. Each sstr is a transmembrane molecule weighing approximately 80 kDa. Somatostatin exerts its action by inhibiting G-protein-dependent 3′,5′cyclic monophosphate (cAMP) formation in a dose-dependent manner at subnanomolar concentrations. Sstr2 is overexpressed in NETs. Sstr2 is the key target molecule for both cold and radiolabelled SSA. Upon binding to its receptor, the complex (SSA-sstr) undergoes cellular internalization thereby enhancing the therapeutic effect of the radiolabelled drug [bib_ref] Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target..., Waser [/bib_ref]. Yttrium- [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] The radiometal [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y is a pure β-emitting isotope with a physical half-life of 64 h. The maximum and mean β-particle energies are 2.28 MeV and 0.934 MeV, respectively. The maximum and mean βparticle penetration depths in soft tissue are 11 mm and 3.9 mm, respectively. Lutetium-177 Lu is a βand γ-emitting radionuclide with a physical half-life of 162 h (6.73 days). Compared to Lu has lower maximum and mean β-particle energies (0.498 MeV and 0.133 MeV, respectively). These translate to maximum and mean soft-tissue penetration depths of 1.7 mm and 0.23 mm, respectively. 177 Lu has two main gamma emission lines: 113 keV (6 % relative abundance) and 208 keV [bib_ref] Somatostatin receptors as targets for nuclear medicine imaging and radionuclide treatment, Maecke [/bib_ref]. # Background NETs have proven to be ideal neoplasms for PRRNT, as the majority of these slow-growing malignancies overexpress sstrs. Appropriate candidates for PRRNT are patients presenting with well-differentiated or moderately differentiated neuroendocrine carcinomas, defined as NETs of grade 1 or 2 according to the WHO classification of 2010 [bib_ref] The ENETS guidelines: the new TNM classification system, Rindi [/bib_ref]. The incidence of NETs has been rising over the past 30 years, particularly those arising from the midgut and pancreas [bib_ref] Gastroenteropancreatic neuroendocrine tumors, Modlin [/bib_ref]. Anatomical imaging of NETs should be as detailed and extensive as possible to provide accurate information about site and extent of the primary tumour, and the location and extent of regional and distant metastases. An exact assessment of liver metastases and degree of liver involvement using ultrasonography, CT or MRI is central for accurate staging and for assessing the response to treatment [bib_ref] Mallorca Consensus Conference participants; European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for..., Sundin [/bib_ref]. Functional imaging procedures applying sstr imaging using 111 In-pentetreotide (OctreoScan) with SPECT or PET with 68 Ga-labelled SSA, combined with morphological imaging procedures, are used to collect essential information for staging, assessing sstr status and making decisions on the most appropriate therapy regimens [bib_ref] Oncology Committee of the EANM. 111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging, Bombardieri [/bib_ref] [bib_ref] Procedure guidelines for PET/CT tumor imaging with 68Ga-DOTA-conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE, Virgolini [/bib_ref]. Serial morphological examinations are mandatory to monitor therapy and detect recurrent disease. Emerging data indicate that 18 F-FDG PET may have additional prognostic value [bib_ref] 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors, Binderup [/bib_ref]. This information, however, needs validation in larger studies. Multiple treatment approaches are now available for patients presenting with metastatic disease, considering recently introduced molecular targeted therapies and multimodality treatment options. For the choice of the most appropriate treatment, information regarding anatomical location and local invasion of adjacent structures, tumour functionality, sstr status, histological grading and staging are required to facilitate the decision-making process within the multidisciplinary tumour board. If the disease is restricted to the liver, surgical and locoregional approaches should be considered primarily. Chemotherapy is appropriate for highly proliferating NETs and pancreatic NETs, keeping in mind the fact that the vast majority of NETs are rather insensitive to this treatment. ## Treatment options in nets Patients with NETs may present with local tumours, with or without regional or distant metastases. The common site of metastasis is the liver. These tumours may remain clinically silent until a significant liver tumour burden is present. Therapeutic options include surgery, SSA, interferon, chemotherapy, molecularly targeted agents, locoregional therapies and PRRNT. Supportive palliative care and pain control also play an important role in patient management. These options are not mutually exclusive and, for the most part, are interchangeable. Options of care, including PRRNT, should be chosen and implemented in a correct sequence by an experienced multidisciplinary team. This approach should provide the highest benefit while minimizing the risks and side effects and ensuring the best quality of life achievable for the patient. Surgery with curative intent should always be performed whenever feasible; in selected cases, and within a multidisciplinary approach, PRRNT may be beneficial as a neoadjuvant therapy to render a patient accessible to surgery. For functionally active tumours, cytoreductive strategies, e.g. transarterial chemoembolization (TACE), transarterial embolization (TAE), radiofrequency ablation (RFA) and other techniques such as selective internal radiation therapy (SIRT), should always be considered with the intention of ameliorating clinical symptoms. The optimal management of NETs is early surgical removal prior to the development of regional or distant metastases. Unfortunately, many patients are diagnosed with metastatic disease, when complete eradication of their tumours will not be possible. Removal of the primary tumour is indicated to prevent complications such as bleeding or small-bowel obstruction. Even in the presence of liver metastases, removal of the primary tumour has several advantages and seems to have a positive prognostic impact on survival [bib_ref] Midgut carcinoid tumors: surgical treatment and prognosis, Kerström [/bib_ref] [bib_ref] Consensus guidelines for the management of patients with digestive neuroendocrine tumors: well-differentiated..., Plöckinger [/bib_ref] [bib_ref] Consensus guidelines for the management of patients with digestive neuroendocrine tumors: well-differentiated..., Ramage [/bib_ref] [bib_ref] Operative resection of primary carcinoid neoplasms in patients with liver metastases yields..., Givi [/bib_ref]. Solitary or isolated liver metastases can be surgically removed, while a more diffuse liver infiltration is usually treated using a locoregional approach. Locoregional approaches or local ablative therapies target predominantly liver metastases aiming at achieving local tumour control and alleviating functional secretory syndromes. Different techniques are applied depending on individual findings (number size and distribution of liver lesions, their morphology, focal or diffuse, and their vascularization), functional activity of the NET and locally available expertise. In an individual with few liver lesions with a preferably resected primary lesion, liver lesions can be treated by surgical resection with or without RFA or laserinduced interstitial thermoablation. In those with multifocal or diffuse liver disease causing a high tumour load, TACE and TAE are the preferred choices [bib_ref] Consensus guidelines for the management of patients with liver metastases from digestive..., Steinmüller [/bib_ref] [bib_ref] Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and..., Vogl [/bib_ref]. Local embolization techniques are particularly useful when treating patients with functionally active liver metastases. Following TACE, symptomatic response rates of 60-95 % and biochemical response rates of 50-90 % are achieved and radiological response of 33-80 % have been reported [bib_ref] Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases, King [/bib_ref]. Response duration is between 18 and 24 months. Similar response rates are achieved with TAE alone [bib_ref] Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and..., Vogl [/bib_ref]. In general, the procedure may require more than one treatment session to ensure effectiveness and consolidation of the treatment and to minimize the risk of complications. The recently introduced SIRT has shown variable response rates among individual centres [bib_ref] Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in..., Kennedy [/bib_ref]. Prospective studies are however lacking. In a single prospective study in 34 patients the objective response rate was 50 % [bib_ref] Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases, King [/bib_ref]. Given the lack of comparative studies of the different techniques used for local ablative and locoregional therapies, the choice of technique will be highly dependent on the physicians' experience in the different centres and on individual criteria such as number, size, vascularization and distribution of the lesions. Among the medical treatments, octreotide and lanreotide are the two most used sstr agonists. They play an essential role in the control of both symptomatic and asymptomatic NETs and should be regarded as first-line therapy. SSA can be used with virtually all of the other therapeutic options available. As the vast majority (87-92 %) of NETs express sstr2, patients should always be offered this therapy alongside other concurrent therapeutic options, and for supportive care. Long-acting SSA possess secretory inhibiting action, and are approved for alleviating the symptoms of the carcinoid syndrome, such as flushing and diarrhoea or bronchial obstruction, and to prevent carcinoid crisis. It is reported that treatment with SSA may control the clinical syndrome in 40-90 % of patients subject to tumour load and dosage [bib_ref] Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumors, Modlin [/bib_ref]. Nevertheless, patients may become refractory to syndrome control, and need incremental dosage increases of SSA. However, most patients with tumour progression require an additional treatment, including the use of PRRNT. The recent PROMID study conducted in Germany showed the effectiveness of long-acting SSA as an antiproliferative therapeutic agent in midgut NET. In this study, time to tumour progression in patients given octreotide LAR 30 mg intramuscularly monthly was more than double that in patients receiving only placebo (6.0 vs. 14.3 months). The NCCN guidelines and very recently the ENETS guidelines have added octreotide as an option for antiproliferative treatment [bib_ref] Consensus guidelines for the management of patients with digestive neuroendocrine tumors -welldifferentiated..., Eriksson [/bib_ref] [bib_ref] Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in..., Rinke [/bib_ref]. Interferon-alpha (IFN-α) has been used for treating patients with NETs, especially those with the carcinoid syndrome, for more than 25 years. It is considered the main antisecretory drug used for the treatment of functional tumours [bib_ref] Interferon in the management of neuroendocrine GEP tumors, Öberg [/bib_ref]. IFN-α effectively reduces hypersecretionrelated symptoms in patients with carcinoid syndrome in a similar manner to SSA. Partial tumour growth responses are also observed in 10-15 % of patients with malignant carcinoids, and stabilization in 39 %. IFN-α has also been demonstrated to be effective in endocrine pancreatic tumours [bib_ref] An update of the medical treatment of malignant endocrine pancreatic tumors, Eriksson [/bib_ref]. The very common side effect of IFN-α, namely a 'flu-like syndrome, limits both the use of high dosages and the duration of treatment due to intolerance forcing its interruption. Systemic chemotherapy is effective in some patients, especially those with poorly differentiated NET/neuroendocrine carcinoma (grade 3, WHO 2010) or progressive NET of the pancreas. However, in welldifferentiated midgut NETs/NETs (grade 1/2, WHO 2010) the response rates to chemotherapy are low (7-20 %) and a survival advantage has not been demonstrated [bib_ref] Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major..., Moertel [/bib_ref] [bib_ref] The management of patients with advanced carcinoid tumors and islet cell carcinomas, Moertel [/bib_ref]. The standard treatment for neuroendocrine carcinoma (grade 3) is cisplatin and etoposide. The response rate with this combination is 42-67 %, and its duration is often short, ranging from 8 to 9 months [bib_ref] Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors, Fjallskog [/bib_ref]. The combination of irinotecan and cisplatin [bib_ref] A phase II study of irinotecan and cisplatin for metastatic or unresectable..., Mani [/bib_ref] or FOLFOX chemotherapy (5-fluorouracil or capecitabine and oxaliplatin) may be an alternative [bib_ref] Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade..., Bajetta [/bib_ref]. PRRNT is very rarely a suitable treatment option for neuroendocrine carcinoma (grade 3), because of the low expression of sstr but it may be considered following the failure of chemotherapy and if 111 In-pentetreotide (OctreoScan) or [bib_ref] Therapeutic nuclear medicine in pediatric malignancy, Schmidt [/bib_ref] Ga-DOTATOC/DOTATATE PET/CT demonstrates moderate to high sstr expression. Systemic chemotherapy based on streptozotocin (Zanosar, STZ) is considered a standard therapy for progressive pancreatic NETs with low or moderate proliferative capacity. Combinations of STZ and 5-fluorouracil and/or doxorubicin have been shown to lead to partial remission rates of 35-40 % [bib_ref] Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced..., Kouvaraki [/bib_ref] [bib_ref] Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors, Fjallskog [/bib_ref] [bib_ref] Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma, Moertel [/bib_ref]. Recent phase II studies have shown efficacy of temozolomide based chemotherapy either with antiangiogenic drugs or capecitabine [bib_ref] First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine..., Strosberg [/bib_ref] [bib_ref] Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine..., Kulke [/bib_ref]. Standards of care for the use of chemotherapy have been defined by ENETS [bib_ref] ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: chemotherapy..., Eriksson [/bib_ref]. In recent years, the efficacy of molecular targeted therapies for treating NETs has been assessed in clinical trials. These therapies include angiogenesis inhibitors, single or multiple tyrosine kinase inhibitors and the novel SSA analogue pasireotide, for which clinical trials are ongoing. The drugs with the highest evidence of efficacy are sunitinib and everolimus (RAD-001). Both lead to extension of progression-free survival (PFS) of patients with advanced pancreatic NET. For everolimus, an mTOR inhibitor, there is evidence of efficacy in controlling NET arising from other sites associated with the carcinoid syndrome [bib_ref] A randomized, doubleblind, placebo-controlled, multicenter phase III trial of everolimus plus octreotide..., Pavel [/bib_ref]. The most developed antiangiogenic drugs are sunitinib and the anti-VEGF antibody bevacizumab. In a phase II study bevacizumab in combination with octreotide LAR led to partial tumour remission in 18 % of patients and stable disease in 77 % [bib_ref] Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment..., Yao [/bib_ref]. A recent international phase III study of sunitinib versus placebo in patients with progressive welldifferentiated endocrine pancreatic tumour was interrupted prematurely due to the striking superiority of sunitinib evident by a PFS of 11.1 vs. 5.5 months [bib_ref] Sunitinib malate for the treatment of pancreatic neuroendocrine tumors, Raymond [/bib_ref]. The objective remission rate was less than 10 %. The drug was recently approved by the US FDA and the European Medicines Agency for the treatment of advanced and progressive well-differentiated pancreatic NETs. Everolimus has been studied in more than 1,000 patients with NET and has been included in several clinical trials (RADIANT-1, RADIANT-2, RADIANT-3 trials, RAM-SETE trial). Antitumour activity of everolimus has been confirmed in RADIANT-1 in patients with progressive metastatic pancreatic NETs after failure of at least one line of cytotoxic chemotherapy. The trial studied 160 patients divided into two groups with or without monthly intramuscular octreotide acetate therapy. The combination therapy group showed significantly longer PFS (16.7 vs. 9.7 months) [bib_ref] Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after..., Yao [/bib_ref]. The efficacy of everolimus has been confirmed in a large international placebo-controlled trial including 410 patients with progressive pancreatic NET (RADIANT-3) [bib_ref] Everolimus for advanced pancreatic neuroendocrine tumors, Yao [/bib_ref]. Everolimus significantly reduced the risk of disease progression and led to a prolongation of PFS by 6.4 months (11 vs. 4.6 months) compared to placebo. Objective tumour response was low (4.8 % partial remissions). Disease control rate (partial response + stable disease) was, however, higher with everolimus than with placebo with best supportive care (77.7 % vs. 52.7 %). Side effects were rarely grade 3 or 4; the most frequently reported side effects included stomatitis, anaemia and hyperglycaemia. In May 2011 the US FDA approved everolimus for the treatment of progressive NETs of pancreatic origin in patients with nonresectable, locally advanced, or metastatic disease. In the global supportive approach to the patient, and when delivering PRRNT, nutrition and pain control are an essential component of care. Treatment of pain in patients with NET follows the general principles followed in adult and paediatric oncology [bib_ref] National Institutes of Health State-of-the-Science Panel. National Institutes of Health State-of-the-Science Conference..., Patrick [/bib_ref]. Effective treatment of NETs, such as PRRNT, may alleviate pain, including bone pain. Treatment of painful bone metastasis is also mandatory with the administration of bisphosphonates as supportive therapy. PRRNT a historical overview PRRNT using radiolabelled octreotide was first attempted in the 1990s. The initial phase I trial investigated the safety and efficacy of using high activities of the diagnostic compound 111 In-octreotide as a therapeutic radiopharmaceutical. The results in terms of clinical efficacy were attributed to the effect of intracellular emission of the Auger and conversion electrons by In following the internalization of the peptidereceptor complex. Partial remissions were exceptional, and furthermore three patients developed leukaemia or myelodysplastic syndrome from the group receiving the highest cumulative dose (90-100 GBq) [bib_ref] Phase I study of peptide receptor radionuclide therapy with, Valkema [/bib_ref]. In Europe, In-pentetreotide was abandoned as a therapy option in favour of the more efficient β emitters 90 Y and 177 Lu. In-pentetreotide is, however, still used by some in the USA mainly due to the lack of availability of β-emitting radiotracers. High-energy β emitters, such as 90 Y with a longer β range in soft tissue, were considered more promising for the treatment of bulky tumour. A novel analogue, Tyr 3 -octreotide, with a similar affinity profile for sstrs, was developed. Linked to a macrocyclic chelator (DOTA), it allows simple and stable radiolabelling of 111 In and 90 Y to [DOTA 0 ,Tyr 3 ]-octreotide ( 90 Y-DOTA-TOC) [bib_ref] Pre-clinical comparison of [DTPA0] octreotide, [DTPA0,Tyr3] octreotide and [DOTA0,Tyr3] octreotide as carriers..., Jong [/bib_ref]. PRRNT using 90 Y-DOTATOC was first used in 1996 in a patient in Basel, Switzerland. The excellent subjective and objective response following several cycles of 90 Y-DOTATOC led to high expectations as to the therapeutic potential of PRRNT in patients with NET. Since then other centres worldwide have conducted clinical trials with 90 Y-DOTATOC [bib_ref] Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin..., Kwekkeboom [/bib_ref]. Since the year 2000, octreotate (Tyr 3 ,Thr 8octreotide), a newer analogue with improved affinity for sstr2, has been synthesized. The chelated analogue [DOTA 0 ,Tyr 3 ]octreotate (DOTATATE) can be labelled with the βand γemitting isotope Lu and has been used in clinical studies. ## Indications and contraindications Indications PRRNT is indicated for the treatment of patients with positive expression of sstr2, or metastatic or inoperable NET [bib_ref] Somatostatin receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors, Kwekkeboom [/bib_ref] [bib_ref] Peptide receptor therapies in neuroendocrine tumors, Bodei [/bib_ref] [bib_ref] Treatment with the radiolabeled somatostatin analog, Kwekkeboom [/bib_ref] [bib_ref] 90Y-Edotreotide for metastatic carcinoid refractory to octreotide, Bushnell [/bib_ref] [bib_ref] Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue..., Imhof [/bib_ref]. Candidate patients for PRRNT using radiolabelled somatostatin analogues are mainly those with sstr2-expressing NET of the gastroenteropancreatic and bronchial tracts, but may also include patients with phaeochromocytoma, paraganglioma, neuroblastoma [bib_ref] 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma, Gains [/bib_ref] or medullary thyroid carcinoma [bib_ref] Peptide receptor radionuclide therapy with (90)Y-DOTATOC in recurrent meningioma, Bartolomei [/bib_ref] [bib_ref] Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized..., Iten [/bib_ref] [bib_ref] Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas, Bodei [/bib_ref] [bib_ref] Yttrium-DOTA]-TOC response is associated with survival benefit in iodine-refractory thyroid cancer: long-term..., Iten [/bib_ref] [bib_ref] Peptide receptor radionuclide therapy for non-radioiodine-avid differentiated thyroid carcinoma, Teunissen [/bib_ref]. The ideal candidates for PRRNT are those with well-differentiated and moderately differentiated neuroendocrine carcinomas defined as NET grade 1 or 2 according to the recent WHO 2010 classification [bib_ref] Somatostatin receptors as targets for nuclear medicine imaging and radionuclide treatment, Maecke [/bib_ref]. & A patient with pending liver failure should be considered with caution before being submitted to PRRNT. ## Contraindications ## Procedure ## Pretherapy assessment The availability of the following information is mandatory when considering a patient for PRRNT: & NET proven by histopathology (immunohistochemistry). & High sstr expression determined by functional wholebody imaging with 111 In-pentetreotide (OctreoScan) or [bib_ref] Therapeutic nuclear medicine in pediatric malignancy, Schmidt [/bib_ref] Ga-DOTA-peptide PET/CT or immunohistochemistry. The following criteria should be taken into consideration when deciding whether or not to perform PRRNT. & Karnofsky/Lansky performance status above 60 % or ECOG performance status less than 2. & Tumour differentiation, preferably grade 1/2. & Tumour proliferation rate, preferably with a Ki-67/mitotic index ≤20 %. In addition, the rate of tumour growth, as determined by CT or MRI, could be considered. Note that, in general, less-differentiated tumours showing high proliferation rates are better candidates for chemotherapy. ## Facility and personnel PRRNT is still considered an investigational treatment and its implementation must comply with national legislation and local requirements, as well as with ethical principles regarding human studies. The decision to provide PRRNT should be taken within a multidisciplinary tumour board, including all the specialists involved in the care of patients with NET. The facility requirements will depend on national legislation on the therapeutic use of radioactive agents. If inpatient therapy is required by national legislation, the treatment should take place in an approved facility. The facility must have appropriate personnel, radiation safety equipment, and procedures for waste management and handling accidental contamination of the site or personnel. [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y-DOTATOC or 177 Lu-DOTATATE should be administered by appropriately trained medical staff with supporting nursing staff with a medical physics expert available. Physicians responsible for treating patients should have a general knowledge of the pathophysiology and natural history of the respective diseases, should be familiar with alternative forms of therapy, and should be able to closely liaise with other physicians involved in managing the patients. Clinicians involved in the utilization of unsealed radionuclide sources for therapy must also be knowledgeable about and compliant with applicable national legislation and local regulations. ## Patient preparation ## Renal protection Together with the bone marrow, the kidneys are the critical organs in PRRNT particularly when using 90 Y-DOTATOC. Proximal tubular reabsorption of the radiopeptide and subsequent retention in the interstitium result in excessive renal irradiation. Nephrotoxicity may be aggravated by risk factors, such as preexisting hypertension or diabetes mellitus [bib_ref] Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC..., Bodei [/bib_ref]. To counteract and reduce the high kidney retention of radiopeptides, positively charged amino acids, such as L-lysine and/or L-arginine, are coinfused to competitively inhibit the proximal tubular reabsorption of the radiopeptide. The coadministration of these amino acids leads to a significant reduction in the renal absorbed dose, which ranges from 9 % to 53 % [bib_ref] New advances in peptide receptor radionuclide therapy, De Jong [/bib_ref]. Renal absorbed dose is further reduced by up to 39 % by extending the infusion time of the amino acid solution over 10 h, and up to 65 % by extending the protection over 2 days following radiopeptide administration, thereby covering the renal elimination phase more efficiently [bib_ref] 86YDOTA0)-DPhe1-Tyr3-octreotide (SMT487) -a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective..., Jamar [/bib_ref] [bib_ref] Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumors, Bodei [/bib_ref]. ## Amino acid protection protocols Lysine and/or arginine should be diluted appropriately in large volumes of normal saline in order to hydrate the patient, unless the patient suffers from cardiac insufficiency (e.g. carcinoid heart valve disease), in which case volume overload, possibly leading to acute exacerbation of the condition, should be avoided. Hyperosmotic solutions in particular should be avoided since they can induce dangerous electrolyte imbalances that might lead to severe metabolic acidosis and cardiac arrhythmias. An appropriate dilution is 25 g of amino acid in 1 l of normal saline. Before beginning the amino acid infusion, appropriate measures against nausea and vomiting should be undertaken by administering an antiemetic (e.g. 5-HT3 antagonist, such as granisetron) and/or a corticosteroid (e.g. dexamethasone). Antiemetic can be repeated if needed. Amino acid infusion should be started 30-60 min before administration of the radiopeptide and should be maintained over 4 h. Particular attention and care should be given to avoiding possible electrolyte imbalance (hyperkalaemia and hypernatraemia), and the consequent metabolic acidosis, that might lead to mild nausea and vomiting [bib_ref] Effect of amino acid infusion on potassium serum levels in neuroendocrine tumour..., Giovacchini [/bib_ref]. These side effects should be managed by hydrating the patient with normal saline and possibly by repeating corticosteroid or antiemetic administrations. ## Three-day 25-g protection protocol During day 1, a cocktail of 25 g of lysine diluted in 1 l of normal saline is infused over 4 h, starting 30-60 min before the PRRNT. This is followed by the administration of a 12.5 g lysine solution in 500 ml of normal saline over 3 h twice a day on the second and third day after therapy. This protocol is aimed at maximizing renal protection while minimizing the side effects of the amino acid infusion. 3. Three-day 50-g protection protocol A 50-g solution of lysine and arginine (25 g/25 g) diluted in 2 l normal saline infused over 4 h during the first day starting 30-60 min before therapy. This is followed by the administration of an additional 12.5 g lysine diluted in 500 ml of normal saline infused over 3 h twice a day on day 2 and day 3 after therapy. ## Single-day 50 g+gelofusine Renal uptake of radiolabelled somatostatin analogues can in part be attributed to the receptor-mediated endocytic renal transporter system involving megalin-mediated cubilindependent endocytosis across the proximal epithelium. Gelofusine, a succinylated bovine gelatin molecule commonly used as a plasma expander, can be administered to further reduce kidney absorbed radiation dose (by about 45 %) through its interaction with the megalin/cubilin receptor-mediated transporter system [bib_ref] Reactions to gelatin plasma expanders, Watkins [/bib_ref] [bib_ref] Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues, Rolleman [/bib_ref]. There have been some safety concerns about the use of Gelofusine following the occurrence of allergic reactions, although mild in most cases. Severe anaphylactoid reactions are described in approximately 0.04 % [bib_ref] A systematic review of the comparative safety of colloids, Barron [/bib_ref] [bib_ref] Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu..., Wehrmann [/bib_ref]. The treating physician should be aware of these effects and be prepared to treat them accordingly with antihistaminic drugs, corticosteroids or epinephrine. A protection protocol consists of a cocktail of 25 g lysine+25 g arginine diluted in 2 l of normal saline infused over 4 h starting 30-60 min before therapy, and Gelofusine infusion as a bolus of 1 ml/kg body weight over 10 min before therapy, followed by Gelofusine infusion at 0.02 ml/kg/min over 3 h after radiopeptide infusion. Due to reported adverse immunogenic reactions, vital parameters should be monitored during Gelofusine infusion [bib_ref] Reactions to gelatin plasma expanders, Watkins [/bib_ref]. Precautions in special clinical conditions In patients with severe cardiac insufficiency, volume overload that might lead to acute cardiac insufficiency and decompensation, should be avoided. Therefore, formulations with lower amounts of amino acids and hence lower volumes should be chosen (e.g. 25 g of lysine or arginine diluted in a maximum of 1 l of normal saline). In any case, a stringent monitoring regimen with participation of a cardiologist is recommended. In patients with preexisting nephrolithiasis, forced diuresis might mobilize kidney stones leading to acute renal colic. These events should be treated appropriately but, if possible, anticipated and avoided by infusing lower volumes. Phlebitis associated with the hyperosmolarity of the infused amino acid solution may occur at the site of injection. This condition can be treated with local vasoprotective creams. ## Somatostatin analogue withdrawal Somatostatin analogues are available as short-acting or long-acting preparations. These should be discontinued prior to PRRNT as they might interfere with receptor targeting. The duration of interruption, however, depends on the halflife of the analogue used. Withdrawal periods of 4-6 weeks for long-acting release formulations and of at least 24 h for short-acting formulations are considered good clinical practice. This topic is still a matter of debate [bib_ref] Mallorca Consensus Conference participants; European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for..., Sundin [/bib_ref] [bib_ref] Oncology Committee of the EANM. 111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging, Bombardieri [/bib_ref]. In practice a long-acting release formulation is substituted by a shortacting formulation 1 month prior to PRRNT. ## Radiopharmaceutical and administration ## Quality control Both 90 Y and 177 Lu are trivalent metals; they form a highly stable complex with the DOTA chelating molecule. "Simple" radiochemical purity (RP) testing to assess the fraction of free radionuclide using thin layer chromatography or solid phase extraction (using a Sep-Pak cartridge) is not mandatory for commercially acquired therapeutic radiopharmaceuticals. However, if such quality control is desired by the end-user, it should be conducted by adequately trained and qualified professionals. Applying this simple test, the RP should not fall below 98 %. It is worth noting that a more sophisticated method such as high-performance liquid chromatography might reveal additional impurities, and thus a RP of 98 % will be difficult to achieve. As to the amount of peptide employed for an individual treatment cycle (single infusion), the consensus is that for formulations labelled with 177 Lu the mass of peptide should be between 100 and 200 μg, and should not exceed 250 μg per patient dose, while for carrier-free 90 Y it should be between 100 and 150 μg per patient. It is common practice to add excess sodium DTPA to the radiopharmaceutical prior to dispensing because it binds free radiometals and facilitates their fast renal clearance. The specific activity should not fall below a certain value. [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y is produced as a carrier-free radionuclide from the parent radioisotope [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Sr with a theoretically maximum achievable specific activity close to 1,295 MBq/μg (35 mCi/μg). Metal impurities, particularly iron, lead to a significant lowering of the specific activity of the radiopeptide and can occasionally impede the labelling procedure. The radioisotope 177 Lu is produced by a nuclear reactor either via the direct or the indirect pathway; the direct pathway involves the n-gamma irradiation of an enriched 176 Lu target. The indirect pathway involves the irradiation 176 Yb to produce the short-lived 177 Yb (T 1/2 1.9 h) that decays to 177 Lu. The latter method avoids the production of the long-lived 177m Lu (T 1/2 60 days). Few high neutron-flux reactors are capable of producing 177 Lu of a specific activity in excess of 0.74 GBq/μg (20 Ci/mg). By the time of radiolabelling the specific activity is around 0.555 GBq/μg (15 Ci/mg); this, however, should not fall below 10 Ci/mg. In practice, a specific activity of 37 to 74 MBq (1-2 mCi) 177 Lu per microgram of precursor is routinely achieved and is accepted for clinical use. ## Administration During the administration of the radiopeptide, a physician must remain nearby. A resuscitation cart as well as a trained emergency team must be available. The radiopharmaceutical should be diluted with saline to a final volume ranging from 10 ml to 100 ml, depending on the infusion system used. The radiopharmaceutical should be administered via an indwelling catheter to ensure safe intravenous administration and prevent paravascular infiltration, and should be administered over 10 to 30 min, depending on the infusion system used. The radiopeptide may be coinfused with amino acid solution via a three-way stopcock ("piggy-back"). The line should be flushed with saline after completion of radiopeptide infusion. PRRNT may reproduce the syndromes of the respective functional tumours due to the sudden massive release of the hormones and stimulation of their corresponding receptors. The clinical manifestation is dependent on the specific hormone involved. The following measures are therefore recommended. Vital signs (at least blood pressure and pulse) should be monitored before and after therapy infusion in symptomatic patients. Therapeutic interventions should be undertaken to treat the functional syndrome effects or exacerbation (e.g. carcinoid syndrome/hypotension, hypoglycaemia, hypergastrinaemia, hypertension, hypotension, WDHA syndrome, electrolyte imbalance). Nursing personnel must be instructed in radiation safety. Any serious or life-threatening medical condition should be noted and contingency plans put in place in case radiation precautions need to be breached to allow emergency medical care. In a medical emergency, concerns about radiation exposure should not hinder the prompt delivery of appropriate medical care to the patient. During the first 2 days after PRRNT the high levels of activity excretion in the urine is of particular concern. Patients should be advised to observe rigorous hygiene to avoid contaminating persons using the same toilet facilities. A double toilet flush is recommended after urination. Patients should wash their hands after urination. If contaminated with urine, patients should wash their hands with abundant cold water without scrubbing. Once discharged, patients should be cautioned to avoid soiling underclothing or areas around toilet bowls for 1 week following PRRNT. Considerably contaminated clothing should be washed separately. Incontinent patients should be catheterized prior to PRRNT and the catheter should be kept for 2 days thereafter. Urine bags should be emptied frequently. Gloves and protective clothing should be worn by staff caring for catheterized patients (or providing any care involving close contact). Women of childbearing potential should use effective contraception while undergoing treatment and avoid pregnancy for at least 6 months thereafter. Male patients should consider sperm banking before therapy. ## The compromised patient For the compromised patient, the administered activity may be reduced and treatment cycles are individualized with due consideration to prevailing clinical and biochemical parameters, and the results of dosimetric studies. In patients with reduced renal function the following additional interventions are used: In patients with reduced haematological values the following additional interventions are used: (a) Haematologist consultation. (b) When required, packed red blood cells or platelet concentrate support may be given following PRRNT. (c) If needed, growth factor support with granulocyte stimulating factors or erythropoietin (or derivatives) can be considered not earlier than 10 days after PRRNT. (d) In patients with severely compromised bone marrow reserves, peripheral stem cell harvesting as a precautionary measure could be considered before PRRNT and, if necessary, reinfusion could be performed after an appropriate time from PPRNT has elapsed. ## Special considerations for prrnt in children NETs and neural crest tumours in children express high levels of sstrs and can potentially be treated with PRRNT. With the exception of appendiceal carcinoid, most NETs in children are metastatic at diagnosis. Children under the age of 18 years have been excluded from participation in PRRNT trials resulting in a lack of information on safety, toxicity and efficacy in this age group. Conservatively, absorbed doses to the kidney are limited to less than 21-23 Gy. [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y-DOTATOC has been used in children with administered activities of 1.5-1.85 GBq/m 2 per cycle for up to three cycles [bib_ref] Phase I trial of 90Y-DOTATOC therapy in children and young adults with..., Menda [/bib_ref]. With regard to the use of 177 Lu-DOTATATE in children, there is no widespread experience, and activities should be adapted per square metre [bib_ref] Therapeutic nuclear medicine in pediatric malignancy, Schmidt [/bib_ref]. ## Retreatment options The decision to re-treat a patient with PRRNT should only be undertaken within the framework of the tumour board. In patients who have previously responded to PRRNT, retreatment may be considered in those with well-documented disease progression and taking into account the total previous radiation dose to the kidneys and bone marrow. This new PRRNT course will be subject to the same eligibility criteria applied to the first radiopeptide treatment cycle. The options include the use of the same or a different radiopeptide. For instance, choosing 177 Lu-labelled peptides may be warranted, especially when considering the preservation of kidney function. When designing a retreatment regimen, due consideration should be given to the possibility of exceeding the renal threshold dose especially in patients with a good prognosis and expectation of long survival. Using 177 Lu-labelled peptides, whole-body imaging should always be performed following each cycle to document the distribution of the radiopharmaceutical and to evaluate the functional response to PRRNT. ## Dosimetry Radiation dosimetry of normal organs and malignant lesions provides an insight for optimizing the delivery PRRNT, thereby allowing the dose delivered to the tumour to be maximized while minimizing the dose delivered to normal organs, particularly the kidney and bone marrow. If feasible, patient-specific dosimetry can provide valuable information to assess organ-specific radiation absorbed doses and to assess the risk of delayed organ toxicity, particularly of the kidneys and bone marrow in a patient with known risk factors (see. Different dosimetry methods, practical and sophisticated, can be applied depending on final objective and availability of resources. Input data include data from blood, urine, and whole-body scans adequately scheduled up to at least 3 days after PRRNT. Planar images are useful to derive biokinetics over time, while SPECT and SPECT/CT fused images, although requiring more time to acquire, provide insight into organ-specific three-dimensional activity distribution. The MIRD scheme provides reference techniques for internal dosimetry. Dedicated software (OLINDA/EXM) has been used to derive mean absorbed dose estimates for 177 Lu and 90 Y peptides; [bib_ref] OLINDA/EXM: the secondgeneration personal computer software for internal dose assessment in nuclear..., Stabin [/bib_ref]. PRRNT dose estimates in organs are generally calculated using the MIRD scheme, with the basic formula: [formula] D ¼ e A Â S ¼ A 0 Â t Â S; [/formula] where Ã is the integral activity in the organ, A 0 is the initial activity in the organ, τ is the residence time corresponding to the total number of decays occurring in the organ divided by A 0 , and S is a dose conversion factor depending on the properties of the radionuclide and the target. The value of S should be corrected for the actual volume and mass of the organ. Once the integral activities in the organs of interest are determined using numerical or compartmental models [bib_ref] Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in..., Siegel [/bib_ref] [bib_ref] Developing and testing integrated multicompartment models to describe a single-input multiple-output study..., Foster [/bib_ref] , absorbed doses are generally calculated using dedicated software programs that use as input the residence time τ or the number of decays (OLINDA/EXM, RADAR) [bib_ref] Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in..., Siegel [/bib_ref] [bib_ref] Developing and testing integrated multicompartment models to describe a single-input multiple-output study..., Foster [/bib_ref]. The typical kinetics of radiopeptides, namely very fast blood clearance and renal elimination, determine the information required to obtain the integral activities in organs and tumour, which includes a whole dataset of scintigraphic images and data from blood and urine samples. Once the rough data are analysed, the activity in normal and tumour tissues is converted into time-activity curves for the calculation of absorbed dose estimates. The residence time for the red marrow is calculated from the residence time for blood, with the assumption that nonspecific uptake of the radiolabel takes place in the bone marrow. Uniform activity distribution and equivalent clearance in red marrow and blood are assumed. Due to the small size of the radiopeptide, the specific activity in bone marrow can be considered equal to the specific activity in blood [bib_ref] Dosimetry of internal emitters, Sgouros [/bib_ref] [bib_ref] Bone marrow dosimetry in peptide receptor radionuclide therapy with, Forrer [/bib_ref]. Overall, the dose to the red marrow results from bone marrow self-irradiation and the contribution from the remainder of the body. Tumour absorbed doses can then be estimated by assuming the lesion is a sphere and assuming a uniform activity distribution [bib_ref] Dosimetry in peptide radionuclide receptor therapy: a review, Cremonesi [/bib_ref] [bib_ref] Dosimetry for treatment with radiolabelled somatostatin analogues. A review, Cremonesi [/bib_ref]. For 90 Y-DOTATOC, the lack of γemission by [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y makes direct dosimetry quite difficult. Bremsstrahlung images are rather difficult to quantify, requiring the application of complex corrections. For this reason two alternative options are used in clinical practice: In and 86 Y simulations. Despite some drawbacks, the extrapolated absorbed doses are reasonably similar. For dosimetric purposes 111 In-DOTATOC has been used in clinical practice as a surrogate for 90 Y-DOTATOC because of its similar chemical and kinetic properties. An alternative but far more demanding solution is to use DOTATOC labelled with the positron emitter 86 Y. PET with 86 Y-DOTATOC offers improved spatial resolution and quantitative analysis. Nevertheless, the short time window for data collection , as a consequence of the physical half-life (14.7 h) of 86 Y, the low positron abundance, the high production cost and the low availability, are a challenge to the routine utilization of this method. 111 In-pentetreotide scintigraphy and PET with 68 Ga-DOTATOC are not suitable for accurate dosimetric calculation, the former due to its different kinetic behaviour and receptor affinity profile and the latter due to the short physical half-life (68 min) of [bib_ref] Therapeutic nuclear medicine in pediatric malignancy, Schmidt [/bib_ref] Ga. Recently, a PET-based method promising quantitative imaging of 90 Y distribution was described [bib_ref] Dosimetry for treatment with radiolabelled somatostatin analogues. A review, Cremonesi [/bib_ref] [bib_ref] Evaluation of quantitative planar 90Y bremsstrahlung whole-body imaging, Minarik [/bib_ref] [bib_ref] Dosimetry of yttrium-labelled radiopharmaceuticals for internal therapy: 86Y or 90Y imaging?, Walrand [/bib_ref]. In the case of 177 Lu-DOTATATE, the gamma photons emission allows both imaging and dosimetry of the same compound. Therefore dosimetry is usually performed [bib_ref] Dosimetry in peptide radionuclide receptor therapy: a review, Cremonesi [/bib_ref] [bib_ref] Dosimetry for treatment with radiolabelled somatostatin analogues. A review, Cremonesi [/bib_ref] 0.07±0.010.17±0.02 [bib_ref] A comparison of 111In-DOTATOC and 111In-DOTATATE: biodistribution and dosimetry in the same..., Forrer [/bib_ref] 0.04 (0.02-0.06) [bib_ref] Dosimetry in patients undergoing 177Lu-DOTATATE therapy with indications for 90Y-DOTATATE, Cremonesi [/bib_ref] 0.09 (0.03-0.18) [bib_ref] Comparison of 111In-DOTA-DPhe1-Tyr3-octreotide and 111In-DOTAlanreotide scintigraphy and dosimetry in patients with neuroendocrine..., Rodrigues [/bib_ref] 0.04±0.02 [bib_ref] Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu..., Wehrmann [/bib_ref] 0.05±0.00 [bib_ref] Preliminary data on biodistribution and dosimetry for therapy planning of somatostatin receptor..., Forster [/bib_ref] 0.02±0.03 [bib_ref] Bone marrow dosimetry in peptide receptor radionuclide therapy with, Forrer [/bib_ref] 0.06±0.02 [bib_ref] Pre-therapeutic dosimetry and biodistribution of 86Y-DOTA-Phe 1-Tyr3-octreotide versus 111In-pentetreotide in patients with..., Helisch [/bib_ref] 0.12±0.02 [bib_ref] Phase I trial of 90Y-DOTATOC therapy in children and young adults with..., Menda [/bib_ref] (paediatric, 111 In) a Kidneys 6.05 (unprotected) Lu-DOTATATE. ## Side effects ## Acute Side effects of PRRNT are usually mild, if necessary precautions are taken. Side effects may be acute, related to the administration of amino acids or to the radiopeptide itself, or chronic. The coinfusion of amino acids enlarges the safety margin for treating with higher activities enabling higher tumour radiation doses to be attained safely. Side effects such as nausea, headache and rarely vomiting due to metabolic acidosis induced by the amino acid coadministration do occur in the majority of patients [bib_ref] 86YDOTA0)-DPhe1-Tyr3-octreotide (SMT487) -a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective..., Jamar [/bib_ref] [bib_ref] Safe and effective inhibition of renal uptake of radiolabelled octreotide by a..., Rolleman [/bib_ref]. Particular attention and care should be given to avoiding possible electrolyte imbalance (hyperkalaemia, hypernatraemia), and the subsequent metabolic acidosis, that might lead to mild nausea and vomiting. The latter side effects should be managed by hydrating the patient with normal saline and possibly by repeating corticosteroid or antiemetic administrations. PRRNT may exacerbate the syndromes related to the respective functional tumours, due to the sudden massive release of the hormones and receptor stimulation. The clinical manifestation is dependent on the specific hormone involved. The following measures are therefore recommended. Vital signs (at least blood pressure and pulse) should be monitored before and after radiopeptide infusion, especially in symptomatic patients. Therapeutic interventions should be undertaken to treat the for functional syndrome effects or exacerbation (e.g. carcinoid syndrome/hypotension, hypoglycaemia, hypergastrinaemia, hypertension, hypotension, WDHA syndrome, electrolyte imbalance) [bib_ref] Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate, De Keizer [/bib_ref]. In patients without or with minor metastatic liver involvement, no significant hepatic toxicity has been reported. However, in patients with massive liver metastases and impaired liver function, liver toxicity may occur, and this should be considered, along with preexisting conditions affecting the liver, when choosing the appropriate radioisotope and dosing. In such cases, 177 Lu-labelled peptides should be used and the administered activity should be reduced accordingly. After treatment, patients should avoid pregnancy for at least 6 months. Due to a temporary impairment of fertility, related to a transient damage to Sertoli cells, male patients should consider sperm banking before therapy. ## Delayed side effects ## Renal toxicity The kidneys are the dose-limiting organs at the activities normally reached with PRRNT. Proper kidney protection, as discussed, is currently mandatory. However, despite kidney protection, loss of kidney function can occur after PRRNT, with a creatinine clearance loss of about 3.8 % per year for 177 Lu-DOTATATE and 7.3 % per year for 90 Y-DOTATOC [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref]. In a series of 1,109 patients treated with 90 Y-DOTATOC, the incidence of grade 4 and 5 kidney toxicity was found to be 9.2 % [bib_ref] Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue..., Imhof [/bib_ref]. Delayed renal toxicity following 90 Y-DOTATOC treatment was observed more frequently in patients with predisposing risk factors including longstanding and poorly controlled hypertension and diabetes mellitus [bib_ref] Peptide receptor radionuclide therapy for non-radioiodine-avid differentiated thyroid carcinoma, Teunissen [/bib_ref]. ## Bone marrow toxicity Severe (grade 3 and 4), mostly reversible, acute bone marrow toxicity is observed in less than 10-13 % of treatment cycles with 90 Y-DOTATOC, and in 2-3 % of cycles with 177 Lu-DOTATATE. Nevertheless, sporadic cases of myelodysplastic syndrome or overt acute myelogenous leukaemia have been reported [bib_ref] Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin..., Kwekkeboom [/bib_ref] [bib_ref] 90Y-Edotreotide for metastatic carcinoid refractory to octreotide, Bushnell [/bib_ref] [bib_ref] Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue..., Imhof [/bib_ref]. ## Endocrine systems Despite the presence of sstr in normal pituitary, thyroid and adrenal glands and Langerhans cells, no significant alteration in endocrine hormone function have been reported [bib_ref] Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate on endocrine function, Teunissen [/bib_ref]. # Results PRRNT with the somatostatin analogues 90 Y-DOTATOC and 177 Lu-DOTATATE has been explored in NET for more than a decade. Present knowledge and clinical studies indicate that it is possible to deliver tumoricidal absorbed doses (e.g. >200 Gy) to neoplastic tumours expressing sst2 receptors, leading to partial or complete objective responses in up to 30 % of patients. The best objective responses have been reported in gastroenteropancreatic NETs (with partial responses ranging from 9 % to 29 % and complete remission from 2 % to 6 %), and similar rates have been achieved in thorax (lung) NETs and neuroectodermal tumours (phaeochromocytomas, paragangliomas). Less favourable results have been reported for thymic NETs, medullary thyroid carcinoma and dedifferentiated thyroid carcinomas. Encouraging results have also been reported for sstr-positive tumours including meningiomas, medulloblastomas and astrocytomas . Survival analyses have shown that patients with high sstr tumour expression at study entry, treated with either 177 Lu-DOTATATE or 90 Y-DOTATOC, show significantly higher objective responses that translate into significantly longer survival [bib_ref] Treatment with the radiolabeled somatostatin analog, Kwekkeboom [/bib_ref] [bib_ref] Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue..., Imhof [/bib_ref]. A favourable biochemical response was also shown to be predictive of improved overall survival in patients with medullary (calcitonin) and dedifferentiated iodide-negative thyroid cancer (thyroglobulin) undergoing 90 Y-DOTATOC treatment [bib_ref] Peptide receptor radionuclide therapy with (90)Y-DOTATOC in recurrent meningioma, Bartolomei [/bib_ref] [bib_ref] Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas, Bodei [/bib_ref]. Symptomatic response, particularly a durable improvement in diarrhoea after 90 Y-DOTATOC treatment, proved to have an impact on PFS [bib_ref] 90Y-Edotreotide for metastatic carcinoid refractory to octreotide, Bushnell [/bib_ref]. Initial data indicate that combination treatments with the two isotopes 90 Y and 177 Lu linked either to DOTATOC or to DOTATATE administered in sequential treatment cycles or as a cocktail infusion for several cycles improve survival [bib_ref] Cohort study of somatostatin-based radiopeptide therapy with, Villard [/bib_ref] [bib_ref] Clinical results of radionuclide therapy of neuroendocrine tumours with 90Y-DOTATATE and tandem..., Kunikowska [/bib_ref]. However, larger prospective randomized trials are needed to confirm these results. In children and young adults only one controlled clinical phase I trial of PRRNT has been conducted utilizing 90 Y-DOTATOC at activity levels of 1.11, 1.48 and 1.85 GBq/m 2 per cycle in three cycles at 6-week intervals [bib_ref] Phase I trial of 90Y-DOTATOC therapy in children and young adults with..., Menda [/bib_ref]. Three patients showed a partial response, five a minor response, five stable disease and two progressive disease. Dosimetry results were similar to the dosimetry estimates in adults. The evaluation of response to PRRNT includes the assessment of functional and morphological responses, biochemical and symptomatic responses, and quality of life. Response is assessed by morphological and functional imaging techniques. Posttherapeutic 177 Lu-DOTATATE scans provide valuable information on the intensity of uptake and localization of the tracer, and thus can be used to assess the response to the prior therapy cycles. The time-line to assess response may vary according to clinical needs (aggressiveness and extent of disease), but usually the first follow-up examination is recommended after 3 months, and subsequent follow-up examinations should be performed after 3-6 months. The reader is also referred to the ENETS guidelines for a more detailed discussion of the standards of care in NET follow-up and documentation [bib_ref] ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: follow-up..., Arnold [/bib_ref]. ## Follow-up The assessment of renal function is of paramount importance, as the kidney, together with the bone marrow, is the critical organ in PRRNT. The follow-up should include the evaluation of serum creatinine levels and the determination of creatinine clearance. In patients with pre-existing risk factors for delayed renal toxicity (high-risk group), in particular long-standing and poorly controlled hypertension and diabetes mellitus, single kidney or previously documented renal insult, mainly nephrotoxic chemotherapy, more precise methods to assess renal function are recommended. These techniques may include GFR measurements by means of 99m Tc-DTPA, [bib_ref] 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma, Gains [/bib_ref] Cr-EDTA or measurement of 99m Tc-MAG3 clearance. ## Between-cycle follow-up A complete blood cell count should be performed every 2-4 weeks. A higher frequency can be adopted if clinically required. Renal and liver function tests should be available before confirming subsequent cycles. Following careful clinical assessment, patients with blood values lower than the limits indicated for the first PRRNT cycle should receive a lower activity and/or the interval to the following PRRNT cycle should be extended. In severe cases, interruption of PRRNT might be considered. Intermediate and long-term follow-up A complete blood cell count (including mean corpuscular volume), and renal and liver function tests should be performed every 8-12 weeks for the first 12 months, and thereafter twice a year if clinically indicated. Evaluation of response to treatment includes consideration of the clinical, biochemical, morphological and PET/SPECT functional status, and wellbeing of the patient. Morphological response is determined by contrast-enhanced CT or MRI. Objective response can be determined using the WHO, SWOG and RECIST criteria [bib_ref] Southwest Oncology Group standard response criteria, endpoint, definitions and toxicity criteria, Green [/bib_ref] [bib_ref] RECIST revised: implications for the radiologist. A review article on the modified..., Van Persijn Van Meerten [/bib_ref]. For assessing morphological response, CT is the preferred imaging technique, but this does not rule out the use of MRI. In some patients, CT and MRI may provide complimentary information. In any case, the same imaging modality should be employed during the follow-up of the individual patient. Depending on the disease duration and on tumour biology, these examinations are repeated every 3-6 months, but may be extended up to once every 12 months in the long-term follow-up in patients with a durable response. Functional imaging is a valuable instrument to assess the course of the disease, and it has been demonstrated to be able to predict morphological response. Combined functional and morphological imaging may in many cases better reflect the true behaviour of the tumour following PRRNT. Such imaging includes 111 In-pentetreotide (OctreoScan) and, if available, PET/CT with 68 Ga-DOTA peptides or metabolic monitoring with, for example, 18 F-DOPA. However, functional imaging is not yet accepted as a substitute for morphological imaging as a means to assess tumour response to a treatment. ## Disclaimer This guidance document is a compilation of recent published evidence on the use of PRRNT in NETs and the personal experience of leading experts in the field reflecting personal opinion based on unpublished data. It pays special attention to and emphasizes gastroenteropancreatic presentations. The guidance is not provided as an inflexible set of rules and is not intended, nor should it be used, to establish legal standards of care. For these reasons as well as those set out below, this guidance should not be used in litigation in which the clinical decisions of practitioners are being called into question. The EANM and the IAEA have written and approved guidelines to promote the cost-effective use of high-quality nuclear medicine therapeutic procedures. These generic recommendations cannot be rigidly applied to all patients in all practice settings. The guidelines should not be deemed inclusive of all proper procedures or exclusive of other procedures reasonably directed to obtaining the same results. Advances in medicine occur at a rapid rate. The date of a guideline should always be considered in determining its current applicability. ## Further reading For additional reading, the book published by the Nuclear Medicine Section, IAEA, entitled "Practical guidance on peptide receptor radionuclide therapy (PRRNT) for neuroendocrine tumours" (Human Health Series no. 12) is available for download using the link http://www.iaea.org/Publications/	None	https://link.springer.com/content/pdf/10.1007/s00259-012-2330-6.pdf	None
0cbaf4bfd634658da8b7719cac1efc1dd6d5f4a8	pubmed	SARS‐CoV‐2 infection, COVID‐19 and timing of elective surgery	SARS‐CoV‐2 infection, COVID‐19 and timing of elective surgery ## Summary The scale of the COVID-19 pandemic means that a significant number of patients who have previously been infected with SARS-CoV-2 will require surgery. Given the potential for multisystem involvement, timing of surgery needs to be carefully considered to plan for safe surgery. This consensus statement uses evidence from a systematic review and expert opinion to highlight key principles in the timing of surgery. Shared decision-making regarding timing of surgery after SARS-CoV-2 infection must account for severity of the initial infection; ongoing symptoms of COVID-19; comorbid and functional status; clinical priority and risk of disease progression; and complexity of surgery. For the protection of staff, other patients and the public, planned surgery should not be considered during the period that a patient may be infectious. Precautions should be undertaken to prevent pre-and peri-operative infection, especially in higher risk patients. Elective surgery should not be scheduled within 7 weeks of a diagnosis of SARS-CoV-2 infection unless the risks of deferring surgery outweigh the risk of postoperative morbidity or mortality associated with COVID-19. SARS-CoV-2 causes either transient or asymptomatic disease for most patients, who require no additional precautions beyond a 7-week delay, but those who have persistent symptoms or have been hospitalised require special attention. Patients with persistent symptoms of COVID-19 are at increased risk of postoperative morbidity and mortality even after 7 weeks. The time before surgery should be used for functional assessment, prehabilitation and multidisciplinary optimisation. Vaccination several weeks before surgery will reduce risk to patients and might lessen the risk of nosocomial SARS-CoV-2 infection of other patients and staff. National vaccine committees should consider whether such patients can be prioritised for vaccination. As further data emerge, these recommendations may need to be revised, but the principles presented should be considered to ensure safety of patients, the public and staff. Introduction SARS-CoV-2 infection has contributed to more than 118 million infections globally and more than 2.6 million deaths from COVID-19. The impact of COVID-19 has been particularly significant in the UK, with more than 4.2 million cases and 125,000 people dying within 28 days of a positive SARS-CoV-2 test. The scale of the pandemic has created substantial pressures on healthcare systems globally, leading to sustained reductions in surgical activity. An estimated 28 million operations were cancelled in 12 weeks of the first pandemic surge [bib_ref] Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to..., Nepogodiev [/bib_ref] , with millions of patients still waiting for surgery. To support delivery of surgical services throughout the pandemic, prioritisation of different procedures has been undertaken. One of the challenges of surgery during the COVID-19 pandemic is the peri-operative risk of morbidity and mortality to patients with active SARS-CoV-2 infection. Evidence suggests a 19.1% 30-day mortality in elective (planned) and 26.0% 30-day mortality in emergency surgical patients, with around half of patients having surgery when infected with SARS-CoV-2 experiencing postoperative pulmonary complications [bib_ref] Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection:..., Collaborative [/bib_ref]. In addition, given the scale of the pandemic, peri-operative outcomes after a previous SARS-CoV-2 infection are an important concern, as a significant number of patients who have previously been infected (estimated at 15-20% of the UK populationwill require surgery. Surgery after a previous SARS-CoV-2 infection should be timed to ensure the safest delivery of peri-operative care. SARS-CoV-2 infection may cause multisystem disease with both short and long-term sequelae, including chronic pulmonary dysfunction, myocardial inflammatory states, renal impairment, psychological distress, chronic fatigue and musculoskeletal deconditioning [bib_ref] Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage..., Rivett [/bib_ref] [bib_ref] 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, Huang [/bib_ref] [bib_ref] Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after..., Carf I [/bib_ref] [bib_ref] Follow-up study of the pulmonary function and related physiological characteristics of COVID-19..., Zhao [/bib_ref]. These short ## Protection of others Elective surgery after SARS-CoV-2 infection must be safe for staff, other patients and the public [bib_ref] Peri-operative COVID-19 infection in urgent elective surgery during a pandemic surge period:..., Kane [/bib_ref] [bib_ref] Airborne transmission of severe acute respiratory syndrome coronavirus-2 to healthcare workers: a..., Wilson [/bib_ref] [bib_ref] Kicking on while it's still kicking off -getting surgery and anaesthesia restarted..., Cook [/bib_ref] [bib_ref] Risks to healthcare workers following tracheal intubation of patients with COVID-19: a..., El-Boghdadly [/bib_ref]. Therefore, adherence to self-isolation guidelines is imperative. Symptoms of COVID-19 present 4-5 days following infection with SARS-CoV-2, and it is most contagious in the 2 days before and the 5 days after the onset of symptoms [bib_ref] Duration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity: When is..., Rhee [/bib_ref]. In asymptomatic and mild to moderately symptomatic patients, it is rare for the virus to be cultured beyond 10 days after symptom onset, which underlies ## Timing of elective surgery after sars-cov-2 infection ## Symptoms and severity of disease The phases of COVID-19and the scale of clinical severity [bib_ref] A minimal common outcome measure set for COVID-19 clinical research, Marshall [/bib_ref] are both important factors in planning surgery and are summarised in. It is important to note that for the majority of patients infected with SARS-CoV-2, it is either a transient or asymptomatic disease followed by full recovery [fig_ref] 1 02: [/fig_ref]. Approximately 15% of infected patients are hospitalised, 5% require advanced oxygen therapies and around 1% of all cases require critical care admission [fig_ref] 1 02: [/fig_ref] also been reported in smaller patient cohorts [bib_ref] Periprocedural complications in patients with SARS-CoV-2 infection compared to those without infection:..., Lal [/bib_ref]. Notably, symptomatic patients are at greater risk of 30day mortality than patients whose symptoms have resolved or those who have asymptomatic infection, even beyond a Phases of COVID-19. ## Phase definition ## Acute covid-19 symptoms and signs of covid-19 for up to 4 weeks after infection ongoing symptomatic covid-19 symptoms and signs of covid-19 from 4 weeks up to 12 weeks after infection Post-COVID-19 syndrome Symptoms and signs that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis. It usually presents with clusters of symptoms, often overlapping, which can fluctuate and change over time and can affect any system in the body. Post-COVID-19 syndrome may be considered before 12 weeks while the possibility of an alternative underlying disease is also being assessed. Long COVID Symptoms and signs that continue or develop after acute COVID-19, which includes both ongoing symptomatic COVID-19 (from 4 to 12 weeks) and post-COVID-19 syndrome (≥12 weeks) Resolved COVID-19 Previous symptoms and signs of acute COVID-19 that have completely resolved. 7-week delay. Moreover, patients with resolved symptoms are also at greater risk of 30-day mortality than those who had asymptomatic infection [bib_ref] Periprocedural complications in patients with SARS-CoV-2 infection compared to those without infection:..., Lal [/bib_ref] [bib_ref] Early postoperative outcomes among patients with delayed surgeries after preoperative positive test..., Baiocchi [/bib_ref]. Thus, both the previous and current clinical condition of patients appear to influence postoperative outcomes. Timing of surgery in patients who have been in critical care requires special consideration. In addition to residual pathophysiological sequelae, many will be deconditioned and require physical rehabilitation. Many will also have had ## Box 1 Prioritisation of urgency of surgical procedures. Categories P5 (patient wishes to postpone surgery due to COVID-19 concerns) and P6 (patient wishes to postpone surgery due to non-COVID-19 concerns) were added in October 2020 as part of the national validation of waiting lists. The complexity and the nature of surgery is a further consideration, as more complex surgery is consistently associated with increased postoperative morbidity and mortality, including in patients with COVID-19 [bib_ref] Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection:..., Collaborative [/bib_ref]. Validated risk prediction tools account for complexity and urgency of surgery, and can be used to aid decision-making regarding timing of surgery after SARS-CoV-2 infection [bib_ref] Developing and validating subjective and objective risk-assessment measures for predicting mortality after..., Wong [/bib_ref]. ## Anaesthetic technique There is currently no strong evidence that anaesthetic technique is associated with an alteration in postoperative outcome in patients who have had peri-operative SARS-CoV-2 infection [bib_ref] Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection:..., Collaborative [/bib_ref]. In patients with persistent respiratory pathophysiological changes after severe COVID-19, the benefits of avoiding general anaesthesia are likely to be the same as in other respiratory disease. The use of local or regional anaesthetic techniques may have outcome and resource-utilisation benefits, but this is not specific to patients with previous or current SARS-CoV-2 infection. # Discussion As the population of patients requiring surgery following SARS-CoV-2 infection grows, so will the need to ensure safe peri-operative care for this cohort. The same general principles of safe and effective peri-operative care as for patients with no history of SARS-CoV-2 infection apply. However, timing of surgery must also be sensitive to the impact of SARS-CoV-2 on both patients and others. In after discharge, need to continue while this remains a significant risk. As further data emerge, these recommendations may need to be revised. [fig] 3: Surgery within 7 weeks of SARS-CoV-2 infection is associated with increased morbidity and mortality. Elective surgery should not be scheduled within 7 weeks of a diagnosis of SARS-CoV-2 infection, unless outweighed by the risk of deferring surgery such as disease progression or clinical priority. [/fig] [fig] 4: Most patients infected with SARS-CoV-2 have either transient or asymptomatic disease and require no additional precautions beyond a 7-week delay, but those who have persistent symptoms or have been hospitalised require special attention. [/fig] [fig] 5: Patients with persistent symptoms of COVID-19 are at increased risk of postoperative morbidity and mortality even after 7 weeks. Therefore, delaying surgery beyond this point should be considered, balancing this risk against their risk of disease progression and clinical priority. Specialist assessment and personalised, multidisciplinary peri-operative managementis required. [/fig] [fig] 6: The time before surgery should be used for functional assessment, rehabilitation from severe illness, prehabilitation and multidisciplinary optimisation. [/fig] [fig] 7: Vaccination several weeks before surgery will reduce risk to patients and might lessen the risk of nosocomial SARS-CoV-2 infection of other patients and staff. National vaccine committees should consider whether such patients can be prioritised for vaccination. [/fig] [fig] 8: As a result of the increased risk of morbidity and mortality of peri-operative COVID-19, precautions to prevent admission of patients who are incubating SARS-CoV-2 and infection within the hospital should continue. These recommendations are based on evidence available at the time of writing and may be subject to future review. [/fig] [fig] 1 02: (0.66-1.56)). The timings of these mortality risks are also consistent in elective surgery, and when stratified by patient demographics, complexity of surgery and urgency of surgery. A similar trajectory is also seen in postoperative pulmonary complications, with risks being greater for the first 6 weeks after SARS-CoV-2 infection when compared with no infection, but returning to comparable rates beyond 7 weeks. Similar time-dependent findings have [/fig] [fig] Figure 1: Estimated population distribution of SARS-CoV-2 presentation. NIV, non-invasive ventilation; HFNO, high-flow nasal oxygen. [/fig] [fig] Priority 1a: Emergency procedures to be performed in < 24 h. Priority 1b: Procedures to be performed in < 72 h Priority 2: Procedures to be performed in < 1 month Priority 3: Procedures to be performed in < 3 months Priority 4: Procedures to be performed in > 3 months 944 [/fig]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/anae.15464	The scale of the COVID‐19 pandemic means that a significant number of patients who have previously been infected with SARS‐CoV‐2 will require surgery. Given the potential for multisystem involvement, timing of surgery needs to be carefully considered to plan for safe surgery. This consensus statement uses evidence from a systematic review and expert opinion to highlight key principles in the timing of surgery. Shared decision‐making regarding timing of surgery after SARS‐CoV‐2 infection must account for severity of the initial infection; ongoing symptoms of COVID‐19; comorbid and functional status; clinical priority and risk of disease progression; and complexity of surgery. For the protection of staff, other patients and the public, planned surgery should not be considered during the period that a patient may be infectious. Precautions should be undertaken to prevent pre‐ and peri‐operative infection, especially in higher risk patients. Elective surgery should not be scheduled within 7 weeks of a diagnosis of SARS‐CoV‐2 infection unless the risks of deferring surgery outweigh the risk of postoperative morbidity or mortality associated with COVID‐19. SARS‐CoV‐2 causes either transient or asymptomatic disease for most patients, who require no additional precautions beyond a 7‐week delay, but those who have persistent symptoms or have been hospitalised require special attention. Patients with persistent symptoms of COVID‐19 are at increased risk of postoperative morbidity and mortality even after 7 weeks. The time before surgery should be used for functional assessment, prehabilitation and multidisciplinary optimisation. Vaccination several weeks before surgery will reduce risk to patients and might lessen the risk of nosocomial SARS‐CoV‐2 infection of other patients and staff. National vaccine committees should consider whether such patients can be prioritised for vaccination. As further data emerge, these recommendations may need to be revised, but the principles presented should be considered to ensure safety of patients, the public and staff.
04ad4c538d21d7cb796c00d8a5db149208af9e8e	pubmed	The clinical nurse specialist's role in head and neck cancer care: United Kingdom National Multidisciplinary Guidelines	The clinical nurse specialist's role in head and neck cancer care: United Kingdom National Multidisciplinary Guidelines This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It discusses the role of the clinical nurse specialist in the head and neck cancer patient journey and provides recommendations on the clinical nurse specialist led assessments and interventions for this group of patients receiving cancer care.Recommendations- All cancer patients should meet a clinical nurse specialist at the point of diagnosis. (R)- Clinical nurse specialists must act as gate keeper to the patients' cancer pathway to provide a seamless journey. (R) - Holistic needs assessment should be completed at different stages of the patient's pathway to reflect the changes of the patients' needs. (R) - Clinical nurse specialists to be part of local and national initiatives for health promotion and raising awareness in the public domain. (G) - Clinical nurse specialists should lead in redesigning of services and policies to ensure they are responsive to patient's needs for the future. (G) - Treatment summaries should become part of practice to provide good communication between primary and secondary care to enable continuity of care for the patient. (G) # Introduction Distress is common among cancer patients; it is multifactorial, comprising of psychological, social and spiritual elements which can impact on an individual's ability to cope effectively with cancer. A diagnosis of cancer leaves patients frightened and vulnerable, often unable to understand the full implication of the treatment they are being offered.It can, in extreme cases, impact on the ability to adhere to treatment and self-management. It is widely recognised that head and neck cancer patients are particularly vulnerable to psychological distress as many suffer life-changing, long-term consequences resulting from the cancer and the treatment. [bib_ref] The patient's concerns inventory: a tool to uncover unmet needs in a..., Ghazi [/bib_ref] [bib_ref] Psychological management for head and neck cancer patients: United Kingdom National Multidisciplinary..., Humphris [/bib_ref] Carers of patients with head and neck cancer are under considerable stress during and after treatment as a result of disruption to daily life, the financial and emotional strain of long-term treatment and in many cases, role reversal within the family unit. Patients and carers look to healthcare professionals to provide information to help manage the psychological and social elements of head and neck cancer. [bib_ref] How head and neck consultants manage patients' emotional distress during cancer follow-up..., Zhou [/bib_ref] Supportive care, appropriate information and individualised care planning is a key to improve the experience of the patient and the carer. It is the function of the clinical nurse specialist (CNS) to give the patient and carer the wherewithal to cope with the diagnosis, treatment and long-term consequences through the use of empathy and experience. [bib_ref] Fear of recurrence among head and neck cancer survivors: longitudinal trends, Ghazali [/bib_ref] The Cancer Reform Strategy 9 recognises that the CNS is critical in the delivery of information, communication and co-ordination of care. It has been recognised that care co-ordination individualised to the patient during and after treatment is vital to deliver appropriate person-centred care. [bib_ref] Nurse-patient communication in follow-up consultations after head and neck cancer treatment, De Leeuw [/bib_ref] The CNS' role within the multidisciplinary team (MDT) also allows for easy and timely referral on to other resources, i.e. palliative care and psychological support. The role of the clinical nurse specialist (figure 1) The National Institute for Health and Care Excellence Improving Outcomes Guidance 11 identified the key worker as 'A person who with the patient's consent and agreement takes a key role in co-ordinating the patient's care and promoting continuity, ensuring the patient knows who to access for information and advice'. The CNS will act as the patient's key worker during their cancer pathway by providing specialist cancer knowledge and expertise to both the patient and carer, which can be both complex and disjointed, involving interventions from multiple professionals or agencies.The CNS reinforces and imparts their specialist knowledge to the other professionals and agencies to improve the cancer process and in turn will improve the cancer journey for the patient and carer. The CNS may pass the key worker role on to another relevant professional when the patient is on a particular part of the pathway, as this may be in their best interests and provide the best support at that particular point of their journey. The CNS workload can be complex and varied dependent on the patient's needs, it can be categorised into themes: - Specialist technical knowledge of the cancer process and treatment options - Acting as the patient's key worker for a specific part of the process and linking in with the MDT - Utilising advanced communication skills to support the patient and carer psychologically through the disease process - Lead on redesigning services to make them responsive to the patient's needs - Health education and promotion to reduce the risk of recurrence and promote a healthy lifestyle - Assisting in local and national initiatives to promote awareness and prevention. The role of the CNS within the MDT The CNS acts as the key accessible professional to the patient within this multiprofessional setting, and allows the CNS to influence the patient's pathway. They are well placed to support the patient at each stage of their pathway and promote integration within the team. The CNS should be recognised as the patient's advocate within the MDT meetings where they deliver patient-centred care tailored to the individual patient's needs. In acting as the patients' advocate, the CNS also plays a key role in ensuring that the multidisciplinary care is responsive to the patients' needs and preferences. [bib_ref] Clinical nurse specialists: adding value to care RN Forum, Leary [/bib_ref] The CNS and the patient's pathway Clinical nurse specialists increasingly take the lead role in shaping patient care pathways and refining systems to make a difference to the patient experience and their safety. By acting as the key worker,they provide information, support and liaison to improve the cancer care process for the patient. They can track the stage of their pathway and ensure it is seamless and prevent any problems from occurring. They are well placed with in the organisation to assist in system changes to ensure the pathway represents a quality service that fulfils the standards of cancer care and patients' expectations. The patient's role as advocate Patients and carers have always been at the centre of cancer services, but have not always been encouraged or empowered to help influence and shape them. 14 Patient support groups have traditionally played a large part in providing information, companionship and peer support for patients and carers throughout their cancer journey. They can also influence policy and services at local, national and at international level. The Cancer Plan 15 saw the patient involvement being embedded in cancer services. This involvement has continued with organisations like National Cancer Research Institute (NCRI) having representation on all its clinical study groups and funding committees. This is also happening on cancer strategy committees and clinical network groups. Patients and carers now have a realisation that they have considerable influence in gaining access to treatments and medicines, can participate in the designing of clinical trials and influence the amount of money spent by central government on research. 14 It is important to understand that patients provide a very different perspective on benefits vs risks of treatment. [bib_ref] Eliciting views of patients with head and neck cancer and carers on..., Birchall [/bib_ref] They will very often opt for extensive and often life threatening treatment even if the benefits and outcomes are unclear. ## Managing patients' and carers' expectations A diagnosis of cancer has far reaching effects beyond the patient to their loved ones. This life-changing experience means that relationships and roles and responsibilities can often be changed. Treatments for head and neck cancer can have devastating effects on the lives of patients, including disfiguration, speech and swallowing impairment.'The Recovery Package' 18 has been designed by Macmillan Cancer Support to help 'provide a series of key interventions, which when delivered together can greatly improve outcomes for people living with and beyond cancer'. It is made up of: - Holistic needs assessment - Treatment summary - Cancer care review - Education and support events. It also compliments stratified care plans, which enable individualised follow-up care and self-support. It facilitates urgent access back to the specialist team if needed or on-going support from healthcare professionals. ## Recommendations - All cancer patients should meet a cinical nurse specialist at the point of diagnosis (R) - Clinical nurse specialists must act as gate keeper to the patient's cancer pathway to provide a seamless journey (R) - Holistic needs assessment (HNA) should be completed at different stages of the patient's pathway to reflect the changes of the patients' needs (R) - Clinical nurse specialists to be part of local and national initiatives for health promotion and raising awareness in the public domain (G) - Clinical nurse specialists should lead in redesigning of services and policies to ensure they are responsive to patient's needs for the future (G) - Treatment summaries should become part of practice to provide good communication between primary and secondary care to enable continuity of care for the patient (G) Holistic needs assessment An HNA ensures that the patients' and carers' physical, emotional and social needs are met in a timely and appropriate way, and that advice and support is available from the right source at the right time.The HNA is the process of assessing the patient and/or carers by developing an understanding of what the person with cancer understands and needs at diagnosis and various time points thereafter which can be agreed by the MDT or when clinically appropriate (i.e. disease progression). This discussion may cover all or some of the following areasphysical, spiritual, emotional, social and environmental needs. Undertaking holistic needs assessment with a patient enables them to more fully engage in their own care and make informed choices. The information gathered at the HNA can also be shared with other members of the MDT and also have influence on service needs and data collection. The National Cancer Survivorship Initiative (NCSI) in 2010 highlights HNA as one of its 'Key Shifts' as well as it being a Peer Review Measure. Different assessment tools are used, i.e. distress thermometer, concerns checklist and more recently the patient concerns inventory. The tools can be used at different stages along the patient trajectory, but with an emphasis being on assessing and eliciting patients' and carers' concerns and expectations. This leads to a discussion and care planning of the patients' needs and helps to manage expectations. Pre-treatment clinics provide an opportunity for patients and carers to meet the CNS and other allied L DEMPSEY, S ORR, S LANE et al. health professionals prior to surgical or oncological treatment. It allows HNA assessment to take place, but also facilitates discussion of acute treatment and rehabilitation with the key professionals involved prior to commencement of such. ## Care plans A care plan is based on the diagnosis and holistic assessment of the patient.It will highlight the patient's issues, outlining any actions, approaches and timings to address them. Care plans change during the patient pathway according to the patient's needs at any one time; however, any change should be discussed and actions agreed with the patient. By working with the patient to develop care plans following an HNA, the patient is able to take more control of what happens to them and support themselves to self-manage their condition. 20 ## Treatment summary A key component to effective patient care is good communication between the primary and secondary care sectors. Making sure that general practitioners are fully informed about their patients' cancer journeys can ease the transition between acute and long-term care. For this to be effective, treatment summaries are provided at the end of any acute treatment by the MDT for the general practitioner and patient. The treatment summary describes the treatment that that person has received, including any adverse reactions, the side effects and signs and symptoms of recurrence. This treatment summary provides confidence to the patient that their care is continuing albeit in the community setting. Patients report feelings of abandonment and vulnerability once initial treatment is complete but with a treatment summary and care plan these feelings can be minimised. Patients' on-going self-management can be well supported through peer support groups and health and wellbeing events. The CNS is obliged to inform patients of what is available in the local area that may be accessed by the patient and carer. ## Key points Clinical nurse specialists should: - meet every patient at the point of diagnosis to assist in a smooth transition along the cancer pathway - ensure effective communication within the MDT, with patient and carer and within the community setting - be at the centre of the patient's pathway and make effective use of resources - act as the patient advocate, utilising support groups to act as patient voices in the changing healthcare environment to make them patientcentred - perform holistic needs assessment for all patients at diagnosis and specific points along their journey to ensure patient-focused care is being provided - offer treatment summaries to all people involved in the patient's recovery to ensure effective communication - offer individualised care plans to help patients take control of the recovery phase. © 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/S0022215116000657	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/795208B4671A7A009640F14DF149139E/S0022215116000657a.pdf/div-class-title-the-clinical-nurse-specialist-s-role-in-head-and-neck-cancer-care-united-kingdom-national-multidisciplinary-guidelines-div.pdf	Abstract This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It discusses the role of the clinical nurse specialist in the head and neck cancer patient journey and provides recommendations on the clinical nurse specialist led assessments and interventions for this group of patients receiving cancer care. Recommendations • All cancer patients should meet a clinical nurse specialist at the point of diagnosis. (R) • Clinical nurse specialists must act as gate keeper to the patients' cancer pathway to provide a seamless journey. (R) • Holistic needs assessment should be completed at different stages of the patient's pathway to reflect the changes of the patients' needs. (R) • Clinical nurse specialists to be part of local and national initiatives for health promotion and raising awareness in the public domain. (G) • Clinical nurse specialists should lead in redesigning of services and policies to ensure they are responsive to patient's needs for the future. (G) • Treatment summaries should become part of practice to provide good communication between primary and secondary care to enable continuity of care for the patient. (G)
d13d583dbd6abef3030f9e54a465e5ee7503d213	pubmed	Safety in magnetic resonance units: an update	Safety in magnetic resonance units: an update ## Summary The number of anaesthetists who are involved in magnetic resonance (MR) units is increasing. Magnetic resonance systems are becoming more powerful and interventional procedures are now possible. This paper updates information relating to safety terminology, occupational exposure, reactions to gadolinium-based contrast agents and the risk of nephrogenic systemic fibrosis. Magnetic resonance examinations of patients with pacemakers are still generally contra-indicated but have been carried out in specialist centres under strictly controlled conditions. As availability of MR increases, so the education of anaesthetists, who are occasionally required to provide a service, must be considered. Anaesthesia in MR units was first described in the 1980s. Guidelines on the provision of anaesthetic services in MR units were published by the Association of Anaesthetists of Great Britain and Ireland (AAGBI) in 2002. Since then, the number of hospitals with MR units, and hence the number of patients requiring anaesthesia for MR, has increased. While the issues relating to setting up anaesthetic services in MR have not changed, there have been a number of developments that warrant this update: 1 Safety terminology and guidelines have changed. 2 MR systems utilise higher magnetic-field strengths and more open designs are available. 3 Interventional and intra-operative MR are now routine in some centres. 4 Mobile MR scanners are increasingly used to reduce waiting lists. 5 Although still generally contra-indicated, some patients with pacemakers have been scanned under strictly controlled conditions in specialist centres. 6 'MR safe' medical implants are now being produced. 7 New equipment is now available for use in MR. 8 Out-of-hours availability of MR investigations has increased. 9 Reports of allergic reactions to MR contrast media have increased. 10 Gadolinium based contrast agents (Gd-CAs) are associated with a varying degree of risk of nephrogenic systemic fibrosis in patients with impaired renal function. ## Safety guidelines and legislation In 2007 the Medicines and Healthcare products Regulatory Agency (MHRA) updated safety guidance as a Device Bulletin. Three terms are now to be used as standard in an attempt to remove any ambiguity caused by the old MR compatible system. These terms are MR conditional, MR safe and MR unsafe. MR conditional refers to an item that has been demonstrated to pose no known hazards in a specified MR environment with specified conditions of use. Many items in the MR environment will now be marked as MR conditional, and the conditions under which they can be safely used must accompany the device. This change of terminology has come about because of reports of injuries and problems with MR compatible equipment [bib_ref] Magnetic resonance compatible equipment: read the small print, Farling [/bib_ref]. Conditions that define the specified MR environment include main magnetic field strength, spatial magnetic field gradient, dB ⁄ dt (time rate of change of the magnetic field), radio frequency (RF) field strength, and specific absorption rate. Additional conditions, including specific configurations of the item of equipment, may be required. Equipment is designated as MR safe if it presents no safety hazard to patients or personnel when it is taken into the MR examination room, provided that instructions concerning its use are correctly followed. This does not, however, guarantee that it will function normally and not interfere with the correct operation of the MR imaging equipment, with degradation of image quality. New equipment, such as infusion pumps [bib_ref] Evaluation of infusion pump performance in a magnetic resonance environment, Bradley [/bib_ref] , warming mattresses and temperature probes are now available. It is important to understand the manufacturers' instructions of all equipment that is brought into the vicinity of the MR scanner. It should be recognised that the supervising MR radiographer is responsible operationally for MR safety within the controlled area and that anaesthetic staff should defer to him/her in relation to MR safety matters, in particular control of access of staff and equipment into the controlled area. Where staff are given access codes or swipe-card access to the controlled area, they should not be shared with others, nor should they provide access to others unless specifically authorised to do so. ## Inspired oxygen concentration The use of 100% O 2 during anaesthesia should be reported to the reporting radiologist as this can produce an artefact in the form of an abnormally high signal in cerebrospinal fluid (CSF) spaces in the T2 weighted fluid attenuated inversion recovery (FLAIR) sequence. ## Acoustic noise The time-varying magnetic field gradients produce audible noise within the magnet interior. Since the guidelines were published by the AAGBI, the Control of Noise at Work Regulations have been updated. This document introduced lower exposure limit values and action values in the working environment. When the noise level exceeds 80 dB (A), it is recommended that staff and others remaining in the scanning room should wear ear protection. Other documents have been published by the Health Protection Agency relating to patient exposure guidanceand static field guidance. The website of the British Association of MR Radiographers (BAMRR) remains an excellent resource for safety issues and provides links to many useful safety sites. ## New mr systems At the end of 2006, it was estimated that there were approximately 500 fixed MR scanners involved in human imaging, installed at some 350 sites across the UK. The SI unit of magnetic field strength or magnetic flux density is the Tesla (T) and initially, most clinical MR systems were 0.5, 1.0 or 1.5 T. In 1992 there were two MR units in Northern Ireland. Today there are 16, of which, one is a 3-T system. Other regions will have experienced a similar expansion but, since the withdrawal of funding from MagNET, up-to-date information for the UK is difficult to obtain. Magnets operating at 3 T appeared in the early 1990s and by 2007 it was estimated that 35 units had installed 3-T systems. The benefits of the higher field strength systems include improved image quality and higher spatial resolution. While it is claimed that 3-T scans are quicker, more efficient and require less Gd-CAs, practically these statements are debatable. It is the responsibility of the equipment manufacturers to indicate the field strength at which their equipment is MR safe or MR conditional. It should not be automatically assumed that equipment that is MR conditional at 1.5 T remains MR conditional at 3 T. A smaller number of ultra-high field MR systems are in use in research institutions world wide and these produce static fields in the range 4.7-9.4 T. Anaesthetists may wish to be aware of the potential implications of replacing a 1.5-T system by a 3-T system. In a magnetic field strength survey of a 1.5-T system all spot measurements taken at 1 m above the floor level were found to be below the 0.5-mT safety limit. A similar survey for a 3-T system indicated that there were areas outside the magnet room where levels exceeded the safety limit. Barriers and warning notices, which indicate the risk of pacemaker malfunction, should be in place to prevent inadvertent public access. ## Open systems The horizontal-bore cylindrical type of scanner is still the commonest, but technology constantly changes and magnets are available with wider bores, which are less claustrophobic. More open scanners have been developed and units now exist that allow the patient to stand upright thus reducing the feeling of claustrophobia. In a conventional MR system operating at 1.5 T, because of its more closed design, it is less likely that radiological and anaesthetic staff would be exposed to significant static and time varying fields. Interventional procedures and intra-operative MR Advances in technology mean MR image-guided surgery is now possible, providing the surgeon with dynamic high-resolution images during intricate stereotactic neurosurgery. Various MR systems have been configured for this application, including 'doughnut' shaped magnets permitting surgery with real-time concurrent imaging, and portable systems set up to allow easy and rapid interchange between scanning and surgery. All the hazards associated with diagnostic MR also apply to Safety in magnetic resonance units . . interventional procedures. There are additional risks from patient repositioning, contamination of the sterile field, and the proximity of ferromagnetic surgical instruments, including scalpels, to the magnetic field. Incorporating MR technology into the operating room provides new challenges [bib_ref] Anesthesia in the intra-operative MRI Environment, Bergese [/bib_ref]. ## Occupational exposure It is difficult to measure occupational exposure to the various electro magnetic fields in MR units routinely. Personal dosimeters have been developed but are not, as yet, widely available. Some studies have suggested that staff members can be exposed to higher than recommended levels of time-varying gradient fields [bib_ref] Occupational exposure to static and time-varying gradient magnetic fields in MR units, Bradley [/bib_ref]. In 2004, the European Union adopted a directive restricting occupational exposure to electromagnetic fields, including those used in MR. Some of the exposure limits threatened to impact on the current use and future development of MR technology. Known adverse effects are adequately addressed in the international standard governing the manufacture of MR systems. Initially, unable to influence the regulatory agencies, the MR community began to lobby both the UK and European Parliaments. Implementation of the directive has been delayed until 30 April 2012 to allow a permanent solution to be found. However, the timescale is short given the political and scientific complexities of the issue. A range of possible outcomes is explored in a report for the Institute of Physics. Each option has advantages and disadvantages, and a great deal of detailed discussion and negotiation will be needed over the next 2 years to ensure satisfactory resolution of the problem. ## Pacemakers and medical implants The MHRA safety guidancestill specifies that pacemakers are an absolute contraindication to MR and it therefore remains the mantra of radiology departments that any individual with a pacemaker should not enter the MR unit. This is due to the concern that the magnet field strengths in excess of 0.5 mT (5 Gauss) could cause a fatal malfunction of the pacemaker. Sudden deaths have been reported in patients with pacemakers during or shortly after MR investigations. However, both pacemaker and MR technology are continually developing and there are times when MR is needed to provide valuable clinical information in patients with pacemakers. There have been a small number of cases when a patient with a non-compatible pacemaker has required MR imaging. Approximately two million Europeans have implanted pacemakers, but these patients are strongly discouraged from receiving MRI scans. According to estimates, 50-75% of patients world-wide with implanted cardiac devices are expected to need a MR scan during the lifetime of their device [bib_ref] Current clinical issues for MRI scanning of pacemaker and defibrillator patients, Kalin [/bib_ref]. Editorials in the American and European literature concluded that the risk:benefit ratio for patients with pacemakers undergoing MR has shifted towards safety, if guidelines are followed [bib_ref] Magnetic resonance imaging and cardiac pacemaker safety at 1.5 Tesla, Martin [/bib_ref] [bib_ref] Can cardiac pacemakers and magnetic resonance imaging co-exist?, Martin [/bib_ref]. Discussion in the correspondence sections has been generated [bib_ref] Safe, sensible sagacious: resposible scanning of pacemaker patients, Gimbel [/bib_ref]. In summary, the presence of a permanent pacemaker no longer represents a strict contra-indication to MR in carefully selected clinical circumstances provided that specific strategies are followed [bib_ref] MR Imaging and electronically activated devices, Shellock [/bib_ref]. MR compatible pacemakers are now available and have been implanted in some patients. One pacemaker manufacturer has received a Conformité Européenne (CE) Mark for its second-generation MR safe pacing system. However, approval has not yet been forthcoming from the Food and Drug Administration in the USA [20]. ## Programmable shunts The pressure setting of programmable hydrocephalus shunts may be unintentionally changed by the magnetic field leading to over-or under-drainage of CSF. If these patients are to undergo an MR examination, a programmer and a trained clinician should be available to verify the correct setting and to reprogram the device, if required, immediately following the MR procedure. Advice must be given to the patient on how to recognise over-and under-drainage and whom to contact should these conditions develop. ## Neurostimulators A wide variety of neurostimulators are now in use. Concerns about MR safety relate to the RF and gradient fields that may interfere with the operation of these devices or cause thermal injury. It is recommended that patients implanted with neurostimulators should not undergo MR. However, some manufacturers are suggesting that MR examinations of specific devices may be safe if strict guidelines relating to scanning parameters, in particular to RF exposure, are followed. ## Out-of-hours mr imaging There are many indications for urgent MR imaging, but they can be grouped into two main areas: suspected spinal cord or cauda equina compression; and investigation of acute neurological conditions. Hospital trusts have faced litigation when treatment has been delayed due to lack of 24-h MR availability. Patients in intensive care units (ICUs) who require urgent MR will need to be accompanied by anaesthetic staff. Intensive care patients have additional sources of hazard including central lines and intracranial pressure transducers [bib_ref] Potential heating caused by intraparenchymal intracranial pressure transducers in a 3-tesla magnetic..., Newcombe [/bib_ref]. Screening .. ## Ó 2010 the authors checklists have been adapted for use in intensive care. It should be remembered that the ultimate operational responsibility for safety issues remains with an appropriately trained MR Authorised Person (usually the supervising radiographer) and the MR radiologist. ## Training Training requirements for any staff entering the MR unit are detailed by the MHRA. The responsibility for safety training lies with the MR Responsible Person who may be the clinical director, head of department, clinical scientist or MR superintendent radiographer. The unit's MR Safety Advisor should provide technical advice. The wide range of staff from differing disciplines who need access to the MR environment have been designated into categories. Anaesthetists fall into MHRA category B; that is, they may be present with a patient in the MR controlled area during scanning. They should be aware of safety aspects related to the main static magnetic fields, RF fields, gradient magnetic fields and electrical safety of equipment. They must understand the significance of the MR controlled area and the inner MR controlled area. They should be familiar with emergency procedures arising from causes other than equipment failure and should be aware of the need to evacuate the patient from the inner controlled area in order to deal with emergency resuscitation. Training also includes an understanding of the projectile effect and the influence of the magnetic field upon medical implants, prostheses and personal effects. Anaesthetists should understand the consequences of quenching of super-conducting magnets, and be aware of the recommendations on exposure to MR and the need for ear protection. How can these training requirements be met? The potential for e-learning should be considered. The Royal College of Anaesthetists includes the physics of MRI in its basic science syllabus . Trainees who have completed an e-learning module and attended an elective MR list would then be certified as suitable to accompany ICU patients for MR imaging. Regular reviews of training status as well as updates and refresher courses will be required. Hospitals will wish to apply local rules regarding consultant supervision of anaesthetic trainees in MR units. ## Contrast reactions Gadolinium-based contrast agents are used in MR for demonstration of vascular structures or to improve contrast resolution of tissues. In comparison with other radiological contrast agents, Gd-CAs are relatively safe with a high therapeutic ratio and low incidence of anaphylaxis (approximately 1:100 000). The side-effects of Gd-CAs are generally mild and include headache, nausea and vomiting, local burning, skin wheals (2%), itching, sweating, facial swelling and thrombophlebitis [bib_ref] Acute adverse reactions to magnetic resonance contrast mediagadolinium chelates, Li [/bib_ref]. More severe reactions have occurred and radiology staff should be familiar with guidelines related to the management of suspected anaphylaxis [bib_ref] Guidelines: suspected anaphylactic reactions associated with anaesthesia, Harper [/bib_ref]. ## Nephrogenic systemic fibrosis There has been recent attention to reports that patients with renal failure are at risk of developing a rare, potentially life-threatening condition with Gd-CAs called nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy (NSF ⁄ NFD). The glomerular filtration rate (GFR) should be estimated in all patients with kidney disease to identify those at risk of developing NSF ⁄ NSD. If the GFR is estimated at less than 30 ml.min )1 per 1.73 m )2 , the risk of Gd-CAs should be balanced against benefit, and a minimal dose of Gd-CAs only administered if an unenhanced scan proves insufficient [bib_ref] MRI safety update 2008: part 1, MRI contrast agents and nephrogenic systemic..., Shellock [/bib_ref]. The Gd-CA should not be administered again for at least 7 days. Current evidence suggests that contrast agents may be classified as high-risk, e.g. gadopentelic acid, mediumrisk, e.g. gadobenic acid, and low-risk e.g. gadoteridol. The use of high-risk agents is contra-indicated in neonates and during the peri-operative period in patients undergoing liver transplantation. The Gd-Cas are not recommended in pregnancy unless absolutely necessary. # Conclusions While some safety terminology has altered, the basic recommendations for provision of anaesthetic services in MR units have remained the same since first published in 2002. Anaesthetists who are involved with 3-T systems, open scanners or interventional and intraoperative procedures should remain acquainted with the constantly changing recommendations relating to occupational exposure. They should take all practical steps to minimise the risk from exposure. MR examinations of patients with pacemakers are no longer absolutely contraindicated but may be carried out under strictly controlled conditions in exceptional cases. Increased requirements for MR imaging in intensive care and postoperative patients have increased the need for repeated training. The employment of e-learning modules may facilitate such training. There has been an increase in the number of allergic reactions to Gd-CAs and it is recognised that patients with renal failure are at risk of developing NSF. Journal compilation Ó 2010 The Association of Anaesthetists of Great Britain and Ireland	None	https://europepmc.org/articles/pmc2904502?pdf=render	The number of anaesthetists who are involved in magnetic resonance (MR) units is increasing. Magnetic resonance systems are becoming more powerful and interventional procedures are now possible. This paper updates information relating to safety terminology, occupational exposure, reactions to gadolinium-based contrast agents and the risk of nephrogenic systemic fibrosis. Magnetic resonance examinations of patients with pacemakers are still generally contra-indicated but have been carried out in specialist centres under strictly controlled conditions. As availability of MR increases, so the education of anaesthetists, who are occasionally required to provide a service, must be considered. Anaesthesia in MR units was first described in the 1980s. Guidelines on the provision of anaesthetic services in MR units were published by the Association of Anaesthetists of Great Britain and Ireland (AAGBI) in 2002 [1]. Since then, the number of hospitals with MR units, and hence the number of patients requiring anaesthesia for MR, has increased. While the issues relating to setting up anaesthetic services in MR have not changed, there have been a number of developments that warrant this update: Safety terminology and guidelines have changed. MR systems utilise higher magnetic-field strengths and more open designs are available. Interventional and intra-operative MR are now routine in some centres. Mobile MR scanners are increasingly used to reduce waiting lists. Although still generally contra-indicated, some patients with pacemakers have been scanned under strictly controlled conditions in specialist centres. ‘MR safe’ medical implants are now being produced. New equipment is now available for use in MR. Out-of-hours availability of MR investigations has increased. Reports of allergic reactions to MR contrast media have increased. Gadolinium based contrast agents (Gd-CAs) are associated with a varying degree of risk of nephrogenic systemic fibrosis in patients with impaired renal function.
ee8f58f3af9e8e9a48a90e2eb5fb69c8dc5ddf07	pubmed	2021 Focused Update Consensus Guidelines of the Asia Pacific Heart Rhythm Society on Stroke Prevention in Atrial Fibrillation: Executive Summary	2021 Focused Update Consensus Guidelines of the Asia Pacific Heart Rhythm Society on Stroke Prevention in Atrial Fibrillation: Executive Summary Elderly Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883-891 9 Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981-992 10 Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369(22):2093-2104 11 Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383(9921):955-962 12 The prevalence of atrial fibrillation (AF) is increasing in recent decades, and the prevalence in the elderly population has increased more rapidly worldwide and also in Asians. 1-3 Stroke prevention in older AF patients is important as stroke risk increases dramatically with age. 4,5 However, oral anticoagulation (OAC) treatment has been underutilized in the elderly. In pivotal trials of non-vitamin K antagonist oral anticoagulants (NOACs), the proportions of elderly patients (age ! 75 years) included ranged from 31 to 43%. 7-10 Metaanalyses of pivotal NOAC trials showed no interaction between different age groups and efficacy/safety of NOAC compared with warfarin. 11 Generally, the higher event rate in the elderly population resulted in a larger absolute risk reduction from NOAC compared with warfarin, but the presence of interaction by different age groups varied by different clinical outcomes in each NOAC trial (►Supplementary . For very elderly (defined as !90 years), a previous observational study reported that OAC treatment may be considered for stroke prevention, with NOACs being the more favorable choice. In a further analysis of 64,169 AF patients !65 years of age, the clear safety signal in favor of NOACs over warfarin was evident irrespective of age strata [bib_ref] Outcomes of direct oral anticoagulants in patients with mitral stenosis, Kim [/bib_ref] [bib_ref] Protocol, rationale and design of DAbigatran for Stroke PreVention In Atrial Fibrillation..., Zhou [/bib_ref] [bib_ref] Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review, Guttmann [/bib_ref] [bib_ref] Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy, Olivotto [/bib_ref] [bib_ref] Impact of atrial fibrillation on the clinical course of apical hypertrophic cardiomyopathy, Lee [/bib_ref] [bib_ref] Temporal trends of the prevalence and incidence of atrial fibrillation and stroke..., Choi [/bib_ref] [bib_ref] Hypertrophic cardiomyopathy in patients with atrial fibrillation: prevalence and associated stroke risks..., Jung [/bib_ref] [bib_ref] Stroke risk stratification for atrial fibrillation patients with hypertrophic cardiomyopathy, Jung [/bib_ref] [bib_ref] Novel oral anticoagulants for primary stroke prevention in hypertrophic cardiomyopathy patients with..., Lee [/bib_ref] [bib_ref] Effectiveness and safety of nonvitamin K antagonist oral anticoagulants in patients with..., Jung [/bib_ref] [bib_ref] ROCKET AF Steering Committee and Investigators. Intracranial hemorrhage among patients with atrial..., Hankey [/bib_ref] [bib_ref] Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran:..., Hart [/bib_ref] [bib_ref] ENGAGE AF-TIMI 48 Investigators. Outcomes with edoxaban versus warfarin in patients with..., Rost [/bib_ref] [bib_ref] ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with..., Hankey [/bib_ref] [bib_ref] RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation..., Diener [/bib_ref] [bib_ref] Nonvitamin-K-antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and previous..., Ntaios [/bib_ref] [bib_ref] Effectiveness and safety of direct oral anticoagulant for secondary prevention in asians..., Park [/bib_ref] [bib_ref] European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K..., Steffel [/bib_ref] [bib_ref] Use of oral anticoagulants for stroke prevention in patients with atrial fibrillation..., Chao [/bib_ref] [bib_ref] Restarting anticoagulant treatment after intracranial hemorrhage in patients with atrial fibrillation and..., Nielsen [/bib_ref] [bib_ref] Outcomes associated with resuming warfarin treatment after hemorrhagic stroke or traumatic intracranial..., Nielsen [/bib_ref] [bib_ref] Use of antithrombotic therapy and long-term clinical outcome among patients surviving intracerebral..., Ottosen [/bib_ref] [bib_ref] Restarting anticoagulant therapy after intracranial hemorrhage: a systematic review and meta-analysis, Murthy [/bib_ref] , !90 years), being most marked in very older adults. 5 Actually, the introduction of NOACs has changed the land-scape for stroke prevention in elderly (!85 years) Asian AF patients. The initiation rates of OACs after AF, which was newly diagnosed, in the elderly significantly increased from 9.5 to 34.3%, mainly due to the introduction of NOACs (from 0 to 26.2%), and the 1-year risk of ischemic stroke (IS) after AF diagnosis decreased in the era of NOACs. In a recent report from Taiwan which focused on "clinically complex" very elderly (!90 years) AF patients with a history of intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), or chronic kidney disease (CKD), NOACs were still associated with a lower risk of composite adverse events compared with warfarin or non-OACs. 17 Therefore, "old age" itself should not be the sole reason to withhold OACs for stroke prevention. What is the "optimal" dose of NOAC in the elderly AF patients with a high bleeding risk is an important and difficult issue. higher incidence of major bleeding than placebo (HR: 1.87, p ¼ 0.09). However, it should be emphasized that the results of ELDERCARE-AF just proved the concept that even the off-labeling low-dose edoxaban was better than nonuse of OACs (rather than being against the use of standard-dose NOACs). NOACs at the on-labeling dose should still be considered first for stroke prevention in elderly AF patients until high-quality data of direct comparisons of different dosing NOACs are available. ## Low body weight Although there is no absolute cut-off for defining low body weight (LBW), Asians tend to be smaller and leaner than non-Asians (e.g., 20 kg less on average in ENGAGE AF-TIMI 48) 20 ; thus, patients with LBW are more common among Asians than among non-Asians. The effects of NOACs are closely related to plasma concentrations, which are affected by body distribution volume. 21 Extremely LBW may influence the efficacy and safety of NOACs. Although NOACs have shown better net clinical benefits than warfarin, being underweight has been associated with an increased risk of major bleeding in patients taking NOACs. 22 Body weight 60 kg was a dose reduction criterion for apixaban and edoxaban. 9,10 For apixaban, there was no interaction between different body weight groups ( 60, 61-120, and >120 kg) and the efficacy of apixaban compared with warfarin. 23 In terms of safety outcome such as major bleeding, a large relative risk reduction was observed in patients with 60 kg than those with 61 to 120 and >120 kg. 23 For edoxaban versus warfarin, there was no significant interaction between different body mass index (BMI) category groups and the outcomes; however, the underweight patients defined as BMI <18.5 kg/m 2 occupied a small proportion of the total population (0.8%, n ¼ 177). 24 A recent subanalysis of ENGAGE AF-TIMI 48 trial which focused on patients at extremes of body weight has demonstrated that the pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across extremes of body weight, resulting in similar efficacy compared with warfarin, while major or clinically relevant nonmajor bleeding and net outcomes were most favorable with edoxaban as compared with warfarin in LBW patients. 25 For rivaroxaban, limited data are available for patients with <60 or <50 kg. In recent observational data including a large population of AF patients with 60 kg taking OACs (n ¼ 21,589), NOAC was associated with lower risks of IS and major bleeding than warfarin and these results were largely consistent in patients with <50 kg. 26 Also, on-label NOAC dosing should still be applied in patients with LBW to achieve the best net clinical benefit. 26 ## Chronic kidney disease CKD is an independent predictor of risk of thromboembolic and bleeding events. 27 All NOACs have some degree of renal elimination, with the greatest renal dependency for excretion with dabigatran (80%) and the least with renal dependency for apixaban (27%). However, there are no head-to-head NOAC comparison trials and therefore insufficient evidence to recommend one agent over another. The dose adapted on the basis of CCr according to approved indications (►Supplementary [fig_ref] References 1: Go AS, Hylek EM, Phillips KA, et al [/fig_ref]. There have been several meta-analyses addressing the efficacy and safety of NOACs compared with warfarin in patients with mild to moderate CKD. [bib_ref] Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized..., Sardar [/bib_ref] [bib_ref] Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on..., Nielsen [/bib_ref] [bib_ref] Non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients with chronic kidney..., Andò [/bib_ref] The data are consistent across studies that all NOACs are associated with lower risks of thromboembolic events compared with warfarin in patients with mild to moderate CKD (CCr: 30-79 mL/min). [bib_ref] Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized..., Sardar [/bib_ref] [bib_ref] Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on..., Nielsen [/bib_ref] For major bleeding, NOAC showed significantly lower risk of major bleeding compared with warfarin in patients with mild CKD (defined as CCr 50-79 mL/min); however, there was no significant difference between NOAC and warfarin in patients with moderate CKD (defined as CCr 30-49 mL/min). [bib_ref] Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized..., Sardar [/bib_ref] [bib_ref] Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on..., Nielsen [/bib_ref] Indirect comparisons suggested that apixaban and edoxaban high-dose regimens might be more likely associated with a better net clinical profile in AF patients with moderate CKD (defined as CCr from 25-30 to 50 mL/min). 30 ## End-stage renal disease undergoing hemodialysis The CHA 2 DS 2 -VASc score could also be used to predict IS risk in AF patients with end-stage renal disease (ESRD) undergoing dialysis. [bib_ref] Incidence and prediction of ischemic stroke among atrial fibrillation patients with end-stage..., Chao [/bib_ref] However, the benefit of OAC treatment in patients with AF and ESRD has been controversial. In a Korean nationwide cohort study, warfarin use was significantly associated with an increased risk of hemorrhagic stroke (HR: 1.44, 95% confidence interval [CI]: 1.09-1.91) without any benefit for preventing thromboembolic events. [bib_ref] Warfarin use in patients with atrial fibrillation undergoing hemodialysis: a nationwide populationbased..., Yoon [/bib_ref] Warfarin-based OAC treatment did not show definite benefit for patients with ESRD and AF compared with no antithrombotic therapy. Recently, there has been a few studies suggesting that apixaban or rivaroxaban can be a safer alternative to warfarin in those population. [bib_ref] Outcomes associated with apixaban use in patients with end-stage kidney disease and..., Siontis [/bib_ref] [bib_ref] Safety and efficacy of apixaban versus warfarin in patients with end-stage renal..., Chokesuwattanaskul [/bib_ref] [bib_ref] Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and severe kidney..., Coleman [/bib_ref] [bib_ref] Safety and efficacy of vitamin K antagonists versus rivaroxaban in hemodialysis patients..., De Vriese [/bib_ref] There was no difference in the risks of stroke/SE between apixaban (n ¼ 2,351) and warfarin (n ¼ 23,172) (HR: 0.88, 95% CI: 0.69-1.12), but apixaban was associated with a significantly lower risk of major bleeding (HR: 0.72, 95% CI: 0.59-0.87). [bib_ref] Outcomes associated with apixaban use in patients with end-stage kidney disease and..., Siontis [/bib_ref] Among patients with nonvalvular AF and stage 4 or 5 CKD or undergoing hemodialysis, rivaroxaban (n ¼ 1,896) did not significantly reduce stroke or SE (HR: 0.55, 95% CI: 0.27-1.10) or IS (HR: 0.67, 95% CI: 0.30-1.50) alone, but it was associated with a significant reduction of major bleeding by 32% compared with warfarin (n ¼ 4,848). [bib_ref] Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and severe kidney..., Coleman [/bib_ref] Despite some favorable data of NOACs, a recent meta-analysis which included 16 observational studies (2 of the 16 investigated NOACs) showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. [bib_ref] Oral anticoagulation for patients with atrial fibrillation on long-term hemodialysis, Kuno [/bib_ref] Also, a recent cohort study and meta-analysis from Taiwan demonstrated that the use of OAC was not associated with a lower risk of IS/SE in ESRD AF patients when compared with those without OAC use. Besides, NOACs did not provide benefit over warfarin regarding effectiveness and safety in AF patients undergoing dialysis. 38 ## Abnormal liver function Liver disease is often accompanied by a combination of complex abnormalities of the coagulation pathways, [bib_ref] The coagulopathy of chronic liver disease, Tripodi [/bib_ref] [bib_ref] Coagulation in Liver Disease Group. Coagulation disorders and hemostasis in liver disease:..., Caldwell [/bib_ref] thus, patients with advanced liver disease have higher risks of thromboembolism and bleeding. [bib_ref] The complex role of anticoagulation in cirrhosis: an updated review of where..., Khoury [/bib_ref] [bib_ref] Oral anticoagulation in patients with liver disease, Qamar [/bib_ref] In addition, significant impairment of liver function can affect hepatic clearance and drug metabolism. [bib_ref] The importance of patientspecific factors for hepatic drug response and toxicity, Lauschke [/bib_ref] However, even in patients with liver cirrhosis, warfarin-based OAC was associated with a lower risk of IS and a positive net benefit compared with no antithrombotic therapy. [bib_ref] Liver cirrhosis in patients with atrial fibrillation: would oral anticoagulation have a..., Kuo [/bib_ref] The use of warfarin in patients with advanced liver disease is challenging due to intrinsically prolonged prothrombin time. [bib_ref] Stratifying the risks of oral anticoagulation in patients with liver disease, Efird [/bib_ref] Although NOAC could be considered as an alternative to warfarin, patients with liver function abnormalities (i.e., active or significant liver disease including vital hepatitis and cirrhosis, alanine transaminase/aspartate transaminase/alkaline phosphatase !2-3 times the upper limit of normal or bilirubin !1.5 times the ULN) were largely excluded from the pivotal NOAC clinical trials. 7-9 Although NOACs were not associated with an increased risk of serious liver injury irrespective of baseline liver status, 46 data about optimal OAC treatment in patients with liver function impairment were limited. In a small retrospective cohort study including patients with impaired liver function (n ¼ 633), NOAC showed similar risks of stroke or SE, major bleeding, and GIB compared with warfarin. [bib_ref] Efficacy and safety of non-vitamin K antagonist oral anticoagulants in atrial fibrillation..., Wang [/bib_ref] In a posthoc analysis of ENGAGE AF-TIMI 48 trial, bleeding, but not thromboembolic events, was increased in patients with liver disease, and a history of liver disease did not alter the relative efficacy and safety of higher dose edoxaban compared with warfarin. [bib_ref] Edoxaban versus warfarin in patients with atrial fibrillation and history of liver..., Qamar [/bib_ref] Also, in a large Asian population with AF and liver disease, NOACs showed better effectiveness and safety than warfarin, which was consistent in those with significant active liver disease, defined as in the pivotal clinical trials. [bib_ref] Direct oral anticoagulants in patients with atrial fibrillation and liver disease, Lee [/bib_ref] All four NOACs may be used in patients with mild and transient liver function abnormalities including Child-Turcotte-Pugh A cirrhosis, and dabigatran, apixaban, and edoxaban may be used with caution in patients with Child B cirrhosis. [bib_ref] Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when..., Intagliata [/bib_ref] [bib_ref] The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in..., Hum [/bib_ref] Rivaroxaban use should be avoided in patients with Child B cirrhosis and all four NOACs are contraindicated in patients with Child C cirrhosis and any liver disease combined with significant coagulopathy and an increased risk of clinically relevant bleeding. [bib_ref] Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single..., Kubitza [/bib_ref] Valvular Heart Disease AF often coexists with various types of valvular heart diseases (VHDs). Valvular AF is defined as patients with AF and VHD including moderate to severe rheumatic mitral stenosis or having mechanical prosthetic valve (Evaluated Heart valves, Rheumatic or Artificial, EHRA type 1 VHDs). [bib_ref] Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: a joint..., Lip [/bib_ref] Patients with valvular AF have significantly higher risks of thromboembolic events than those with nonvalvular AF. [bib_ref] What is 'valvular' atrial fibrillation? A reappraisal, Caterina [/bib_ref] Other VHDs are defined as EHRA type 2 VHDs 54 and these patients also showed higher thromboembolic and bleeding risk. [bib_ref] Thromboembolism and bleeding complications in anticoagulated patients with atrial fibrillation and native..., Melgaard [/bib_ref] The efficacy of warfarin in stroke prevention in patients with valvular AF has long been established. Although the [fig_ref] References 1: Go AS, Hylek EM, Phillips KA, et al [/fig_ref] Recommendations about the dosing of NOACs according to renal function. bid, twice daily; CCr, creatinine clearance; ESRD, end-stage renal disease; qd, once daily; NOACs, non-vitamin K antagonist oral anticoagulants; RRT, renal replacement therapy. pivotal clinical trials of NOACs did not include patients with valvular AF (EHRA type 1 VHDs), patients with EHRA type 2 VHDs were allowed to participate. [bib_ref] Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular..., Ezekowitz [/bib_ref] [bib_ref] Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular..., Avezum [/bib_ref] [bib_ref] ROCKET AF Steering Committee & Investigators. Clinical characteristics and outcomes with rivaroxaban..., Breithardt [/bib_ref] [bib_ref] Valvular heart disease patients on edoxaban or warfarin in the ENGAGE AF-TIMI..., Caterina [/bib_ref] The efficacy and safety of NOACs do not appear to be different with respect to the valvular status of patients, including those with bioprosthetic valves, 61 and the pooled high-dose NOAC group shows a significantly lower risk of thromboembolic events and a similar risk of major bleeding compared with the warfarin group 62 and consistent results were observed in a large Asian nationwide cohort with VHDs. [bib_ref] Non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and valvular..., Moon [/bib_ref] There has been only one published randomized controlled study comparing warfarin and NOAC in patients with mechanical prosthetic valves. [bib_ref] RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves, Eikelboom [/bib_ref] This study was prematurely terminated because of excessive thromboembolic and bleeding events with dabigatran. [bib_ref] RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves, Eikelboom [/bib_ref] Although there was a signal for the positive net benefit of NOACs compared with warfarin in patients with mitral stenosis, 65 further randomized clinical trials are needed to consider NOAC as an alternative to warfarin in patients with rheumatic mitral stenosis. [bib_ref] Protocol, rationale and design of DAbigatran for Stroke PreVention In Atrial Fibrillation..., Zhou [/bib_ref] Hypertrophic Cardiomyopathy AF is the most common cardiac arrhythmia in patients with hypertrophic cardiomyopathy. [bib_ref] Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review, Guttmann [/bib_ref] Observational data highlight a high stroke risk in patients with hypertrophic cardiomyopathy and AF, confirming the need for OAC. [bib_ref] Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy, Olivotto [/bib_ref] [bib_ref] Impact of atrial fibrillation on the clinical course of apical hypertrophic cardiomyopathy, Lee [/bib_ref] In a large nationwide observational cohort including Asian population, the annual risk of AF-associated stroke in hypertrophic cardiomyopathy was over 1% even in younger patients and those with CHA 2 DS 2 -VASc score of 0 or 1 point. [bib_ref] Temporal trends of the prevalence and incidence of atrial fibrillation and stroke..., Choi [/bib_ref] Consistent with these results, the risk of stroke in patients with hypertrophic cardiomyopathy and AF without any CHA 2 DS 2 -VASc stroke risk factors was similar to that of those patients without hypertrophic cardiomyopathy with CHA 2 DS 2 -VASc score of 3. 71,72 Despite the higher stroke risk, the use of OACs among patients with hypertrophic cardiomyopathy and AF is suboptimal in the daily practice. [bib_ref] Hypertrophic cardiomyopathy in patients with atrial fibrillation: prevalence and associated stroke risks..., Jung [/bib_ref] Although most experience was from warfarin, recent observational studies demonstrated that NOACs were associated with lower risks of thromboembolic events and major bleeding compared with warfarin. [bib_ref] Novel oral anticoagulants for primary stroke prevention in hypertrophic cardiomyopathy patients with..., Lee [/bib_ref] [bib_ref] Effectiveness and safety of nonvitamin K antagonist oral anticoagulants in patients with..., Jung [/bib_ref] Prior Stroke and ICH ## Prior stroke Prior stroke or transient ischemic attack (TIA) is a powerful predictor of subsequent stroke, with an increased risk by 2.2 to 2.5.When prescribing OACs to patients with prior stroke/TIA, physicians should consider that these patients are also at higher risk for ICH during OAC than those without prior stroke/TIA. [bib_ref] ROCKET AF Steering Committee and Investigators. Intracranial hemorrhage among patients with atrial..., Hankey [/bib_ref] [bib_ref] Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran:..., Hart [/bib_ref] [bib_ref] ENGAGE AF-TIMI 48 Investigators. Outcomes with edoxaban versus warfarin in patients with..., Rost [/bib_ref] [bib_ref] ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with..., Hankey [/bib_ref] [bib_ref] RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation..., Diener [/bib_ref] Previous pivotal randomized clinical trials of NOACs that included a varied number of patients with AF and a history of stroke/TIA reported following subgroup analyses for these population. [bib_ref] ENGAGE AF-TIMI 48 Investigators. Outcomes with edoxaban versus warfarin in patients with..., Rost [/bib_ref] [bib_ref] ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with..., Hankey [/bib_ref] [bib_ref] RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation..., Diener [/bib_ref] The efficacy and safety of NOACs between patients with and without prior stroke/TIA were similar, indicating that NOACs can be used safely even in patients with prior stroke/TIA. [bib_ref] ENGAGE AF-TIMI 48 Investigators. Outcomes with edoxaban versus warfarin in patients with..., Rost [/bib_ref] [bib_ref] ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with..., Hankey [/bib_ref] [bib_ref] RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation..., Diener [/bib_ref] An updated meta-analysis includ-ing 20,500 AF patients with previous stroke/TIA showed that NOACs were associated with a significant reduction of stroke, IS or SE, hemorrhagic stroke, and ICH compared with warfarin. [bib_ref] Nonvitamin-K-antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and previous..., Ntaios [/bib_ref] In a recent report from South Korea, NOACs were associated with lower risks of recurrent stroke, major bleeding, composite clinical outcomes, and mortality in Asian AF patients with a history of stroke. [bib_ref] Effectiveness and safety of direct oral anticoagulant for secondary prevention in asians..., Park [/bib_ref] The 2021 EHRA (European Heart Rhythm Association) practical guide on the use of NOACs suggests initiation of OACs between 1 and 28 days after an IS, depending on the presence of hemorrhagic transformation at brain imaging on admission and stroke severity. [bib_ref] European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K..., Steffel [/bib_ref] For patients without hemorrhagic transformation, OACs could be considered between 1 and 12-14 days depending on the severity of stroke. For patients with hemorrhagic transformation, OACs would be considered once clinical status improved and significant reduction of hemorrhagic transformation was documented at follow-up brain computed tomography or magnetic resonance imaging performed 1 day before restarting/initiations of NOACs. A multidisciplinary team approach including stroke neurologists and cardiologists should help in decision-making, taking patients' values and preferences into consideration. The suggestions about the use of OACs after acute IS are summarized in ►Supplementary . [bib_ref] European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K..., Steffel [/bib_ref] Prior ICH AF patients with a history of prior ICH have a higher risk of both IS and recurrent ICH. [bib_ref] Use of oral anticoagulants for stroke prevention in patients with atrial fibrillation..., Chao [/bib_ref] The positive net clinical benefits of OAC therapy in patients with prior ICH were consistently observed in previous observational studies. [bib_ref] Restarting anticoagulant treatment after intracranial hemorrhage in patients with atrial fibrillation and..., Nielsen [/bib_ref] [bib_ref] Outcomes associated with resuming warfarin treatment after hemorrhagic stroke or traumatic intracranial..., Nielsen [/bib_ref] [bib_ref] Use of antithrombotic therapy and long-term clinical outcome among patients surviving intracerebral..., Ottosen [/bib_ref] [bib_ref] Restarting anticoagulant therapy after intracranial hemorrhage: a systematic review and meta-analysis, Murthy [/bib_ref] In a previous report from the Taiwan nationwide claims database, use of warfarin was found to be possibly beneficial for AF patients with prior ICH having a CHA 2 DS 2 -VASc score !6 compared with no antithrombotic therapy. [bib_ref] Use of oral anticoagulants for stroke prevention in patients with atrial fibrillation..., Chao [/bib_ref] Since all pivotal clinical trials of NOACs excluded patients with a history of spontaneous ICH, 7-10 data about comparisons between warfarin and NOACs among these patients were only available from retrospective observation studies. It seems that NOACs were associated with a lower risk of all-cause mortality (adjusted HR [aHR]: 0.517), ICH (aHR: 0.556), and major bleeding (aHR: 0.645) compared with warfarin, whereas the rate of IS was similar. [bib_ref] Association of ischemic stroke, major bleeding, and other adverse events with warfarin..., Tsai [/bib_ref] Similar findings have been reported from South Korea. [bib_ref] Oral anticoagulation in Asian patients with atrial fibrillation and a history of..., Lee [/bib_ref] The small randomized trial the Start or STop Anticoagulants Randomized Trial (SoSTART) was inconclusive, although rates of recurrent ICH were lower than expected.Therefore, among AF patients with prior ICH, OACs should generally still be considered with NOACs being as the preferred choice for stroke prevention. For AF patients who experienced acute ICH, OAC treatment can be resumed/initiated after 4 to 8 weeks, especially when the cause of bleeding or the relevant risk factor has been treated.A multidisciplinary team approach including stroke neurologists and cardiologists should help in decision-making, taking patients' values and preferences into consideration. However, further studies are needed to find optimal timing point of OAC resumption and subgroups of patients who are more beneficial for early OAC resumption, especially in the NOAC era. ## Adherence issue It is critical to educate patients about the importance of strict adherence. Strict adherence to NOAC intakes is more crucial as its anticoagulation effect diminishes within 12 to 24 hours after the last intake. [bib_ref] Adherence to oral anticoagulant therapy in patients with atrial fibrillation. Focus on..., Raparelli [/bib_ref] Although actual adherence of NOAC intake varied depending on the data sources and definition, 95-100 adherent NOAC users (proportion of days covered ! 80%) accounted for 64% of all NOAC users in a recent Asian real-world observational cohort study. [bib_ref] The optimal drug adherence to maximize the efficacy and safety of non-vitamin..., Kim [/bib_ref] Adherent use of NOAC showed better outcomes without increasing bleeding risk and maintaining !90% of adherence achieved optimal effectiveness of NOAC. [bib_ref] The optimal drug adherence to maximize the efficacy and safety of non-vitamin..., Kim [/bib_ref] Cost-effective and feasible tools should be developed for high-risk patients with low adherence. 102 [fig] References 1: Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285 (18):2370-2375 2 Lee SR, Choi EK, Han KD, Cha MJ, Oh S. Trends in the incidence and prevalence of atrial fibrillation and estimated thromboembolic risk using the CHA 2 DS 2 -VASc score in the entire Korean population. Int J Cardiol 2017;236:226-231 3 Chao TF, Liu CJ, Tuan TC, et al. Lifetime risks, projected numbers, and adverse outcomes in Asian patients with atrial fibrillation: a report from the Taiwan nationwide AF cohort study. Chest 2018; 153(02):453-466 4 Chao TF, Wang KL, Liu CJ, et al. Age threshold for increased stroke risk among patients with atrial fibrillation: a nationwide cohort study from Taiwan. J Am Coll Cardiol 2015;66(12):1339-1347 5 ChaoTF, Chiang CE, Liao JN, Chen TJ, Lip GYH, Chen SA. Comparing the effectiveness and safety of nonvitamin K antagonist oral anticoagulants and warfarin in elderly Asian patients with atrial fibrillation: a nationwide cohort study. Chest 2020;157(05): 1266-1277 6 Cheng WH, Chiang CE, Lin YJ, et al. Non-vitamin K antagonist oral anticoagulants in elderly (!85 years) patients with newly diagnosed atrial fibrillation: changing clinical practice and outcomes for stroke prevention in a nationwide cohort study. Mayo Clin Proc 2021;96(01):52-65 7 Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12): 1139-1151 Supplementary Fig. S2 Use of OACs after acute ischemic stroke or TIA. The figure was redrawn and modified from the 2021 European Heart Rhythm Association Practical Guide on the use of NOACs in patients with AF by Steffel et al. 84 CT, computed tomography; MRI, magnetic resonance imaging; NOAC, non-vitamin K antagonist oral anticoagulant; TIA, transient ischemic attack. 8 Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. [/fig]	None	http://www.thieme-connect.de/products/ejournals/pdf/10.1055/s-0041-1739411.pdf	Abstract The consensus of the Asia Pacific Heart Rhythm Society (APHRS) on stroke prevention in atrial fibrillation (AF) has been published in 2017 which provided useful clinical guidance for cardiologists, neurologists, geriatricians, and general practitioners in the Asia-Pacific region. In these years, many important new data regarding stroke prevention in AF were reported. The practice guidelines subcommittee members comprehensively reviewed updated information on stroke prevention in AF, and summarized them in this 2021 focused update of the 2017 consensus guidelines of the APHRS on stroke prevention in AF. We highlighted and focused on several issues, including the importance of the AF Better Care pathway, the advantages of non-vitamin K antagonist oral anticoagulants (NOACs) for Asians, the considerations of use of NOACs for Asian AF patients with single one stroke risk factor beyond gender, the role of lifestyle factors on stroke risk, the use of oral anticoagulants during the “coronavirus disease 2019” pandemic, etc. We fully realize that there are gaps, unaddressed questions, and many areas of uncertainty and debate in the current knowledge of AF, and the physician's decision remains the most important factor in the management of AF.
9f23fdeec42a8fc56e376d9bb7e756e3500ca556	pubmed	International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people	International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people # Methods The consensus process was initiated by the Network for Early Onset Cystic Kidney Disease (NEOCYST), which is a consortium of clinical, genetic and translational researchers devoted to the study of early-onset cystic kidney diseases. In addition to paediatric nephrologists from the consortium, external experts in paediatric ADPKD, adult ADPKD, cystic kidney disease genetics, paediatric radiology and patient representatives were invited to participate Initial recommendations were developed during the conference by discussion in thematic workgroups and plenary sessions. Evidence and recommendations were graded according to the method used in the current American Academy of Pediatrics (AAP) guidelines . The grading of recommendations into strong, moderate and weak recommendations takes into account not only the quality of the evidence but also the balance of potential benefits and harms assessed by the consensus group. The preliminary results of the consensus meeting were presented on 2 December 2017 at an international symposium on 'Management of Polycystic Kidney Diseases from Childhood to Adulthood' in Leuven, Belgium, where 104 participants voted live and anonymously on the major drafted recommendations. A first written draft was compiled by C.G. and reviewed by all members of the consensus group. Consequently, two rounds of anonymous voting were performed using the Delphi method until each recommendation reached at least 70% support. The results of the symposium votes and the Delphi votes are presented in the Supplementary information. The final draft of the Consensus Statement was endorsed by the council of the International Pediatric Nephrology Association (IPNA) and the European Society of Paediatric Nephrology (ESPN) after thorough review by members of the ESPN Workgroup for inherited kidney diseases. The manuscript was also reviewed by ADPKD experts from the European Rare Kidney Disease Reference Network (ERKNet), whose helpful comments were incorporated. Suggestions for further research are listed in the Supplementary information. ## Screening in at-risk minors The question of whether to screen at-risk children of parents affected by ADPKD is a regularly encountered but often contentious clinical issue. Both genetic testing and ultrasonography screening should be considered diagnostic and require prior counselling (Box 1). ## Counselling Uncertainty about a child's disease status causes a high psychological burden for many families. Parents of atrisk children should be informed about the possibilities, limits and consequences of genetic and clinical testing of their children by appropriately skilled personnel. They should understand that screening examinations do not always yield definitive results and importantly that a normal kidney ultrasonography scan has a low negative predictive value in children. Offering diagnostic screening does not imply that this screening is advised but provides parents with the opportunity to make an informed choice. As time for non-directional genetic counselling may be limited in general practice and adult nephrological care, referral to a geneticist or specialized ADPKD clinic may be required. In the case of a child being presented to a paediatric nephrology clinic for testing, adequate parental understanding of the ethical issues should be confirmed before screening. Reliable external information, such as patient support groups, can also help in decision-making. An important argument against diagnostic testing for ADPKD in childhood is respecting the autonomy of the children or young adults to decide whether to undergo testing for a genetic disease for which a diagnosis might not have therapeutic consequences until adulthood. Treatments to slow disease progression in children with ADPKD are limited, and no clear evidence exists to suggest that presymptomatic detection improves outcomes. In addition, establishing a clinical or genetic diagnosis may have a substantial impact on the future ability of the child to secure insurance policies or to gain access to certain professions. Considerations about insurance vary substantially by place of residence; in some countries, the results of genetic screening tests can legally be kept confidential, whereas in others a positive family history alone will affect insurability. On the other hand, both the American and the European Society of Human Genetics consider presymptomatic testing of minors for conditions with adult-onset acceptable if preventive actions can be initiated before adulthood. Cohort studies in children with ADPKD show an elevated incidence of hypertension, proteinuria and left ventricular hypertrophy, which affect prognosis and are amenable to treatment. Although these data are from tertiary referral centre populations and thus may be biased towards more severe cases, they demonstrate that a subgroup of children exists in whom preventive treatment may be beneficial. Another potential advantage of early diagnosis is that the teenage years can provide a valuable opportunity to integrate lifestyle interventions such as a healthy, low-salt diet and adequate fluid intake into the development of eating habits (discussed further below). The advent of treatment to slow disease progression and of pre-implantation genetic diagnosis have persuaded some clinicians to advocate screening for young adults. For children, the situation is less clear as pharmacological studies in paediatric patients are ongoing and safe treatment options for children with acceptable adverse effects and proven benefits have not yet been established. ## Immediate or delayed screening In our view, parents and young people may reasonably opt for either immediate diagnostic testing to confirm disease status or regular clinical screening to identify disease manifestations with the option of later diagnostic testing. Regular clinical screening mainly comprises measurement of blood pressure and proteinuria, which should be performed at the same intervals as those recommended for children with proven symptomatic or asymptomatic disease (see below). The feasibility of regular blood pressure monitoring in the community may vary in different settings and should be taken into account. We recommend that parents receive non-directional counselling about the potential benefits and uncertainties of current diagnostic screening tests. Health-care professionals should inform parents with the aim of shared decision-making and encourage them to keep the best interests of the child in mind. Teenagers and competent younger children should be involved in the decision-making process as much as possible, and ideally a family approach will facilitate discussion to balance the views of the parents and the young person. We also encourage talking to children and adolescents about the possibility of disease transmission early on in an ageappropriate way as this positively influences coping and family interactions. If discussion with the child is deferred until the formal age of majority, families may benefit from the help of a genetic counselling service or a similarly trained professional. ## Radiological diagnosis ## Renal ultrasonography The current gold standard for radiological diagnosis of ADPKD is renal ultrasonography (Box 2). Ultrasonography is an inexpensive and non-invasive method of examination that is particularly suitable for children because of their smaller body size and the fact that the procedure does not require sedation or ionizing radiation. Diagnostic ultrasonography criteria for ADPKD have been established only for adults; however, in children, there is usually no clinical need to make a genetic diagnosis regardless of the ultrasonography findings or to perform more sensitive diagnosis using MRI (which may require sedation) if the renal ultrasonography scan is normal as cyst burden correlates with the risk of the main complications such as hypertension. In line with clinical practice guidelines for adults, we recommend reserving genetic testing to selected situations (see below). We have provided detailed guidance on the prenatal and postnatal imaging of single and multiple kidney cysts and their differential diagnosis in separate statements. Diagnostic specificity and sensitivity. In a PKD1 gene linkage analysis study, the diagnostic specificity of one or more cysts on ultrasonography in at-risk children was 89% in those younger than 5 years of age and 100% in those older than 5 years of age. Failure to confirm cysts on follow-up has been reported rarely with single but not with multiple cystsand may be due, for example, to a mistaken dilated calyx, mistaken prominent medullary pyramid or technical difficulties in obese children. For young adults, established imaging diagnostic criteria require at least three renal cysts on ultrasonographyor ten on MRI. However, the studies on which these criteria are based did not include patients younger than 15 years of age. Numerous studies have shown that, owing to the gradual appearance of cysts, children with ADPKD usually have a much lower number of cysts than adults, and young children may not yet have detectable cysts on ultrasonography, especially in families with a mild phenotype. Diagnostic sensitivity is therefore better in older than in younger children and with the use of high-resolution versus lower-resolution ultrasonography. Parents should be counselled that the negative predictive value of a normal ultrasonography scan in childhood is limited and that later appearance of cysts may be due to a milder underlying genetic alteration (for example, PKD2 or GANAB (glucosidase-α neutral ultrasonography is the current radiological method of choice to screen for autosomal dominant polycystic kidney disease (ADPKD) in children (evidence level B; recommendation level moderate). ## Recommendation 2.2 In a child under 15 years with a positive family history of ADPKD, sonographic detection of one or more kidney cysts is highly suggestive of ADPKD (evidence level B, recommendation level moderate). In a fetus or neonate with a positive family history of ADPKD, hyperechogenic and/or enlarged kidneys (>2 s.d.) on ultrasonography are suggestive of ADPKD (evidence level C; recommendation level moderate). ## Recommendation 2.3 If kidney ultrasonography is normal in an at-risk child, this finding does not exclude ADPKD. However, if making a diagnosis based on ultrasonography is requested, it is not necessary to rescreen at intervals shorter than 3 years (evidence level C; recommendation level moderate). ## Recommendation 2.4 multiple cysts with negative family history require clinical work-up for cystic kidney diseases (evidence level B, recommendation level moderate). ## Recommendation 2.5 Detection of a solitary cyst in childhood requires followup imaging (evidence level C; recommendation level moderate). ## Recommendation 2.6 There are no established mRI-based diagnostic criteria for ADPKD in children younger than 15 years (evidence level B-C; recommendation level moderate). ## Box 1 \| screening in at-risk minors recommendation 1.1 All parents of at-risk minors should be counselled about inheritance of autosomal dominant polycystic kidney disease (ADPKD) and the potential benefits and harms of diagnostic screening (evidence level X; recommendation level strong). ## Recommendation 1.2 Parents of at-risk minors should be offered access to diagnostic screening after counselling (evidence level X; recommendation level moderate). ## Recommendation 1.3 For asymptomatic minors at risk of ADPKD, repeated screening for treatable, but usually asymptomatic disease manifestations (that is, hypertension and proteinuria) without diagnostic testing or immediate diagnostic screening (by ultrasonography or genetic testing) should be considered equally valid approaches to clinical care. The decision whether to perform diagnostic screening should be shared between parents (or legal guardians) and health-care professionals. minors should be involved where possible (evidence level X; recommendation level moderate). ## Recommendation 1.4 If the decision is taken not to perform diagnostic screening in childhood, parents should be made aware of their responsibility to inform their children of disease risk when they reach legal age of majority (evidence level X, recommendation level moderate). AB form) mutations) or variability of the individual clinical course. As cysts develop slowly and children with fewer cysts have later onset of hypertension and proteinuria, children with a normal ultrasonography scan should not be subjected to frequent repeat scans. Multiple cysts. The incidence of simple cysts in children is very low. Multiple kidney cysts in childhood are therefore highly suggestive of ADPKD or another cystic nephropathy (such as cystic dysplasia or multicysticdysplastic kidney) and should be investigated. Clinical work-up will include inquiry about (related) symptoms, detailed history and physical examination and may require further investigations of other organ systems. Parental examination may reveal previously undetected ADPKD. ## Solitary cysts. In children with a positive family history, a solitary cyst is a very likely sign of ADPKD, but in rare cases the cyst may not be confirmed on follow-up. In children with a negative family history, ultrasonography of the parents should be performed and, if the results are normal, further work-up or follow-up of the child is needed to exclude the appearance of multiple cysts or the development of a complex cyst. ## Mri In adults and probably also teenage children, MRI is more sensitive than ultrasonography for detection of kidney cysts in ADPKD. In neonates and infants, high-resolution ultrasonography can detect even small cysts, but no studies have defined a gold standard for imaging kidney cysts in this age group. As MRI usually requires sedation in children younger than 6 years and is more expensive than ultrasonography imaging, it is not the diagnostic method of choice for paediatric ADPKD. ## Molecular diagnosis In adults, genetic testing for ADPKD is usually not done because of the clearly established imaging diagnostic criteria and the technical challenges of sequencing PKD1. However, knowledge about genotype-phenotype correlations is increasing, as is the need for more accurate estimation of prognosis in view of novel therapies. Both very-early-onset ADPKD and rapidly progressive disease may be due to unusual genetic constellations, such as biallelic mutations (homozygous, compound heterozygous or digenic) with at least one weak PKD1 or PKD2 hypomorphic allele 5,50-52 . Combinations of an ADPKD allele with an allele of another cystic nephropathy such as TSC2 (for example, as a contiguous gene deletion syndrome (CGS)) may also radically alter the renal disease phenotype. HNF1B mutations can mimic ADPKD with important consequences for prognosis, the likelihood of comorbidities (for example, congenital hepatic fibrosis in PKHD1 or maturity onset diabetes of the young type 5 (MODY5) in HNF1B) and the risk of disease in siblings. Where available, simultaneous analysis of a panel of polycystic kidney disease genes is recommended for children with very-early-onset disease independent of their family history or rapidly progressive cystic kidney disease and negative family history (Box 3). An unusually severe clinical course with a positive family history may also be a sign of an unusual genetic constellation, but the likelihood is much lower than in the aforementioned cases. Patients with incidental finding of a single cyst and no extrarenal features should primarily receive clinical work-up and be followed up by imaging. Genetic testing is unlikely to reveal a monogenic cause or change management. We currently recommend next-generation sequencing panel examination rather than testing single ADPKD genes because of the large phenotypic overlap between different cystic kidney diseases and large genetic heterogeneity. A cystic kidney disease panel should include adequate coverage of PKD1, PKD2, PKHD1, Dazinteracting zinc-finger protein 1-like (DZIP1L), HNF1B and genes for other ciliopathies such as nephronophthisis (NPHP) and Bardet-Biedl syndrome (BBS). ## Hypertension Hypertension is one of the most common complications of ADPKD in childhood. A systematic review by Marlais et al. that included >900 children with ADPKD from 14 studies reported that the prevalence of hypertension was 20% (95% CI 15-27%); this prevalence was shown to increase with age in a meta-regression analysis. This finding might be influenced by tertiary centre referral bias because the clinical experience with adult patients suggests that hypertension frequently becomes apparent later in life. The average age of onset of hypertension in adults with ADPKD is 30-34 yearsand precedes loss of renal function. A study from large centres that included children and adults confirmed a risk of hypertension of approximately 20% for those younger than 19 years volume 15 \| NovemBeR 2019 \| 717 NATuRe RevIeWS \| NePHRoLogy C o n S e n S u S S tat e m e n t Box 3 \| Molecular diagnosis Recommendation 3.We recommend offering genetic testing for cystic kidney disease genes to infants and children with very-earlyonset (veo) symptomatic disease independent of family history and to those with progressive disease (increasing cyst number or kidney volume) and a negative family history (evidence level B; recommendation level moderate). ## Recommendation 3.2 In patients with a positive family history and unusually severe clinical course, genetic testing may be beneficial (evidence level D; recommendation level weak). ## Recommendation 3.3 We do not recommend genetic testing in patients with a single cyst, no extrarenal findings and a negative family history of autosomal dominant polycystic kidney disease (ADPKD) (evidence level B-C; recommendation level moderate). ## Recommendation 3.4 For genetic testing in children with veo polycystic kidney disease or unusually progressive disease with a negative family history, we suggest using a multigene panel, including cystic kidney disease genes with a protocol adequately covering PKD1 rather than testing single ADPKD genes (evidence level C; recommendation level weak). of age, which is significantly higher than that of this age group in the healthy population (<2%). Elevated blood pressure is significantly associated with kidney volume and cyst score in children with ADPKD. ## Blood pressure measurement As hypertension is the main treatable disease manifestation of ADPKD in childhood, we recommend adhering to the stringent yearly monitoring intervals for clinic blood pressure measurements recommended by the AAP and the European Society of Hypertension (ESH) for otherwise healthy children 13 (Box 4). This recommendation also applies to at-risk children of affected parents who have chosen to defer diagnostic testing. Ambulatory blood pressure monitoring (ABPM) is more reproducible and accurate than clinic blood pressure measurement, and ABPM values associate more closely with left ventricular hypertrophy in childrenand with renal disease progression or death in adults with chronic kidney disease (CKD) 60 than do clinic blood pressure values. A substantial proportion of children with CKD have masked hypertension 61 , justifying the routine use of ABPM for high-risk children. In addition, ABPM can exclude white coat hypertension and help to avoid unnecessary treatment. ABPM becomes more useful as children age because measurements are less well tolerated by younger children, who also have a lower prevalence of hypertension, and reliable reference values are available only for individuals with a height of ≥120 cm. Isolated night-time hypertension with normal daytime blood pressure, which can be picked up only on ABPM, has been reported in 16-18% of children with ADPKD. This finding underlines the usefulness of ABPM in this patient group. Monitoring intervals will depend on local availability, level of clinic blood pressure and/or the use of antihypertensive medication. Home blood pressure measurements are less suitable than repeated clinic or ABPMs for initial diagnosis of hypertension owing to the current lack of definitive paediatric reference values. However, home measurements can be useful to assess changes over time, monitor treatment and increase compliance, thus helping to reduce the frequency of more costly ABPM. The use of home blood pressure measurement will depend on the compliance of the family and the child, as well as the availability of monitors that have been specifically validated for children. Antihypertensive treatment Blood pressure thresholds. No studies on blood pressure thresholds for antihypertensive treatment in paediatric hypertension have been published. Owing to the high cardiovascular mortality of patients with childhood-onset CKDand the beneficial effect of lowering blood pressure on progression of renal disease 66 , we support the low antihypertensive treatment threshold (ninetieth percentile for age, sex and height, which equals 130/85 mmHg on clinic measurements for those ≥16 years of age) that is recommended for children with CKD by Kidney Disease: Improving Global Outcomes (KDIGO). ## Blood pressure targets. A randomized controlled trial (RCT) of antihypertensive therapy in children with CKD stage 2-4 showed a significant beneficial effect on renal survival when treatment was targeted to reduce 24-hour mean arterial pressure to below the fiftieth percentile on ABPM. However, a post hoc analysis reported no further benefit for an achieved blood pressure below the seventy-fifth percentile. The HALT-PKD Study A demonstrated a significant benefit of a lower blood pressure goal (95/60 to 110/75 mmHg) versus a standard blood pressure target (120/70 to 130/80 mmHg) in terms of total kidney volume (TKV), left ventricular mass index (LVMI) and albuminuria in adults with ADPKD and stage 1-2 CKD 68 . However, a smaller randomized trial of intensive blood pressure control in children with ADPKD did not reach statistical significance. Thus, the long-term benefits of lower blood pressure need to be balanced against the need for more medications and higher risk of adverse effects in the short term. We consider the KDIGO and ESH blood pressure target for children with CKD (less than the seventy-fifth percentile) to be more evidence-based for use in children with ADPKD than the stricter AAP target (less than the fiftieth percentile). All children at risk of or diagnosed with autosomal dominant polycystic kidney disease (ADPKD) should have their blood pressure measured at least once a year (that is, at the same interval as healthy children) (evidence level C; recommendation level moderate). ## Recommendation 4.2 Twenty-four-hour blood pressure on ambulatory blood pressure monitoring (ABPm) is the preferred method for defining hypertension in children aged 5 years and older (evidence level C; recommendation level moderate). ## Recommendation 4.3 In children with confirmed ADPKD, ABPm should be performed at least once from age 5 years (evidence level B; recommendation level moderate). ## Recommendation 4.4 For children with ADPKD on antihypertensive medication, we suggest monitoring blood pressure control by regular home blood pressure measurements (evidence level C; recommendation level weak). ## Recommendation 4.5 We suggest that children with ADPKD receive antihypertensive treatment if their blood pressure repeatedly exceeds the ninetieth percentile or is >130/85 mmHg if age >16 years (evidence level D; recommendation level moderate). ## Recommendation 4.6 For treatment of hypertensive children with ADPKD, we suggest a target blood pressure below the seventy-fifth percentile or <125/72 mmHg if age >16 years (evidence level C; recommendation level moderate). ## Recommendation 4.7 lowering blood pressure below the fiftieth percentile or <120/70 mmHg if age >16 years may provide additional long-term benefit for hypertensive children with ADPKD (evidence level D; recommendation level weak). ## Recommendation 4.8 We recommend using angiotensin-converting enzyme (ACe) inhibitors or angiotensin receptor blockers as first-line antihypertensive treatment in children with ADPKD who have hypertension and albuminuria (evidence level B; recommendation level moderate). ## Recommendation 4.9 We suggest using ACe inhibitors or angiotensin receptor blockers as first-line antihypertensive treatment in children with ADPKD who have hypertension without albuminuria (evidence level C; recommendation level moderate). ## First-line treatment. Compared with other antihypertensive agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have the largest evidence base for efficacy and safety in paediatric patients and in patients with renal hypertension. In patients with proteinuria, the superiority of ACE inhibitors and ARBs over other antihypertensive drug classes has been clearly demonstrated. Whether renin-angiotensin-aldosterone system (RAAS) inhibitors have superior efficacy to β-blockers or calcium channel blockers in adults with ADPKD is less clear. Dual RAAS blockade does not seem to have additional benefit on disease progression over that of improved blood pressure control compared with an ACE inhibitor or ARB alone in adults with early or late ADPKD. Diuretics should be used with caution as they may increase vasopressin levels and seem to have deleterious effects on estimated GFR (eGFR) in comparison to ACE inhibitors in ADPKD. In an animal model of ADPKD, calcium channel blockers promoted cyst growth 77 , but the findings of human studies are inconsistent 73,78,79 . ## Proteinuria As mentioned above, the incidence of proteinuria is increased in children with ADPKD. In the systematic review by Marlais et al., the prevalence of proteinuria in these children was 20% (96% CI 9-40%); however, this finding may also be influenced by tertiary centre bias. Proteinuria does not seem to be associated with hypertension but is one of the most established risk factors for progression of CKD in adults and children regardless of the cause of CKD. Owing to its therapeutic and prognostic relevance, monitoring of proteinuria and/or albuminuria should be considered standard care for children with ADPKD (Box 5). Proteinuria can be considered not only as a marker of CKD but also as a cause of further tubulointerstitial damage and fibrosis, as well as glomerular hypertrophy. Reduction of proteinuria using ACE inhibitors or ARBs is associated with significant improvement in renal survival in patients with CKD 87 , although RCTs in children are lacking. Control of proteinuria is therefore an important aspect of current treatment recommendations for CKD. In children with ADPKD who have protein uria, ACE inhibitors or ARBs should be used as the primary treatment as in other chronic kidney diseases. Albuminuria tends to be mild in adults with ADPKD; for example, in the TEMPO 3:4 study, the median albumin/creatinine ratio (ACR) was 3.2 mg/mmol. Of all patients, 49% of patients had moderate albuminuria (ACR ≥3 mg/mmol) and just 3.4% had severe albuminuria (ACR ≥30 mg/mmol). We therefore recommend measuring ACR in a laboratory rather than performing dipstick testing, which is a less sensitive and specific method. ## Routine monitoring of cyst growth In asymptomatic children, routine monitoring of cyst growth should not be performed too frequently as ultrasonography findings are very unlikely to influence clinical management decisions and the psychological burden of regular 'cyst counting' should be considered. Cyst number and TKV correlate with hypertension 25,43-45 , but ultrasonography cannot replace direct measurement of blood pressure, which remains essential in clinical practice. Although children with very-early-onset ADPKD have poorer outcomes, no studies have examined whether the prediction of 'rapid progressors' by repeated imaging in children is feasible and clinically helpful. Our recommendation (Box 6) would change in the future if paediatric studies show a predictive value of kidney imaging on later progression to end-stage renal disease (ESRD; as has been shown in adultsand a treatment to slow disease progression is licensed specifically for children who are at risk of early progression to ESRD. As discussed below, ultrasonography examination is an essential tool in the investigation of symptomatic children, for example, when investigating urinary tract infections (UTIs), cyst haemorrhage, gross haematuria, renal stones or cyst infections. Before transition from paediatric to adult care, ultrasonography findings may also provide some guidance as to whether to refer the patient to a general practitioner or directly to a nephrologist. ## Monitoring progression in adpkd trials Patient and renal survival are the most meaningful long-term outcomes in ADPKD trials but are difficult to assess in paediatric populations. GFR is nearly always within the normal range during childhood ADPKD, thus eGFR decline is a suitable marker of disease progression only in the small subgroup of children with very advanced ADPKD 89 . Height-adjusted TKV (htTKV) on MRI is the most established imaging surrogate parameter for monitoring disease progression in adult ADPKD trials. To date, only one study has investigated the correlation of MRI measurements with disease severity in Children with autosomal dominant polycystic kidney disease (ADPKD) and those at risk of ADPKD should be monitored for albuminuria (evidence level C; recommendation level weak). ## Recommendation 5.2 If proteinuria is present, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be used as primary treatment as in other chronic kidney diseases (evidence level C; recommendation level moderate). ## Box 6 \| routine monitoring of cyst growth ## Recommendation 6.1 In asymptomatic children with autosomal dominant polycystic kidney disease (ADPKD), the clinical value of repeated ultrasonography is unclear. Depending on the clinical course and the age of the patient, ultrasonography may provide insights into the dynamics of disease progression but, in routine clinical care of classical ADPKD, we suggest that monitoring intervals shorter than 3 years are unnecessary (evidence level X, recommendation level weak). children with ADPKD. This study found a correlation of MRI cyst volume and TKV with current hyper tension status, as well as a predictive value of cyst volume for the development of hypertension. In contrast to adults, kidneys in children with early ADPKD can usually be imaged within one ultrasonography viewing field (maximum dimension ~17 cm), which enables adequate measurements for volume calculation using the ellipsoid formula. However, quantification of cyst number in older children is probably more accurate with MRI once multiple small cysts become too numerous for counting on ultrasonography. For TKV, MRI measurements seem to be slightly larger than ultrasonography measurements in children with ADPKD, with discrepancies mainly for larger kidneys. Correlation of hypertension to kidney volume on renal ultrasonography has been demonstrated in three paediatric studies. 3D ultrasonography is a promising new tool for TKV measurements in children but requires further validation. As non-cooperative children require sedation for MRI, use of this approach does not seem to be warranted in a research setting without direct benefit for the child (Box 7). Use of MRI planimetry to measure TKV may be appropriate for adolescents in clinical trials or children with very large kidneys. ## Lifestyle interventions and treatments ## Maintenance of normal weight No RCTs of lifestyle interventions with relevant outcome measures have been conducted in patients with ADPKD. However, there is no evidence to suggest that lifestyle recommendations for the general paediatric population, as well as those for children and adults with CKD, do not apply to children with ADPKD (Box 8). The importance of maintaining normal weight is underlined by the observation that obesity is an independent predictor of faster loss of renal function in adults with early ADPKD 93 . ## Salt intake The dietary salt intake of the general population of infants, toddlers and older children on a Western diet far exceeds the recommended amounts. In adults with CKD, high salt intake is associated with higher blood pressure, proteinuria and progression to ESRD. Higher sodium intake also blunts the antihypertensive and antiproteinuric effects of RAAS blockade. In patients with ADPKD, urinary sodium excretion correlates with kidney growth. Moreover, in patients with later-stage ADPKD, higher urinary sodium levels (a surrogate for sodium intake) increased the risk of a composite end point of a 50% reduction in eGFR, ESRD or death. Few interventional trials exist, but restricting salt intake lowers blood pressure and proteinuria in adults with ADPKD or CKD. In accordance with numerous guidelines for CKD, we recommend that children with ADPKD should aim to achieve the recommended intake for healthy children, which may require extra assistance (for example, advice from a dietician). ## Water and protein intake High water intake to suppress endogenous vasopressin production is often recommended for patients with ADPKD. However, evidence from interventional and observational studies does not confirm a benefit of this intervention, and a randomized trial is still ongoing. Studies suggest that adults with ADPKD are more sensitive to water deprivation than those with IgA nephro pathy and produce higher levels of endo genous vasopressin to reach similar levels of urine osmo lality to those of healthy individuals. Dehydration should therefore be avoided, and patients should be encouraged to drink to satisfy thirst. A low-osmolar diet (low sodium, low protein and adjusted water intake to decrease urinary osmolality to <280 mOsM/kg (280 mmol/kg)) decreased the levels of endogenous copeptin (a surrogate marker of vasopressin) in a short study of adults with ADPKD, but a potential long-term benefit on cyst growth remains speculative. In children with non-ADPKD CKD, an RCT did not find a beneficial effect of a low-protein diet on GFR decline. Unnecessary protein restriction should be avoided in children to reduce the risk of malnutrition. ## Vasopressin analogues Vasopressin analogues are one of several treatment options for nocturnal enuresis in school-age children. A 1994 study reported a significant increase in urinary frequency and a decrease in urinary concentrating ability in children with severe ADPKD (more than ten cysts). By contrast, children with ten or fewer cysts had a nonsignificantly increased self-reported urinary frequency and no decrease in concentrating ability compared with children of parents with ADPKD who did not have any cysts on ultrasonography. A study that included 16 children who were diagnosed with ADPKD because of their symptoms found that only 1 of these children presented with enuresis; this frequency is probably similar to that of the general paediatric population. As vasopressin antagonists reduce the rate of cyst growth and eGFR loss in patients with ADPKD, vasopressin analogues can reasonably be considered to be detrimental in these patients; therefore, it seems wise to prefer other treatment options for the management of nocturnal enuresis in children with ADPKD 111 . Clinical trials in children with autosomal dominant polycystic kidney disease (ADPKD) should monitor hypertension, proteinuria, kidney volume, cyst volume (or number) and (estimated) glomerular filtration rate (evidence level X; recommendation level moderate). ## Recommendation 7.2 For kidney volume measurements in clinical trials, total kidney volume determined by mRI is recommended to monitor progression in cooperative children. ultrasonography monitoring of kidney size and cyst number is preferable to mRI in non-cooperative children (evidence level X; recommendation level moderate). ## Statins In a prospective, double-blind RCT in 110 children and young adults aged 8-22 years with ADPKD and good renal function, the addition of pravastatin to lisinopril (with target blood pressure in the fiftieth to seventy-fifth percentile) resulted in a significantly slower increase in htTKV than placebo. As expected, eGFR did not differ between the groups. Although LDL and total cholesterol levels did not correlate directly with clinical outcome variables (htTKV, albuminuria and LVMI), the statininduced change in urinary biomarkers of endothelial dysfunction was associated with prospective change in htTKV. Routine statin treatment for cardiovascular indications is more prevalent in adults than in children. A secondary analysis of the HALT-PKD trials reported no effect of self-reported statin use versus no statin use on TKV or composite end points in adults with ADPKD 116 . Therefore, the encouraging findings in the only controlled paediatric study of statin therapy in ADPKD published to date need to be balanced against the lack of evidence of beneficial effects on renal outcome in the uncontrolled adult studyand the lack of regulatory approval of statins for ADPKD. A controlled trial in adults is ongoing 117 . Paediatric safety data for statins in large cohorts have been published only for children with familial hypercholesteremia, and the risk of statin therapy in pregnancy is unclear. We were therefore unable to reach a consensus on the use of statins to slow disease progression in children with ADPKD. ## Vasopressin antagonists Tolvaptan has been licensed to delay disease progression in adults with ADPKD who are likely to go on to develop ESRDand has also been shown to reduce ADPKDrelated pain. Currently, no direct data exist to support the use of vasopressin antagonists in children and adolescents with ADPKD, and no safety studies in this group have been published. However, a multinational, doubleblind, placebo-controlled trial of tolvaptan in teenagers with ADPKD is currently underway 124 . Although early initiation of treatment resulting in a longer lifetime treatment period may theoretically lead to a greater absolute prevention of eGFR loss than that achieved with later treatment initiation, the medium-term protection against relative eGFR loss is much lower in patients with preserved renal function than in those with more advanced CKD. Tolvaptan is known to cause occasional hepatic injury in adult ADPKD, but the impact of this agent on liver enzymes in children is not yet known. In addition, treatment with vasopressin antagonists causes substantial polyuria, which is likely to affect sleep and daily activities and thus may influence quality of life. Patients are likely to require additional counselling and support to successfully adhere to such a disruptive treatment during adolescence. ## Mtor inhibitors Prospective RCTs did not find an eGFR benefit of mTOR inhibitors in adults with ADPKD, and these agents were associated with important adverse effects such as worsening proteinuria, hyperlipidaemia and cytopenias. We therefore recommend that mTOR inhibitors should not be used in children and adolescents with classical ADPKD. In patients with PKD1/TSC2 CGS, mTOR inhibitors are potentially beneficial as renal cysts have been reported to decrease in children with tuberous sclerosis receiving treatment with mTOR inhibitors for other indications. However, as cyst volume does not automatically equate to GFR benefitand there is no published experience of these drugs in PKD1/TSC2 CGS, they should be reserved for the licensed indications of subependymal giant cell astrocytoma and large angiomyolipomas. ## Somatostatin analogues Use of somatostatin analogues to delay disease progression in ADPKD has been studied only in adults. RCTs indicate that these agents are beneficial in patients with severe liver disease but do not have a sustained beneficial effect on renal function. No severe cases of ADPKDrelated liver disease in children have been reported in the literature, and paediatric experience with these drugs volume 15 \| NovemBeR 2019 \| 721 NATuRe RevIeWS \| NePHRoLogy C o n S e n S u S S tat e m e n t ## Box 8 \| lifestyle interventions and treatments a recommendation 8.1 A healthy lifestyle including physical activity and maintenance of normal weight should be promoted in all patients with autosomal dominant polycystic kidney disease (ADPKD) (evidence level B-C; recommendation level moderate). ## Recommendation 8.2 Children with ADPKD should be encouraged to achieve the recommended low dietary salt intake (evidence level B; recommendation level moderate). ## Recommendation 8.3 High water intake and avoidance of excessive protein intake may be beneficial in slowing progression of renal failure in children with ADPKD (evidence level D; recommendation level weak). ## Recommendation 8.4 use vasopressin analogues (for example, desmopressin) with caution in children and young people with ADPKD and enuresis due to potential negative effects on cyst growth (evidence level X, recommendation level moderate). ## Recommendation 8.5 Do not routinely offer vasopressin antagonists to children and young people with ADPKD. off-label use of vasopressin antagonists can be considered at clinician discretion in children at high risk of early progression based on large total kidney volume, rapid kidney growth, family history, etc. (evidence level D, recommendation level weak). ## Recommendation 8.6 mToR inhibitors should not be used in children and adolescents with classical ADPKD (evidence level B, recommendation level moderate). ## Recommendation 8.7 There is insufficient evidence from adult studies supporting the use of somatostatin analogues in ADPKD. They should not be used in children with ADPKD (evidence level C, recommendation level moderate). a No consensus could be reached on the use of statins to slow disease progression in children with ADPKD. is limited. We therefore recommend that somatostatin analogues should not be used in children with ADPKD. ## Management of complications abdominal pain Abdominal pain is reported in 10-20% of children with ADPKD. As abdominal and back pain are very common symptoms among children and adolescents in general, further investigations and treatment need to be guided by acuity, intensity and associated findings 137 (Box 9). Even in the early stages of ADPKD, episodes of nonspecific abdominal pain are frequently reported by adults and tend to be underestimated by physicians. However, patients might have a biased perception of pain, especially if investigations for abdominal pain led to their incidental diagnosis of ADPKD. Chronic pain requires a multidisciplinary approach to avoid overtreatment or undertreatment and to improve self-management. Chronic and/or high-dose use of nonsteroidal anti-inflammatory agents (NSAIDs) should be avoided because of potential renal adverse effects. ## Urinary tract and cyst infections Cohort studies suggest an increased incidence of UTIs in children with ADPKD (up to 15-25%). These studies may be biased as imaging for UTI may have prompted the diagnosis of ADPKD. As no studies have suggested an increased incidence of complicated or prolonged infections in children with ADPKD, local standards for the diagnosis and treatment of UTI in otherwise healthy children should be applied. Suspicion of upper UTI in children with ADPKD should lead to examination of urine (and blood) cultures, as well as renal ultrasonography, much the same as in otherwise healthy children. Cyst infection is a very rare complication of childhood ADPKD. If suspected clinically or on ultrasonography imaging, experience in adults suggests that 18 F-FDG-PET/computed tomography (CT) is superior to contrast CT or MRI to confirm the diagnosis and localize the infected cyst, but this approach can produce false-negative results. Treatment of cyst infection has a high failure rate and requires long-term use of antibiotics. Precise localization of an infected cyst can be extremely difficult in patients with many cysts but is necessary only for refractory infection when cyst drainage may be required. ## Haematuria and cyst haemorrhage Macroscopic haematuria is reported in 5-15% of children with ADPKD. However, studies may overestimate the incidence, as imaging for haematuria may have prompted the diagnosis. Macroscopic haematuria is associated with enlarged TKV in adults 147 but was not more common in children with severe versus moderate versus no cysts, nor in children with veryearly-onset disease versus those with later onset. Gross haematuria before the age of 30-35 years is associated with worse renal survival in adults with ADPKD. Observations in adults with severe cyst haemorrhage seem to suggest a benefit of treatment with tranexamic acid, but the efficacy of this therapy has not been investigated in children. ## Nephrolithiasis Nephrolithiasis is an exceedingly rare complication in children with ADPKD, and ultrasonography should be used as the first-line imaging modality to rule out stones or other urinary tract obstructions. If kidney stones are found, additional risk factors for stone disease should be investigated, and a high fluid intake and symptomatic treatment are recommended. ## Liver cysts As the size and number of ADPKD-related liver cysts are known to increase in pregnancy, avoidance of exogenous oestrogens and hormone replacement therapy is generally recommended for women with ADPKD 152 . However, the prevalence of hepatic cysts in children with ADPKD is <5%, with no reports of severe cases. The risk of future aggravated liver disease in young women with ADPKD considering hormonal contraceptive therapy should be balanced against the risk of unplanned pregnancy. Assessment of the burden of liver cysts and family history might assist in clinical decision-making. ## Screening for extrarenal complications Mitral valve prolapse A systematic study published in 1995 reported mitral valve prolapse in 12% of children with ADPKD 154 . This prevalence was significantly higher than that of their healthy siblings (3%) but is within the range reported for healthy children and is lower than that reported for adults with ADPKD (25%). As children without a murmur are unlikely to have haemodynamically relevant mitral valve prolapse, they do not require echocardiographic screening for mitral valve prolapse (Box 10). Children with autosomal dominant polycystic kidney disease (ADPKD) presenting with abdominal pain should receive normal work-up also considering other causes of pain (evidence level D, recommendation level weak). ## Recommendation 9.2 Diagnosis and treatment of lower urinary tract infection in children with ADPKD should be the same as in otherwise healthy children (evidence level D, recommendation level weak). ## Recommendation 9.3 In a child with ADPKD and fever, pyelonephritis and cyst infection should be considered. Kidney ultrasonography is the first imaging modality to investigate the aetiology (evidence level D, recommendation level weak). ## Recommendation 9.4 In a child with ADPKD and gross haematuria, cyst haemorrhage and nephrolithiasis should be considered. Kidney ultrasonography is the first imaging modality to investigate the aetiology (evidence level D, recommendation level weak). ## Recommendation 9.5 All young women with ADPKD considering contraceptive therapy should receive counselling on potential aggravation of polycystic liver disease with exogenous oestrogen exposure (evidence level D, recommendation level weak). ## Intracranial aneurysm In adults with ADPKD, screening for intracranial aneurysms is generally recommended only if additional risk factors are present such as a positive family history, previous intracranial aneurysms or a high-risk profession. However, some authors disagree with this recommendation, arguing that screening is costeffective. Treatment strategies for unruptured intracranial aneurysms are still controversial. As rupture of intracranial aneurysm is an exceedingly rare complication in childhood, routine screening is not justified. In rare cases with a positive family history and a strong desire to ease anxiety by screening, an individualized approach is justified. ## Liver cysts No reports exist of clinically relevant complications of ADPKD-related liver cysts in children. Congenital hepatic fibrosis is not a feature of classical ADPKD. Ultrasonography of the liver may be a reasonable investigation at first presentation of children with suspected ADPKD if alternative diagnoses are being considered or in the case of acute abdominal pain. However, we do not recommend regular screening for liver cysts in children with confirmed ADPKD. ## Referral to specialized centres Newborn babies and infants with severe cystic disease comprise a heterogeneous group who pose numerous challenges to diagnosis and management. Extended genetic testing of these patients is recommended to inform genetic and prognostic counselling in a specialized centre. However, neonates or fetuses with hyperechogenic kidneys and a family history of ADPKD who do not have symptoms or enlarged kidneys should not be considered to have severe disease. Children with TSC2/PKD1 CGS typically have severe polycystic kidney disease and may reach ESRD in young adulthood. We recommend referral to a specialized centre and multidisciplinary care for these patients. ## Psychosocial aspects The consensus group shares the view of a current multidisciplinary position statement on ADPKD that emphasizes the need for "a holistic and comprehensive assessment of the manifestations, complications, prognosis and impact of the disease (in physical, psychological and social terms) on the patient and their family". Although young adults with ADPKD usually carry a much lower burden of physical impairment than older patients, they have to make lifestyle, career and family planning choices that will have lifelong effects. Studies in families with ADPKD have shown a high psychological burden of both 'genetic guilt' and anxiety about future health problems. We recommend that families of children with ADPKD should be encouraged to discuss the risk of disease transmission with their children (Box 11). Parents affected by inheritable disease often find communication with their children difficult and desire professional assistance, including developmentally appropriate disease information and advice on managing their children's emotional reactions. Qualitative studies show that avoiding such discussions can be a source of family tensions through misunderstanding, blame and secrecy, whereas open communication with younger children promotes effective coping strategies and makes families more resilient. Multi-family discussion groups can be a valuable tool for promoting such intrafamilial discussions. Several lifestyle interventions can be recommended for patients with ADPKD (see above), irrespective of their CKD stage. As teenage and young-adult years provide the unique opportunity to establish healthy living habits without having to break previous habits, this period is an important age for counselling. Relevant messages include the importance of a healthy, low-salt diet, adequate fluid intake, regular physical exercise, avoiding obesity, abstention from smoking and avoidance of nephrotoxic medication. Young women should also be counselled to avoid high-oestrogen-containing volume 15 \| NovemBeR 2019 \| 723 NATuRe RevIeWS \| NePHRoLogy C o n S e n S u S S tat e m e n t Box 10 \| Screening for extrarenal complications Recommendation 10.1 In children with autosomal dominant polycystic kidney disease (ADPKD) without a heart murmur, screening for mitral valve prolapse is not recommended (evidence level D, recommendation level weak). ## Recommendation 10.2 Screening for intracranial aneurysms is not recommended for children with ADPKD (evidence level D, recommendation level weak). ## Recommendation 10.3 Regular screening for liver cysts is not recommended in children with confirmed ADPKD (evidence level D, recommendation level weak). ## Recommendation 10.4 early referral to a specialized centre is recommended for the management of children with very-early-onset ADPKD or autosomal recessive polycystic kidney disease-like presentations (evidence level D, recommendation level moderate). ## Recommendation 10.5 Referral to a specialized centre and multidisciplinary care is recommended for patients with TSC2/PKD1 contiguous gene syndrome (evidence level D, recommendation level weak). ## Box 11 \| psychosocial aspects Recommendation 11.1 Families should be encouraged to openly discuss their disease and future genetic risks with their children, for example, by provision of age-appropriate information and by providing support for family members in managing their own and their children's emotions (evidence level B, recommendation level moderate). ## Recommendation 11.2 Care of teenagers with autosomal dominant polycystic kidney disease (ADPKD) should address lifestyle measures, as well as relevant medical issues of prevention (evidence level X, recommendation level moderate). ## Recommendation 11.3 Care of teenagers with ADPKD should address psychological issues and convey positive messages (evidence level X, recommendation level moderate). ## Recommendation 11.4 Transition to adult nephrology care should follow bestpractice guidelines (evidence level X, recommendation level moderate). # Conclusions Although the main burden of disease in ADPKD does not occur until adulthood, a substantial proportion of paediatric and adolescent patients have treatable disease manifestations and a small percentage have symptomatic disease or very-early-onset disease in infancy. This consensus group hopes that our recommendations will improve the care of children with or at risk of ADPKD. We recommend the provision of balanced counselling for families with respect to diagnostic screening, regular monitoring of blood pressure and proteinuria and the avoidance of frequent imaging to monitor cyst growth. We also provide guidance on managing complications, lifestyle interventions and psychosocial aspects. As the pharmacological management of adult ADPKD advances and the results of a paediatric trial of tolvaptan are pending, future challenges will include defining in medical, psychological and economic terms which patients will benefit from early initiation of treatment to delay disease progression. ## Published online 22 may 2019 contraception products because of potential exacerbation of later liver disease. Issues of genetic guilt or fear of the future disease course can have a substantial impact on the psychological well-being of young people and families affected by ADPKD. Integrated care should therefore include active inquiry about anxieties and sources of psychological support. Positive messages that can be used to promote a proactive attitude towards disease management are, for example, 'you are not ill' , 'you have the opportunity and time to influence later outcome by preventive measures' or 'many career choices are open to you' . Young adults may also value discussion about wise disclosure of their renal disease to outsiders. Contact with affected peers via patient communities should be encouraged. Finally, reminding parents of their value as positive role models may be helpful. Discontinuity of care because of transfer from paediatric to adult nephrology care is an important risk factor for adverse outcome in more severely affected individuals. Local and international guidance on transition should be followed to prevent loss of medical follow-up.	None	https://www.nature.com/articles/s41581-019-0155-2.pdf	None
40964a64b81d7ee20dd9caf5241b12440b56a4dd	pubmed	Morphine and alternative opioids in cancer pain: the EAPC recommendations	Morphine and alternative opioids in cancer pain: the EAPC recommendations An expert working group of the European Association for Palliative Care has revised and updated its guidelines on the use of morphine in the management of cancer pain. The revised recommendations presented here give guidance on the use of morphine and the alternative strong opioid analgesics which have been introduced in many parts of the world in recent years. Practical strategies for dealing with difficult situations are described presenting a consensus view where supporting evidence is lacking. The strength of the evidence on which each recommendation is based is indicated.The relative potency by intravenous and subcutaneous routes is the same. When converting from oral to intravenous morphine the oral dose should be divided by three(Kalso and Vainio, 1990). Most pain in cancer responds to pharmacological management using orally administered analgesics and adjuvants. Current treatment is based on the World Health Organization (WHO)'s concept of an 'analgesic ladder' which involves a stepwise approach to the use of analgesic drugs and is essentially a framework of principles rather than a rigid protocol . This allows considerable flexibility in the choice of specific drugs and the WHO ladder should be regarded as but one part of a comprehensive strategy for managing cancer pain. Symptomatic drug treatment is used in an integrated way with disease-modifying therapy and non-drug measures. The most important part of the WHO method, and the reason for its success, is the efficient use of oral opioids for moderate to severe pain. Morphine is the benchmark 'step 3' opioid and in 1996 we published guidelines for the use of this drug in cancer pain management (Expert Working Group of the . Since our earlier publication, a number of alternatives to morphine have become available though these are generally not new molecules but novel formulations of existing drugs. There are few randomized controlled trials (RCTs) involving head to head comparisons between different opioids and this may make it difficult to choose the most appropriate drug for specific situations. In view of the paucity of RCT data the European Association for Palliative Care's Expert Working Group on Opioid Analgesics has revised its recommendations for the use of morphine in cancer pain and extended them to cover the use of alternative opioids . The strength of the evidence supporting each recommendation is indicated. ## The opioid of first choice for moderate to severe cancer pain is morphine c Morphine is the standard 'step 3' opioid analgesic against which others are measured and is the most widely available in a variety of oral formulations. Morphine appears to have no clinically relevant ceiling effect to analgesia: doses of oral morphine may vary 1000fold or more to achieve the same end point of pain relief. ## Unfounded fears associated with morphine Morphine has long been feared by both the general public and physicians. Underlying the fear is the mistaken belief that the problems associated with abuse of opioids are inextricably linked to therapeutic use. Concerns about addiction, excessive sedation, and respiratory depression have resulted in widespread avoidance or under-dosing. Yet extensive, carefully documented clinical experience has shown that these fears are unfounded. Regular doses of morphine may be indicated and safely instituted early in the course of a patient's illness and continued for many months. Patients treated with morphine whose pain ameliorates can reduce the dose and discontinue it without difficulty. Daytime drowsiness, dizziness or mental clouding commonly occur at the start of treatment but resolve when patients are stabilized (usually within a few days). For most patients receiving stable doses of morphine effects on cognitive and psychomotor function are minimal. In particular, there are data indicating that patients' driving ability is not significantly impaired, in alert patients receiving a stable dose. Similarly, nausea and vomiting, which occur in up to two-thirds of patients when morphine is started, usually resolve. The main continuing adverse effect from morphine is constipation, and the prophylactic use of a laxative is almost always required. # Morphine: limitations The systemic availability of morphine by the oral route is poor (20-30%) and this contributes to a sometimes unpredictable onset of action and great interindividual variability in dose requirements and response. Active metabolites may contribute to toxicity, particularly in patients with renal impairment. And some types of pain do not always respond well or completely to morphine, notably neuropathic pain. However, none of the alternatives to morphine has so far demonstrated advantages which would make it preferable as the first line oral opioid for cancer pain. Morphine remains our first choice but for reasons of familiarity, availability and cost rather than proven superiority. 2. The optimal route of administration of morphine is by mouth. Ideally, two types of formulation are required: normal release (for dose titration) and modified release (for maintenance treatment) C The oral route is the simplest and most acceptable to patients. There is large interindividual variation in kineticsand dynamics in cancer patients whose pain will also vary in 1. The opioid of first choice for moderate to severe cancer pain is morphine. C 2. The optimal route of administration of morphine is by mouth. Ideally, two types of formulation are required: normal release (for dose titration) and modified release (for maintenance treatment). C 3. The simplest method of dose titration is with a dose of normal release morphine given every 4 hours and the same dose for breakthrough pain. This 'rescue' dose may be given as often as required (up to hourly) and the total daily dose of morphine should be reviewed daily. The regular dose can then be adjusted to take into account the total amount of rescue morphine. C 4. If pain returns consistently before the next regular dose is due the regular dose should be increased. In general, normal release morphine does not need to be given more often than every 4 hours and modified release morphine more often than 12 or 24 hours (according to the intended duration of the formulation). Patients stabilized on regular oral morphine require continued access to a rescue dose to treat 'breakthrough' pain. A 5. Several countries do not have a normal release formulation of morphine, though such a formulation is necessary for optimal pain management. A different strategy is needed if treatment is started with modified release morphine. Changes to the regular dose should not be made more frequently than every 48 hours, which means that the dose titration phase will be prolonged. C 6. For patients receiving normal release morphine every 4 hours, a double dose at bedtime is a simple and effective way of avoiding being woken by pain. C 7. Several modified release formulations are available. There is no evidence that the 12-hourly formulations (tablets, capsules or liquids) are substantially different in their duration of effect and relative analgesic potency. The same is true for the 24-hour formulations though there is less evidence to draw on. A 8. If patients are unable to take morphine orally the preferred alternative route is subcutaneous. There is generally no indication for giving morphine intramuscularly for chronic cancer pain because subcutaneous administration is simpler and less painful. C 9. The average relative potency ratio of oral morphine to subcutaneous morphine is between 1:2 and 1:3 (i.e. 20-30 mg of morphine by mouth is equianalgesic to 10 mg by s.c. injection). C 10. In patients requiring continuous parenteral morphine, the preferred method of administration is by subcutaneous infusion. C 11. Intravenous infusion of morphine may be preferred in patients: a. who already have an in-dwelling intravenous line; b. with generalized oedema; c. who develop erythema, soreness or sterile abscesses with subcutaneous administration; d. with coagulation disorders; e. with poor peripheral circulation. C 12. The average relative potency ratio of oral to intravenous morphine is between 1:2 and 1:3. A 13. The buccal, sublingual and nebulized routes of administration of morphine are not recommended because at the present time there is no evidence of clinical advantage over the conventional routes. B 14. Oral transmucosal fentanyl citrate (OTFC) is an effective treatment for 'breakthrough pain' in patients stabilized on regular oral morphine or an alternative step 3 opioid. A 15. Successful pain management with opioids requires that adequate analgesia be achieved without excessive adverse effects. By these criteria the application of the WHO and the EAPC guidelines (using morphine as the preferred step 3 opioid) permit effective control of chronic cancer pain in the majority of patients. In a small minority of patients adequate relief without excessive adverse effects may depend on the use of alternative opioids, spinal administration of analgesics or non-drug methods of pain control. B 16. A small proportion of patients develop intolerable adverse effects with oral morphine (in conjunction with a non-opioid and adjuvant analgesic as appropriate) before achieving adequate pain relief. In such patients a change to an alternative opioid or a change in the route of administration should be considered. B 17. Hydromorphone or oxycodone, if available in both normal release and modified release formulations for oral administration, are effective alternatives to oral morphine. A 18. Methadone is an effective alternative but may be more complicated to use compared with other opioids because of pronounced interindividual differences in its plasma half-life, relative analgesic potency and duration of action. Its use by non-specialist practitioners is not recommended. C ## 19. Transdermal fentanyl is an effective alternative to oral morphine but is best reserved for patients whose opioid requirements are stable. It may have particular advantages for such patients if they are unable to take oral morphine, as an alternative to subcutaneous infusion. B 20. Spinal (epidural or intrathecal) administration of opioid analgesics in combination with local anaesthetics or clonidine should be considered in patients who derive inadequate analgesia or suffer intolerable adverse effects despite the optimal use of systemic opioids and non-opioids. B Morphine and alternative opioids in cancer pain severity so that the dose must be titrated against effect for each patient, and the starting dose will be determined by previous analgesic treatment. Patients changing from regular administration of a step 2 opioid (in combination with a non-opioid) will usually start with 10 mg every 4 hours. If step 2 of the analgesic ladder is omitted 5 mg every 4 hours may suffice, whereas patients converted from another step 3 opioid will require more. During dose titration it is preferable to use a formulation of morphine that has a rapid onset and a short duration of action to allow steady state to be achieved as quickly as possible. Normal release formulations fulfil these requirements. Peak plasma concentrations usually occur within the first hour after oral administration, with a reasonably rapid onset of analgesia which then lasts for about 4 hours. In contrast modified release morphine formulations produce a delayed peak plasma concentration after 2-6 hours, the peak is attenuated, and analgesia lasts for 12 or 24 hours. This means that with modified release morphine it is more difficult to rapidly assess the adequacy of analgesia and to adjust the dose during the dose-finding period. 3. The simplest method of dose titration is with a dose of normal release morphine given every 4 hours and the same dose for breakthrough pain. This 'rescue' dose may be given as often as required (up to hourly) and the total daily dose of morphine should be reviewed daily. The regular dose can then be adjusted to take into account the total amount of rescue morphine C The plasma elimination half-life of morphine is 2-4 hoursand steady state is achieved within 4-5 half-lives (that is within 24 hours)after the start of treatment and following dose adjustment. This is an important interval in which to re-evaluate a patient and adjust the daily dose. This method of dose titration avoids the need to remember predetermined increments and has been shown to be safe and effective. During the dose titration phase using 4-hourly normal release morphine, the full 4-hourly dose should be used for 'rescue'. The frequency with which the rescue dose can be offered depends on the route of administration and the time to peak effect. Oral rescue doses are usually offered up to every 1-2 hours and parenteral doses (equivalent to the 4-hourly parenteral dose) can be offered as frequently as every 15-30 minutes. 4. If pain returns consistently before the next regular dose is due the regular dose should be increased. In general, normal release morphine does not need to be given more often than every 4 hours and modified release morphine more often than 12 or 24 hours (according to the intended duration of the formulation). Patients stabilized on regular oral morphine require continued access to a rescue dose to treat 'breakthrough' pain A The drug regimen should be as simple as possible. Increasing the frequency of administration may adversely affect compliance and convenience for the patient. Increasing the dose allows a 4hourly or 12-or 24-hourly regimen to be achieved without producing troublesome adverse effects associated with the increase in peak blood concentrations. A few patients receiving 12-hourly formulations do not seem to achieve a 12 hour duration of analgesia and require administration every 8 hours. Occasionally patients taking a high dose prefer dosing every 8 hours to avoid taking too many tablets at a time, particularly in countries where no high-dose formulations are available. Patients receiving regular oral opioids may experience acute episodic breakthrough pain which may be a function of the pain itself or may be precipitated by some voluntary act such as weightbearing or movement. There are no RCT data to establish the appropriate dose of morphine for breakthrough pain and anecdotal experience supports the use of doses varying from 30 to 100% of the 4-hourly dose. It may be that the optimal dose for breakthrough pain can only be determined by titration but we suggest that a simple approach is to use the equivalent 4-hourly dose of morphine (as during the dose-finding period). requires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation (evidence levels Ia and Ib). B: requires the availability of well-conducted clinical studies but no randomised clinical trials on the topic of recommendation (evidence levels Ila, Ilb and III). C: requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality (evidence level IV). ## Category of evidence Ia evidence from meta-analysis of randomised controlled trials. Ib evidence from at least one randomised controlled trial. IIa evidence from at least one controlled study without randomization. IIb evidence from at least one other type of quasi-experimental study. III evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies. IV evidence from expert committee reports or opinions or clinical experience of respected authorities, or both. ## Several countries do not have a normal release formulation of morphine, though such a formulation is necessary for optimal pain management. a different strategy is needed if treatment is started with modified release morphine. changes to the regular dose should not be made more frequently than every 48 hours, which means that the dose titration phase will be prolonged c Total daily dose requirements should be estimated on the basis of previous analgesic intake. Breakthrough pain is managed with single doses of a non-opioid (non-steroidal anti-inflammatory drug or paracetamol) as required, or with another short-lasting strong opioid available for oral administration (such as oxycodone), or with oral or rectal administration of morphine injection solution (or a solution of morphine made from powder, if this is available and cheaper). ## For patients receiving normal release morphine every 4 hours, a double dose at bedtime is a simple and effective way of avoiding being woken by pain c No formal investigations of this practice are available. However, it has been widely adoptedand does not seem to cause problems. ## Several modified release formulations are available. there is no evidence that the 12-hourly formulations (tablets, capsules or liquids) are substantially different in their duration of effect and relative analgesic potency. the same is true for the 24-hour formulations though there is less evidence to draw on a Although in principle it is unwise to change between preparations when using modified release products because of possible variations in release profiles and oral bioavailability there is no consistent evidence that the various oral formulations of morphine designed for administration every 12 hours have a different pharmacokinetic or pharmacodynamic profile in patients. Several once-a-day formulations of morphine have also been developed. There are significant differences between some in their pharmacokinetic profilesbut there is no evidence that this is reflected in clinically significant differences in patients: they appear to be equivalent in efficacy and in the duration of effect. ## If patients are unable to take morphine orally the preferred alternative route is subcutaneous. there is generally no indication for giving morphine intramuscularly for chronic cancer pain because subcutaneous administration is simpler and less painful c The advantages of subcutaneous injection are that a smaller needle is required, the chance of damage to nerves is less so that the site of injection is not crucial, and the possibility of inadvertent intravenous injection is less because veins can be seen more easily. Absorption is similar and peak plasma concentrations are achieved within 15-30 minutes, with a more rapid onset of drug action than after oral administration. Alternative drugs, particularly diamorphine(in the UK) and hydromorphone, may be preferred for parenteral administration because they are more soluble than morphine so that a smaller volume injection is necessary. Transdermal fentanyl may be a useful non-invasive alternative in patients with stable opioid requirements. Rectal administration may be preferred by some patients. The bioavailability of morphine and duration of effect is similar to the oral route and the equianalgesic dose by oral and rectal routes is the same. 9. The average relative potency ratio of oral morphine to subcutaneous morphine is between 1:2 and 1:3 (i.e. 20-30 mg of morphine by mouth is equianalgesic to 10 mg by s.c. injection) C Drugs administered by parenteral routes do not undergo presystemic ('first pass') metabolism. The relative potency ratio of oral to parenteral morphine has been highly controversial. It seems that relative potency varies according to the circumstances in which morphine is used and between individual patients. When converting from oral morphine to subcutaneous morphine, the dose should be divided by three to get a roughly equianalgesic effect, but upward or downward adjustment of the dose may then be required. ## In patients requiring continuous parenteral morphine, the preferred method of administration is by subcutaneous infusion c Portable battery-operated syringe drivers are now widely used to administer drugs by continuous slow infusion to patients with advanced cancer who are unable to take oral medication. 11. Intravenous infusion of morphine may be preferred in patients: a. who already have an indwelling intravenous line; b. with generalized oedema; c. who develop erythema, soreness or sterile abscesses with subcutaneous administration; d. with coagulation disorders; e. with poor peripheral circulation C Subcutaneous infusions have several advantages over intravenous infusions: venous access is not required, close supervision is unnecessary, and infection is unlikely. However, intravenous infusion may have advantages in the specific circumstances listed above. Transdermal fentanyl may be a useful non-invasive alternative in patients with stable opioid requirements. 12. The average relative potency ratio of oral to intravenous morphine is between 1:2 and 1:3 A ## The buccal, sublingual and nebulized routes of administration of morphine are not recommended because at the present time there is no evidence of clinical advantage over the conventional routes b The absorption of morphine by these routes is unpredictable, and they are best avoided for this drug. In contrast, the highly lipophilic drugs methadone, fentanyl and buprenorphine are well absorbed sublingually and buprenorphine is used by this route. Sublingual buprenorphine may be a useful alternative to low-dose oral morphine for patients who have difficulty swallowing, but experience of long-term use in cancer pain is limited. ## Oral transmucosal fentanyl citrate (otfc) is an effective treatment for 'breakthrough pain' in patients stabilized on regular oral morphine or an alternative step 3 opioid a OTFC produces a rapid onset of analgesia in 5-15 minutes with a short duration of action of about 2 hours. This is a new treatment with which there is very limited clinical experience but good RCT data to support efficacy . More safety data are required from wider and longer term clinical use. 15. Successful pain management with opioids requires that adequate analgesia be achieved without excessive adverse effects. By these criteria the application of the WHO and the EAPC guidelines (using morphine as the preferred step 3 opioid) permit effective control of chronic cancer pain in the majority of patients. In a small minority of patients adequate relief without excessive adverse effects may depend on the use of alternative opioids, spinal administration of analgesics or non-drug methods of pain control B A number of observational studies have been carried out to validate the WHO approach and have involved some 8000 patients in different countries and different clinical environments . Reported response rates (for adequate analgesia) have varied between 71 and 100% ## A small proportion of patients develop intolerable adverse effects with oral morphine (in conjunction with a non-opioid and adjuvant analgesic as appropriate) before achieving adequate pain relief. in such patients a change to an alternative opioid or a change in the route of administration should be considered b In some patients experiencing troublesome adverse effects a reduction in dose of morphine may alleviate these effects while maintaining adequate analgesia. If this is unsuccessful switching to an alternative opioid agonist may allow titration to adequate analgesia without the same disabling effects. Dose-limiting adverse effects most often involve CNS toxicity (drowsiness, cognitive impairment, confusion, hallucinations, myoclonic jerks). In some centres it has been found necessary or beneficial to change to an alternative opioid in up to 40% of patients. Sometimes several changes of drug are employed and the term 'opioid rotation' has been coined to describe this practice. Others estimate that the proportion of patients who develop intolerable adverse effects with oral morphine is much smaller. Switching between opioids complicates pain management and this is a disadvantage for non-specialists (for whom it is not recommended without expert advice). Appropriate strategies for the management of this situation are the subject of a separate expert report (Expert Working Group of the EAPC, in press). ## Hydromorphone or oxycodone, if available in both normal release and modified release formulations for oral administration, are effective alternatives to oral morphine a Hydromorphone is a semi-synthetic congener of morphine and a potent µ-selective agonist similar to morphine and between 5 and 10 times as potent. There appear to be no major differences between hydromorphone and morphine in terms of efficacy and adverse effects when used in equianalgesic doses. Oxycodone is a semi-synthetic congener of morphine which until recently was most often prescribed in low-dose combination products (with a non-opioid) for oral administration or as a rectal suppository. In some countries it has been more widely used as a single agent to treat post-operative pain and cancer pain. It has now become available in new oral formulations (normal and modified release). Oxycodone is similar to morphine in terms of analgesia and adverse effects. Because of its better systemic availability (about 60-90%) the equianalgesic dose of oral oxycodone is between half and two-thirds that of oral morphine. 18. Methadone is an effective alternative but may be more complicated to use compared with other opioids because of pronounced interindividual differences in its plasma half-life, relative analgesic potency and duration of action. Its use by non-specialist practitioners is not recommended C Methadone is a synthetic opioid widely available in oral formulations. It has no known active metabolites. There is a discrepancy between the duration of its initial analgesic effect (4-6 hours) and its plasma elimination half-life which averages approximately 24 hours with a range of 17 to over 100 hours. The drug accumulates on chronic dosing so that it should not be given more frequently than 8-hourly to avoid potential adverse effects. When switching from another opioid it is often difficult to accurately determine the equianalgesic dose, particularly in patients tolerant to high doses of opioids. 19. Transdermal fentanyl is an effective alternative to oral morphine but is best reserved for patients whose opioid requirements are stable. It may have particular advantages for such patients if they are unable to take oral morphine, as an alternative to subcutaneous infusion B Fentanyl is a semi-synthetic opioid and an established intravenous anaesthetic and analgesic drug which is about 80 times as potent as Morphine and alternative opioids in cancer pain 591 parenteral morphine. It is not used by mouth because it rapidly undergoes extensive first-pass metabolism. The low molecular weight and high lipid solubility of fentanyl facilitate absorption through the skin. After application fentanyl is undetectable in the systemic circulation for 1 to 2 hours, but then serum levels rise with analgesic effects evident within 8 to 16 hours and steady state is achieved at 72 hours . Each patch is applied for 3 days. An intradermal depot develops so that following removal of the patch serum levels take about 16 hours to drop to 50%. Transdermal fentanyl is effective and well tolerated in the management of cancer pain, but is generally less flexible than shorter-acting preparations. Although the 3 day duration of action is an important advantage for patients with stable opioid requirements it can complicate management of patients with unstable pain whose opioid requirements are fluctuating. There is some experimental and clinical evidence that transdermal fentanyl is associated with less constipation than morphine . ## Spinal (epidural or intrathecal) administration of opioid analgesics in combination with local anaesthetics or clonidine should be considered in patients who derive inadequate analgesia or suffer intolerable adverse effects despite the optimal use of systemic opioids and non-opioids b Spinal opioids (± a local anaesthetic or clonidine) are indicated in patients who have intolerable adverse effects with systemically administered opioids. The addition (by the epidural route) of a local anaesthetic may be particularly useful in managing movement-related, incident pain, and of clonidine for neuropathic pain.	None	https://www.nature.com/articles/6691680.pdf	An expert working group of the European Association for Palliative Care has revised and updated its guidelines on the use of morphine in the management of cancer pain. The revised recommendations presented here give guidance on the use of morphine and the alternative strong opioid analgesics which have been introduced in many parts of the world in recent years. Practical strategies for dealing with difficult situations are described presenting a consensus view where supporting evidence is lacking. The strength of the evidence on which each recommendation is based is indicated. © 2001 Cancer Research Campaign
483858a512a25b92d6140bd1498b51b871fef076	pubmed	Capillary blood sampling: national recommendations on behalf of the Croatian Society of Medical Biochemistry and Laboratory Medicine	Capillary blood sampling: national recommendations on behalf of the Croatian Society of Medical Biochemistry and Laboratory Medicine Capillary blood sampling is a medical procedure aimed at assisting in patient diagnosis, management and treatment, and is increasingly used worldwide, in part because of the increasing availability of point-of-care testing. It is also frequently used to obtain small blood volumes for laboratory testing because it minimizes pain. The capillary blood sampling procedure can influence the quality of the sample as well as the accuracy of test results, highlighting the need for immediate, widespread standardization. A recent nationwide survey of policies and practices related to capillary blood sampling in medical laboratories in Croatia has shown that capillary sampling procedures are not standardized and that only a small proportion of Croatian laboratories comply with guidelines from the Clinical Laboratory Standards Institute (CLSI) or the World Health Organization (WHO). The aim of this document is to provide recommendations for capillary blood sampling. This document has been produced by the Working Group for Capillary Blood Sampling within the Croatian Society of Medical Biochemistry and Laboratory Medicine. Our recommendations are based on existing available standards and recommendations (WHO Best Practices in Phlebotomy, CLSI GP42-A6 and CLSI C46-A2), which have been modified based on local logistical, cultural, legal and regulatory requirements. We hope that these recommendations will be a useful contribution to the standardization of capillary blood sampling in Croatia. # Introduction Capillary blood sampling, which refers to sampling blood from a puncture on the finger, heel or an earlobe, is increasingly common in medicine. It enjoys several advantages over venous blood sampling: it is less invasive, it requires smaller amounts of blood volume and it can be performed quickly and easily. This technique has become more and more popular, especially with the widespread use of point-of-care testing (POCT), which has become the fastest growing area in laboratory medicine [bib_ref] Contribution of industry to POCT implementation, Koumantakis [/bib_ref]. Obtaining blood by skin puncture instead of venipuncture can be especially important in pediatric patients in order to avoid the effects of blood volume reduction [bib_ref] Blood sample volumes in child health research: review of safe limits, Howiea [/bib_ref] and reduce the risk of anemia. Thus, 56% of all procedures in the neonatal unit are performed using capillary blood samples, making it the most frequent invasive procedure performed during the neonatal period [bib_ref] A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive..., Johnston [/bib_ref]. Skin puncture blood sampling is also recommended for adult patients with severe burns, those who are obese or older or anxious about sampling, those with a tendency toward thrombosis, those whose surface veins need to be spared for intravenous therapy, those with fragile or inaccessible veins, and those who self-test their blood, such as for glucose. If carried out incorrectly, capillary blood sampling can cause inaccurate test results, pain and tissue damage [bib_ref] Capillary blood sampling (heel pricks) in the neonatal period, Crabtree [/bib_ref]. In addition, the small volumes involved and the variability in sample quality based on puncture site and technique make capillary sampling particularly susceptible to errors during the pre-preanalytical phase, which are beyond the control of clinical laboratory personnel [bib_ref] Preanalytical quality improvement: in quality we trust, Lippi [/bib_ref] [bib_ref] The prevalence of preanalytical errors in Croatian ISO 15189 accredited laboratory, Simundic [/bib_ref]. This highlights the need for standardized procedures, yet capillary blood sampling procedures are not standardized in Croatia [bib_ref] Institutional practices and policies in acid-base testing: a self reported Croatian survey..., Dukić [/bib_ref] [bib_ref] Nationwide survey of policies and practices related to capillary blood sampling in..., Krleža [/bib_ref]. In this country, capillary sampling is performed mainly by nurses, laboratory technicians, and individuals with undergraduate degrees in laboratory medicine [bib_ref] Nationwide survey of policies and practices related to capillary blood sampling in..., Krleža [/bib_ref]. While these individuals have theoretical and practical qualifications for performing blood sampling procedures [bib_ref] Dokument Hrvatske komore medicinskih sestara . Zagreb: Alfacommerce d .o .o .;..., Šepec [/bib_ref] , most are not systematically taught Clinical Laboratory Standards Institute (CLSI) or the World Health Organization (WHO) standardized procedures for capillary sampling. A recent survey of medical laboratories in Croatia showed that 22% of laboratories do not provide their staff with written procedures and instructions for capillary blood sampling, and only 30% of laboratories provide written instructions for the order of draw for cases when multiple tubes with different additives are sampled [bib_ref] Nationwide survey of policies and practices related to capillary blood sampling in..., Krleža [/bib_ref]. This argues for the need to develop and promote standardized recommendations for medical staff across the country. These recommendations should be carefully elaborated based on medical evidence and provided in written form at every workstation. As a first step towards the development and promotion of standardized capillary sampling procedures, the Working Group for Capillary Blood Sampling within the Croatian Society of Medical Biochemistry and Laboratory Medicine has generated the following recommendations, based on thorough review of the relevant literature, particularly WHO Guidelines on Drawing Blood (13) and CLSI document GP42-A6 (formerly H04-A6) (3), from which some material was adapted by permission of the CLSI. These recommendations are intended primarily for laboratory staff who sample capillary blood, but they may also be useful for educating nurses and other medical professionals. ## Recommendations Recommendations on where to perform heel prick sampling were published by and continue to form part of the guidelines issued by the CLSI and WHO. Since then, various national and international professional and regulatory bodies have published standards and recommendations. The most relevant CLSI documents for capillary blood sampling are 'Procedures and Devices for the Collection of Diagnostic Capillary Blood Specimens' (GP42-A6), 'Blood Gas and pH Analysis and Related Measurements' (C46-A2)and 'WHO Guidelines on Drawing Blood: Best Practices in Phlebotomy' (13). Other standards and recommendations have been published as part of ISO standardsand in CLSI document POCT07-P. The American National Academy of Clinical Biochemistry has issued Laboratory Medicine Practice Guidelines for POCT and POCT-based diagnostics. Croatian standards for capillary blood sampling have been published by the Croatian Chamber of Medical Biochemists. Despite the existence of these various sets of recommendations, a recent nationwide survey of policies and practices related to capillary blood sampling in medical laboratories in Croatia has indicated low compliance with CLSI and WHO guidelines [bib_ref] Nationwide survey of policies and practices related to capillary blood sampling in..., Krleža [/bib_ref]. Therefore the Working Group for Capillary Blood Sampling felt the need to prepare the present recommendations. The aim of this document is to provide step-by-step recommendations for capillary blood sampling, as a first step towards developing and promoting standardized capillary sampling procedures in Croatia. The document is intended primarily for laboratory staff performing capillary blood sampling within medical biochemistry laboratories, but it may also help other medical and non-medical professionals who perform capillary sampling. These recommendations have been issued after a review of relevant literature on capillary sampling procedures, and they are based primarily on WHO Best Practices in Phlebotomy (2010) (13) and the following CLSI guidelines: 'Procedures and Devices for the Collection of Diagnostic Capillary Blood Specimens' (GP42-A6), 6th Edition of Approved The recommendations are presented with the steps of the sampling procedure first, followed by explanation and discussion of relevant literature. Sampling steps are summarized schematically in [fig_ref] Figure 7: Steps in the skin puncture technique [/fig_ref]. Item 24 contains recommendations about the limitations of capillary sampling. The draft of this document was sent to numerous national and international experts for their comments and document was corrected, following their valuable suggestions. The list of their comments and corresponding changes in the Annex is an integral part of this document. ## Recommendation 1: preparation of supplies for capillary blood sampling Before performing capillary blood sampling, every workstation should be fully equipped with the following materials [bib_ref] Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous..., Nikolac [/bib_ref] : - a written procedure for capillary blood sampling; - alcohol disinfectant (ethyl or isopropyl alcohol); - non-alcohol disinfectant (benzen) - lukewarm tap water; - test request form; - capillaries and microcontainers with various additives; - capillary blood sampling device (retractable incision device) with different blade lengths for different incision depths; - cotton pads; - gauze; - adhesive bandages or tape; - single-use gloves; and - container for disposal of used sampling devices after skin puncture. The workstation for capillary blood collection should preferably also include an automatic mixing device. For the analysis of gases in the blood samples of blood capillaries, additional materials are needed and will be prescribed by Croatian national recommendations on blood gases and acid-base balance. All supplies should be confirmed to be within the expiry date, and the blood sampling specialist should enjoy unhindered access to all necessary supplies. According to European Council Directive 2010/32/EU, all blood sampling devices must be engineered to adequate safety standards in order to minimize the risk of professional injury. ## Recommendation 2: hand disinfection To minimize risk of infection, all patients and all samples must be treated and handled using standard safety precautions. To avoid infection, Croatian national guidelines on hand hygiene in healthcare facilities should be followed. These guidelines recommend that workers sanitize their hands using warm water and soap or disinfection gels or foams immediately before their first contact with the patient. Similar recommendations can be found in CLSI and WHO guidelines on capillary sampling . ## Recommendation 3: approaching the patient The healthcare worker performing the skin puncture should identify him-or herself to the patient, establish communication, gain the patient's confidence and explain the procedure. The skin puncture procedure must not be conducted without the consent of the patient or accompanying person. In that case, the attending physician should be notified and this must be recorded according to facility policy. If the patient is a legal minor or is unable to communicate, the worker should obtain Recommendation for capillary blood sampling consent from the parent or accompanying person and explain the procedure to him or her (3). ## Recommendation 4: inspecting the test request form The test request form should be inspected as described in the Croatian national recommendations for venous blood sampling [bib_ref] Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous..., Nikolac [/bib_ref]. These national guidelines are in accordance with ISO 15189 standards on quality and competence. The request form should include the following information: - patient name, surname, gender, date of birth, contact details (address, telephone number) and unique identifier (health insurance number or personal identification number); - requesting physician's name, professional identifier code and contact details (address of primary healthcare provider or full name of hospital ward); - the specific tests requested; and - all clinically relevant information about the patient and his or her condition that may influence how the sampling is performed or how the results will be interpreted, such as whether the patient is scheduled for certain tests or therapies. ## Recommendation 5: identifying patients Failure to correctly identify the patient may lead to some serious diagnostic errors and affect patient management. Accurate patient identification is therefore a crucial step during blood sampling. International standards emphasize the use of at least two patient identifiers, which do not include the patient's room number or physical location, whenever "administering medications, blood, or blood components; when collecting blood samples and other specimens for clinical testing; and when providing treatments or procedures". Patient identification should be performed according to the following guidelines: - For accurate patient identification, at least two and preferably three patient identifiers are necessary. - The following patient data are recommended as appropriate patient identifiers: full patient name, date of birth, address or health insurance number in the case of outpatients. - Identification should be done by engaging the patient and asking open-ended questions such as: "Please state your name." and "Please state your date of birth." - The information obtained should be compared with the information on the request form. - Any discrepancies should be reported, recorded and resolved before sample collection. Barcode wristbands should be used if available because this type of identification significantly reduces misidentifications [bib_ref] Causes, consequences, detection, and prevention of identification errors in laboratory diagnostics, Lippi [/bib_ref] [bib_ref] Self reported routines and procedures for the extraanalytical phase of laboratory practice..., Bilić-Zulle [/bib_ref]. The options for correct patient identification can be limited in some cases, such as in unconscious or semi-conscious patients, young children, deaf or cognitively impaired patients or non-native speakers. In fact, capillary blood sampling often involves such patients because it is the recommended sampling method in pediatrics and for follow-up blood oxygenation testing of intensive care patients, many of whom are unconscious. In such cases, the patient should be identified with the assistance of the ward nurse, legal guardian, parent or accompanying person. The question should be phrased in an open-ended way, such as: "Please state the child's (or patient's) name" and "Please state the child's (or patient's) date of birth". The healthcare worker must not rely on a bed tag, crib card or charts placed on the bed, nearby tables or equipment. All data must match the data on the sampling request form, and the name of the person who helped verify the patient's identity must also be documented. ## Recommendation 6: verifying patient preparation for skin puncture Croatian national recommendations for venous blood sampling stipulate that laboratory staff should verify that the patient has been properly prepared for blood collection. The necessary preparations may depend on the specific tests requested [bib_ref] Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous..., Nikolac [/bib_ref]. The healthcare worker about to perform capillary blood sampling should verify whether the patient is undergoing any therapy or has any dietary restrictions or latex allergies (3). In certain situations, capillary sampling requires different patient preparation than venous sampling. For example, when capillary samples will be used to assess the effects of ventilatory changes or to assess pulmonary function, a ventilation 'steady state' is recommended. Detailed sampling recommendations in such cases will be a part of Croatian national recommendations on blood gases and acid-base balance. ## Recommendation 7: labeling the microcollection device for capillary blood collection Capillaries and microcontainers should be labelled with appropriate small labels [fig_ref] Figure 1a: Microcontainer labelled with a barcode [/fig_ref]. Whether the labelling is performed before or after sampling depends on the policy of the healthcare institution. It is recommended that microcontainers be labelled immediately after patient identification and verification of patient preparation for laboratory testing, but before skin puncture. If microcontainers are labelled after skin puncture, labelling should be performed immediately after blood collection, in front of the patient, while he or she is still sitting in front of the phlebotomist. Failure to follow these procedures increases the risk that the microcontainers will remain unlabelled [bib_ref] Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous..., Nikolac [/bib_ref]. The sample should be labelled with a barcode sticker, and the barcode number should be traceable to the following information in the Laboratory Informatics System (LIS): - patient's first and last names; - patient's date of birth; - laboratory identification number; - patient's health insurance number; - patient's address and telephone number; - the name of physician who requested capillary blood sampling; - requested laboratory tests; - method of collection (venipuncture or skin puncture); - time and date of sampling; and - Identification of the health professional making the skin puncture. The more information is printed on the microcontainers, the lower is the risk of incorrect patient identification. Thus, capillary specimens should be identified using at least two independent identifiers. In addition, the patient's first and last names and laboratory identification number must be present on the label [fig_ref] Figure 1c: A barcode containing at least two independent identifiers [/fig_ref]. The size of the barcode sticker depends on the type of microcollection device and the type of barcode reader on the analyzer. It is important that identifiers on the barcode sticker be clearly legible. If a laboratory does not have a LIS, and if labelling samples with a barcode sticker is impossible, the laboratory must establish its own uniform labelling system to ensure traceability to the patient information mentioned above. ## Recommendation 8: positioning the patient Skin puncture should be performed when the patient is sitting. Chairs should have arm holders to provide support and to prevent falls if the patient loses consciousness. In addition, the patient should not have any foreign objects in the mouth, such as chewing gum or a thermometer, during the skin puncture [bib_ref] Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous..., Nikolac [/bib_ref]. A pediatric patient should be immobilized with the parent's assistance [fig_ref] Figure 2: Recommended procedure for immobilizing a pediatric patient during capillary blood sampling [/fig_ref]. A parent should be asked to sit in the phlebotomy chair and to place the child in his or her lap. The parent should then position his or her own legs around the child's in a cross-legged pattern, immobilizing the child's legs. The parent should take his or her own arm opposite to that of the child's arm receiving the skin puncture, extend it across the child's chest and immobilize the child's free arm by tucking it under his or her own. The parent should use the hand on this arm to secure the elbow on the child's arm to receive the puncture, while using his or her other hand to secure the wrist on the child's arm to receive the puncture. The child's hand on the arm to be punctured should remain oriented with the palm facing downward (13). ## Recommendation 9: putting on gloves Gloves must be worn when performing skin puncture to minimize worker exposure to pathogens. The golden rule is that new gloves should be worn for every patient [bib_ref] Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous..., Nikolac [/bib_ref]. ## Recommendation 10: selecting the skin puncture site Recommended skin puncture sites are the finger for adult patients and older children and the heel for infants and younger children. In young children, whether the finger or heel is pricked de-pends on the child's weight and age, because the distance between skin surface and bone varies with age and body weight. Finger pricking is recommended for capillary sampling of children older than 6 months or children heavier than 10 kg, which corresponds to the average body weight of a 12-month-old. For younger children, puncturing the medial or lateral plantar surface of the heel is A parent should sit in the phlebotomy chair and place the child in his or her lap. For immobilizing the child's legs, parent should put own legs around the child's in a cross-legged pattern. The parent should take own arm opposite to that of the child's arm receiving the skin puncture, extend it across the child's chest and immobilize the child's free arm by tucking it under own. To secure the elbow on the child's arm to receive the puncture, the parent should use the same hand while using other hand to secure the wrist on the child's arm to receive the puncture. recommended. However, this site should not be pricked if the child has already begun to walk. In special situations, such as patients with extensive burns, capillary blood should be sampled from areas of preserved skin, regardless of recommendations. Ultimately, the choice of puncture site depends on the lancet/incision devices available, blade length and incision depth. ## Finger puncture The following rules apply when capillary blood sampling is performed from a finger: 1. The puncture must be on the palm-up surface of the distal segment (fingertip) of the middle or ring finger [fig_ref] Figure 3: Recommendations for finger pricking [/fig_ref]. 2. The puncture must be performed on the side of the fingertip where tissue depth is sufficient to prevent bone injury. 3. The puncture should be made across the fingerprint, not parallel to it [fig_ref] Figure 3: Recommendations for finger pricking [/fig_ref]. 4. Under no circumstances should capillary sampling be performed: a) on the smallest finger, because tissue depth is insufficient to prevent bone injury; b) on the thumb or index finger because these are more sensitive than other fingers and may have calluses or scars; c) on swollen or previously punctured sites, because the accumulated tissue fluid will contaminate the blood sample; d) on fingers of the hand where infusion is being performed; or e) on fingers on the side of the body where mastectomy has been performed. ## Heel puncture Preferred method for blood sampling in term neonates is venipuncture, since heel prick procedure is more painful, less efficient, consumes more time and requires more resampling [bib_ref] Venipuncture versus heel lance for blood sampling in term neonates, Shah [/bib_ref]. When performing heel prick in newborns, pain relief measures should be used, involving a mother whenever is possible. Measures include breastfeeding, skin-to-skin contact, swaddling com-bined with positioning neonates upright. Also, sucrose and non-nutritive sucking can be used to manage pain during the procedure [bib_ref] Guidelines for procedural pain in the newborn, Lago [/bib_ref] [bib_ref] Academy of Breastfeeding Medicine Protocol Committee . ABM clinical protocol #23: Non-pharmacologic..., Bunik [/bib_ref]. Local (EMLA cream) or pre-emptive analgesia (paracetamol) is not recommended as they are ineffective [bib_ref] A Systematic Review of Lidocaine-Prilocaine Cream (EMLA) in the Treatment of Acute..., Taddio [/bib_ref] [bib_ref] Randomized controlled trial of paracetamol for heel prick pain in neonates, Shah [/bib_ref]. The following rules apply when capillary sampling is performed on an infant's heel: 1. The medial or lateral plantar surface of the heel [fig_ref] Figure 4: Recommendations for heel pricking [/fig_ref] is the preferred puncture site for infants up to one year old, including premature newborns. In nearly all infants, the heel bone (calcaneus) is not located below the skin in this area, so the heel bone is protected from injury and related complications. 2. Skin puncture on the plantar surface of the heel must be performed at a depth of no more than 2.0 mm to prevent bone injury. This limit is based on the fact that the minimum distance between the skin and perichondrium is 2.4 mm on the plantar surface and 1.2 mm over the posterior surface; the vascular bed of the skin lies 0.35-1.6 mm below the skin surface of the heel (3,13,14,34). 3. Under no circumstances should capillary sampling be performed: a) on the posterior curved part of an infant's heel (red line, [fig_ref] Figure 3: Recommendations for finger pricking [/fig_ref] or the central area of the infant's heel (yellow area, [fig_ref] Figure 3: Recommendations for finger pricking [/fig_ref] because of greater risk of injury to nerves, tendons or cartilage due to the fact that the distance between the skin and perichondrium is 1.2 mm, only half the value in recommended puncture areas, or b) on swollen or previously punctured sites because the accumulated tissue fluid will contaminate the blood sample. ## Earlobe puncture Earlobe puncture is recommended for blood gas analysis and will be described in Croatian national recommendations for blood gases and acid-base balance. The earlobe is also used occasionally in sports medicine, such as for lactate monitoring, for mass screening and in research studies (13). Relevant recommendations for these specific contexts can be found in the specialized literature. ## Recommendation 11 . 1: selecting lancet length The recommended lancet length depends on whether the patient is a child or adult and on the depth of incision . Retractable incision devices are recommended because they minimize risk of patient and healthcare worker injury (3). Various retractable incision devices are available commercially, and they are designed to control the blade length and depth of incision. Healthcare institutions should consider using a retractable incision device with a blade slightly shorter than the recommended incision depth. This is because the pressure applied on the device during puncture results in an incision slightly deeper than the nominal blade length. For exam- ple, if the incision depth should be less than 2.4 mm in the case of older children and adults, the longest blade should be 2.2 mm (13). Regardless of the incision device selected, the incision depths in should be respected. In pediatric and neonatal patients, applying strong pressure to the incision device should be avoided in order to prevent the puncture from being deeper than necessary and thereby damaging bone or nerves. The major blood vessels of the skin are located 0.35-1.6 mm beneath the skin surface (3), and the distance between the skin surface and bone in a 3-kg baby is 3.2 mm on the medial or lateral heel (13). Therefore, punctures that are 2.0mm deep should penetrate the major skin vasculature without puncturing bone [bib_ref] Update of the EBF recommendation for the use of DBS in regulated..., Timmerman [/bib_ref]. The posterior heel and toe should be avoided as puncture sites because the distance between the skin surface and the bone in each case is only 2.33 or 2.19 mm, respectively, which means greater risk of bone damage (3,13). ## Recommendation 11 .2: selecting a microcollection device for capillary blood collection We recommend plastic microcollection devices for capillary blood specimens. Various microcollection devices are commercially available, and they are designed to control the volume of capillary blood and to contain different additives. Microcontainers with different additives usually bear color-coded caps similar to those on venous sampling tubes. The most appropriate microcollection device depends on the tests requested. The microcontainer or capillary must be filled with the correct volume of capillary blood to ensure the correct final blood-additive ratio. ## Recommendation 12: arterialization of the puncture site We recommend performing arterialization when the capillary blood sample will be used for blood gas analysis or when the puncture area (hand/finger or heel) is cold or circulation is poor. Arterialization increases the arterial blood flow at the puncture site and should always be performed when the capillary blood sample will be used to analyze pH and blood gases. The arterialization procedure involves covering the puncture site with a warm, moist towel or other warming device at a temperature of 42 °C or less for 3-5 min prior to puncture. This increases arterial blood flow to the puncture area up to 7-fold (3). Creams containing a hyperemic or vasodilatory agent can be used for arterialization. A warm, well-vascularized puncture area usually provides adequate sample volume without the need to apply pressure to the surrounding tissue. A survey of medical laboratories in Croatia suggests that 88% of laboratories never apply arterialization before capillary sampling [bib_ref] Nationwide survey of policies and practices related to capillary blood sampling in..., Krleža [/bib_ref]. ## Recommendation 13: cleansing the skin puncture site The skin puncture site must be properly cleansed using sterile cotton or gauze and disinfected with a 70% aqueous solution of isopropanol [bib_ref] Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous..., Nikolac [/bib_ref]. After these steps, the puncture area must be dried to allow the antiseptic to take effect and to prevent discomfort due to residual alcohol. Povidone iodine should not be used for capillary skin puncture (13) because it can contaminate blood and lead to inflated measurements of potassium, phosphorous or uric acid [bib_ref] Povidone-iodine ('Betadine') disinfectant as a source of error, Van Steirteghem [/bib_ref]. ## Recommendation 14: performing skin puncture The retractable incision device is placed upon the cleaned and disinfected skin surface at the puncture site. We recommend that the patient's hand be held firmly to prevent sudden movement. The incision should be made quickly and appropriately according to the manufacturer's instructions. A pediatric patient should be immobilized with the assistance of the parent or nurse as described in Recommendation 8. The child should be kept warm throughout the procedure, leaving only the extremity of the skin puncture area exposed. ## Recommendation 15: elimination of the first drop of capillary blood sampled It is crucial to wipe away the first drop of blood with clean gauze, which the healthcare worker should hold in his or her hand during sampling. This applies to all capillary sampling situations, except when the manufacturer of a POCT device specifically requires testing the first drop of blood, as is the case for some self-test glucometers (3). The first drop of blood contains interstitial and intracellular fluid that can contaminate the blood sample. ## Recommendation 16: capillary blood collection After a site is punctured and wiped, a second drop of blood forms. When the tip of the microcollection device touches the drop, blood flows into the microcollection device by capillary action or the gravity-flow principle, depending on the type of microcollection device [fig_ref] Figure 5: Recommended steps in capillary blood collection [/fig_ref]. Blood flow can be enhanced by holding the puncture site downwards and applying gentle pressure to the tissue near the puncture site. If blood flow stops during collection, gently tapping the microcontainer on a hard surface can move the blood to the bottom of the tube and restart capillary collection (3). Excessive massaging or squeezing of the puncture site should be avoided in order to prevent hemolysis, contamination of the blood with interstitial and intracellular fluid, and obstruction of blood flow. ## 16.1: order of draw in capillary blood collection When collecting more than one capillary blood samples, special attention must be paid to the order of draw, which differs from the standards for venipuncture. Multiple capillary blood samples should be collected in the following order (3) This order of draw is essential to minimize the effect of platelet clumping. If more than two capillary blood samples are needed, venipuncture should be requested because it may provide more accurate laboratory results (13). When blood is collected on filter paper in newborn screening programs, samples should be collected separately and from different puncture sites in order to prevent blood sample quality from being affected by clotting, smearing, contamination, scratching or abrading that can occur during capillary blood spotting. ## Recommendation 17: disposal of incision device for capillary blood collection Incision devices must be immediately discarded into a puncture-resistant container with a lid and a prominent biohazard label that satisfies local regulations. We recommend using only safety devices for capillary blood sampling. All disposable equipment used in skin puncture should be disposed of according to the manufacturers' recommendations. Suspected or confirmed injuries or contamination with patient blood should be handled according to institution policies [bib_ref] Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous..., Nikolac [/bib_ref]. ## Recommendation 18: filling, closure and mixing of microcollection device for capillary blood samples Capillaries and microcontainers for capillary blood collection should be filled with blood according to the manufacturer's recommendations. Underfilling can cause sample dilution in the case that the additive is a liquid anticoagulant, as well as changes in cellular morphology due to excess anticoagulant. Conversely, overfilling can cause clot formation due to insufficient anticoagulant. After sample collection, microcollection devices should be capped immediately to prevent exposure to the air, especially if the blood sample will be used for blood gas analysis. Capped samples should immediately be mixed to prevent clotting. The mixing procedure should follow the recommendations of the microcollection device manufacturer. In the case of blood gas analysis, mixing can be performed as follows: After the capillary has been filled, the capillary end that was submerged in the drop of blood should be closed with the end cap. A metal mixing bar is inserted into the tube, and the other end of the capillary is closed. The sample is mixed by moving the metal bar using a magnet. The magnet should be moved from one end of the capillary to the other five times (38) [fig_ref] Figure 6a: Capillary mixing. [/fig_ref]. [fig_ref] Figure 6b: Mixing of microcollection devices with adapter for capillary sampling [/fig_ref]. shows the mixing of microcontainer with adapter for capillary sampling. Number of inversion mixing depend of microcollection device manufacturer. Vigorous shaking should be avoided because it can cause hemolysis (3). ## Recommendation 19: bandaging the skin after capillary sampling After capillary blood collection and while mixing the tube, the healthcare worker should apply direct pressure to the wound with a clean gauze pad and he or she should slightly elevate the extremity. The person performing the collection, the patient or the accompanying person, should hold the pad on the puncture site for 30 sec to 1 min. After bleeding has stopped, a bandage can be applied to patients older than 2 years. Adhesive bandages are not recommended for children younger than 2 years because they can irritate the skin [bib_ref] Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous..., Nikolac [/bib_ref]. ## Recommendation 20: glove removal Before proceeding to the next patient, the healthcare worker should dispose of his or her gloves after capillary blood collection and then wash his or her hands in accordance with local regulations and procedures. ## Recommendation 21: recording relevant information during sampling Any nonconformity that occurs during skin puncture must be recorded according to standard laboratory procedures [bib_ref] Croatian Society of Medical Biochemistry and Laboratory Medicine: national recommendations for venous..., Nikolac [/bib_ref]. For example, excessive crying by babies can alter blood gas tests [bib_ref] Changes in arterial blood gas in crying neonates, Kim [/bib_ref] , leading to under-or overestimates of pO 2 and of oxygen saturation calculated from pO 2 [bib_ref] Evaluation of the newborn's blood gas status, Broullette [/bib_ref] , as well as to overestimates of glucose and lactate concentrations. Therefore such an event must be recorded on the laboratory test report (3) with a note, such as "Excessive crying during capillary blood sampling. Caution when interpreting pO 2 values." ## Recommendation 22: dry blood spot sampling Dried blood spots are widely used in many bioanalyses such as screening for inherited metabolic diseases, diagnosis and treatment of infectious diseases, therapeutic drug monitoring, and pharmacokinetics studies. Spot homogeneity affects accuracy, precision and analyte recovery. This homogeneity depends directly on hematocrit: blood with low hematocrit spreads more rapidly and to a greater extent over the paper surface. Spot homogeneity also depends on the type of spotting paper [bib_ref] Update of the EBF recommendation for the use of DBS in regulated..., Timmerman [/bib_ref]. After the capillary has been filled, a metal mixing bar is inserted into the tube before ends of the capillary are closed. The sample is mixed by moving the metal bar using a magnet. The magnet should be moved from one end of the capillary to the other five times. After microcontainer has been filled and adapter for capillary blood was removed, microcontainer have to be closed with device cup. Inversion mixing have be preformed acording manufacturer's instructions. The following procedure is recommended for collecting dry spot blood samples (43): 1. Clean the sampling site with lukewarm water. Avoid using alcohol-based skin cleansers on babies with immature skin (< 28 weeks), because they can cause burns and blisters [bib_ref] Alcohol burns in extremely low birthweight infants: still occurring, Reynolds [/bib_ref]. The sampling site should be completely dry before the sample is collected. The preferred sampling site in full-term and preterm infants is within the external and internal limits of the calcaneus. 2. Wash hands and put on gloves. 3. Use an automated, arch-shaped incision device to make a skin puncture to a depth of 2 mm or less. 4. Fill each circle on the blood spot card by allowing a single blood drop to flow naturally from the front to the back side of the card. Contact between the sampling site and the card must be avoided. 5. Air-dry the blood spot away from direct sunlight or heat. If necessary, perform a second puncture on the other foot or at a different place on the same foot. ## Recommendation 23: capillary blood sampling for non-medical personnel The preceding recommendations also apply to capillary blood sampling carried out by non-medical personnel using POCT instruments, which is the case for most diabetic patients who self-monitor blood glucose. We recommend that non-medical personnel use POCT instruments according to the manufacturer's instructions, especially since the sampling procedure may differ with the device, such as elimination of the first drop (see . ## Recommendation 24: minimizing the influence of the limitations of capillary blood sampling Capillary blood sampling is associated with several disadvantages, many of which can lead to greater risk of false test results. A capillary blood sample contains unknown proportions of blood from ven-ules, arterioles and capillaries. Capillary blood samples can also be contaminated to unknown extents by interstitial and intracellular fluid. In fact, capillary blood is often sampled into multiple microcollection devices at the same time and from the same puncture site in order to provide sufficient material for several analyses; the risk of contamination with interstitial or intracellular fluid increases as sampling is repeated. Such multiple sampling also increases the risk of hemolysis and clotting (13). Hemolysis and lipaemia, which can significantly alter blood analysis results, cannot be detected in whole-blood capillary samples because some analyses (e.g. POCT) can consume the entire sample. Hemolysis can occur in such samples due to strong and repetitive squeezing ('milking') of the puncture site, as well as vigorous sample mixing after collection (3). Milking poses particular dangers to assay reliability because it can cause not only hemolysis but also sample dilution with extracellular fluid. ## Recommendation 24.1: patients and laboratory tests for which capillary blood sampling is not recommended Capillary sampling is not recommended for dehydrated patients, patients with poor peripheral circulation or edematous patients (3). Capillary sampling is not recommended for coagulation analysis or erythrocyte sedimentation rate or for blood cultures [bib_ref] Capillary blood sampling (heel pricks) in the neonatal period, Crabtree [/bib_ref]. In all these cases, venous blood sampling is recommended. Erythrocyte sedimentation rate and blood cultures require large volumes of blood, making them inappropriate for capillary blood sampling. According to the Croatian Chamber of Medical Biochemists, capillary sampling is not appropriate for determination of erythrocyte sedimentation rate. Concentrations of potassium and calcium in capillary samples differ significantly from values in venous blood samples [bib_ref] On the composition of capillary and venous blood serum, Kupke [/bib_ref] [bib_ref] Simultaneously obtained skin-puncture plasma and venous serum compared and effects of warming..., Blumenfeld [/bib_ref] [bib_ref] Clinical chemical analyses of serum obtained from capillary versus venous blood, using..., Falch [/bib_ref] [bib_ref] Venous serum, capillary serum and capillary plasma compared for use in determination..., Haymond [/bib_ref]. Therefore, when accuracy is critical, the concentrations of these analytes in capillary blood should always be confirmed by venous blood sampling. ## Recommendation 24.2: requesting a venous or arterial blood sample instead of a capillary blood sample Venous blood samples or, if blood gases are requested, arterial blood samples are recommended instead of capillary blood samples when two attempts at capillary sampling fail to give a satisfactory sample, and when more than two microcollection devices for capillary blood are needed for the laboratory tests requested (13). If necessary, the puncture procedure can be repeated at another site using new equipment [bib_ref] Approved IFCC recommendations on whole blood sampling, transport and storage for simultaneous..., Burnett [/bib_ref]. ## Recommendation 24.3: rejection of capillary samples with clots in anticoagulant microcollection devices We recommend rejecting capillary samples with clots in anticoagulant microcollection devices. Healthcare workers should not attempt to remove the clot from the sample. Instead, capillary blood sampling should be repeated. Microclots in the specimen render it non-homogeneous, affecting the accuracy of analytical results, especially in hematological analysis. Erythrocyte lysis during clot formation can lead to falsely elevated potassium measurements made by blood gas analyzers that can also measure electrolytes. Clots can block the flowpath of the analyzer and give erroneous results or even render the analyzer inoperable. This highlights the need for thorough mixing of the blood specimen immediately upon collection in order to avoid clot formation. In addition, gentle mixing during collection can help prevent clotting, especially when capillary blood collection is difficult. ## Recommendation 24.4: differences in analyte concentrations between skin puncture and venipuncture samples Laboratory test results based on capillary blood samples should be clearly marked as such on the laboratory reports. Differences between venous and capillary blood analyte concentrations are generally minor, though clinically important differences have been reported in concentrations of glucose, potassium, total protein, calcium, electrolytes, lactate dehydrogenase and aspartate aminotransferase. Studies suggest that glucose levels are higher in capillary blood samples [bib_ref] On the composition of capillary and venous blood serum, Kupke [/bib_ref] [bib_ref] Simultaneously obtained skin-puncture plasma and venous serum compared and effects of warming..., Blumenfeld [/bib_ref] [bib_ref] Capillary versus venous bedside blood glucose estimation, Boyd [/bib_ref]. Glucose diffuses through the capillaries and is consumed by the cells, so the glucose concentration should be higher in arteries (which feed the capillaries) than in veins (where the capillaries drain). Potassium levels in capillary blood samples can be lower (47), higher [bib_ref] Clinical chemical analyses of serum obtained from capillary versus venous blood, using..., Falch [/bib_ref] or even similar [bib_ref] On the composition of capillary and venous blood serum, Kupke [/bib_ref] to those in venous blood samples. Levels of total proteins, calcium and electrolytes are lower in capillary blood samples [bib_ref] On the composition of capillary and venous blood serum, Kupke [/bib_ref] [bib_ref] Simultaneously obtained skin-puncture plasma and venous serum compared and effects of warming..., Blumenfeld [/bib_ref] [bib_ref] Clinical chemical analyses of serum obtained from capillary versus venous blood, using..., Falch [/bib_ref] , while levels of lactate dehydrogenase and aspartate aminotransferase are higher [bib_ref] Venous serum, capillary serum and capillary plasma compared for use in determination..., Haymond [/bib_ref]. While CLSI document GP42-A6 (3) reports no significant differences in hematological parameters between capillary and venous blood values, other studies have reported significant differences. Platelet counts are generally lower in capillary blood than in venous blood [bib_ref] Platelet counts in capillary blood, Feusner [/bib_ref]. Capillary values of hemoglobin (Hb), hematocrit (Htc), white blood cells count (WBC), red blood cells count (RBC), mean corpuscular volumen (MCV), mean corpuscular hemoglobin (MCH), are significantly higher than the corresponding venous values; whereas the capillary mean corpuscular hemoglobin concentration (MCHC) value is lower [bib_ref] Use of capillary blood count parameters in adults, Schalk [/bib_ref]. Blood smear is also one of the most frequently performed tests on capillary blood. Native drop or EDTA capillary blood from microconteiner can be used. There is no relevant literature data on the morphological differences between cells from capillary and venous blood sample. These differences highlight the need to compare analyte concentrations in capillary blood samples with reference values also from capillary blood. However, current practice is to compare capillary blood results against reference values for venous blood. We urge the clinical research community to establish true reference values for analytes determined in capillary blood samples. Until such reference intervals are available, we recommend that all laboratory findings from capillary blood samples be clearly marked as such. providing access to the CLSI guidelines on capillary sampling. The authors also thank Nora Nikolac, PhD and Prof. Ana-Maria Simundic, PhD for critical comments on the manuscript, as well as the reviewers for useful commentaries and sugges-tions. The authors are grateful to the CLSI for granting permission to use their internationally copyrighted material. ## Potential conflict of interest None declared. ## Reviewer comments Author responses REVIEWER 1 1. Structure of the paper. The manuscript comprises three main chapters: Introduction, Recommendations, and Limitations. In the Recommendation section, the different recommendations are numbered from 1 to 22, then there are three paragraphs (Dry blood spot sampling, Capillary blood sampling for POCT, Recommended capillary blood sampling procedures in specific situations and in the presence of complications) and then a section of Questions and Answers. For an easier reading, I suggest that these three paragraphs should be numbered (from 23 to 25) as they also contain Recommendations; furthermore I suggest including a heading for the Question and answering section. The section "Questions and Answers" replaced with Recommendations 21-24. ## 2. Pain control in newborns. In my opinion, the issue deserves more attention in the paper, since the heel pricks is a painful procedure. New text about pain control in newborns added to Section 10.2. 3. The flow chart indicated as "Steps in the skin puncture technique" is [fig_ref] Figure 7: Steps in the skin puncture technique [/fig_ref]. The flow chart indicated as "Steps in the skin puncture technique" correctly labeled as [fig_ref] Figure 7: Steps in the skin puncture technique [/fig_ref]. ## 4. In the text the word "level" is used to indicate the blood concentration of analytes; the term "concentration" is perhaps more appropriate. "Level" replaced with "concentration" throughout text. ## Reviewer 2 ## 5. Both CLSI and WHO documents should be referenced. CLSI and WHO documents now referenced. ## 6. Reference (8) is wrong because the paper of Blumenfeld has been referenced as 22. All the involved references must be modified accordingly, including the paper mentioned as ref. 8. All references checked, corrected when necessary and rearranged, including reference 8. ## 7. Even though it is self-explanatory (these are the recommendations and no other approach is admitted), it could be useful to stress that no other disinfectant rather than a volatile alcohol must be used to do not affect the capillary blood sampling. Suggestion accepted and point stressed in Recommendation 13. ## Appendix -expert reviewer comments and author responses . Lenicek Krleza J. et al. ## Recommendation for capillary blood sampling ## Reviewer comments author responses 8. Earlobe puncture. This approach is widely adopted in sports medicine to monitor lactate concentrations that may provide a guide to an optimal training intensity. Ideally, lactate concentrations should be measured during a training session and immediately reported to the athlete to ensure that the athlete is working at the desired intensity. In many sports (e.g. cycling, ski, climbing, rowing) earlobe is the only or most accessible site. This is probably outside the scope of the document. Otherwise it could be interesting to mention this specific field of utilization of the earlobe puncture. Text edited to mention this specific use of earlobe puncture in Recommendation 10.3. ## 9. Reference (8) on Dried Blood Spots is probably wrong, because I can't find any information on the topic discussed here. All references checked, corrected when necessary and rearranged, including reference 8. ## 10. Reference (26) on spuriously haemolysis induced by wipe alcohol is probably wrong here where Dried Blood Spots procedure is described. Please check. Reference 26 corrected. ## 11. Ref. 28 and 31 is the same, doubled. Please correct. All references checked, corrected when necessary and rearranged. ## 12. The same is for ref. 33 and 37, according to the same web address. Please check. All references checked, corrected when necessary and rearranged. ## 13. In the references, when web address is cited often the typo Acessed for Accessed is found. Please correct. Corrected. 14. In the references, some journal is cited with the full title instead of the official title abbreviation. Please check. References checked and all journal titles now cited using official abbreviations. ## Reviewer 3 ## 15. Certain parts of the text are shaded gray. The assumption is that these are the specific recommendations of the working group (WG) that have to be emphasized. Maybe authors should consider having these parts additionally marked as: Recommendation 1, Recommendation 2... Or entitle these for example as a Recommendation for the sample labelling…etc. to clarify to the readers that these are specific recommendations of this Society. Specific comments and suggestions: Text in the grey box. It is a little unclear whether this applies to every referral from or just to specific ones, because it is known that hospital referrals have no information for example about the patient's address but such data is possible to find in an electronic database associated with patients unique hospital number. The text in the grey box. Do the all laboratories have possibility of generating a bar code? Or perhaps do the authors thinking of a unique laboratory number which is associated with appropriate information's on patients? Is it number of insurance really necessary for labelling capillary tubes? Gray sections removed and reformatted as Recommendations. ## 16. Furthermore, in the individual sections it should be clearly emphasized what is the recommendation of the authors, or whether the authors for a particular procedure refer themselves to the guidelines that already exist in the literature. The Working Group's recommendation now clearly emphasized in all Recommendations. ## 17. My suggestion to the authors is harmonization of names and expressions in the recommendations. For example through the all manuscript authors use different terminology for the personnel involved in phlebotomy or capillary blood drawn: healthcare blood sampling specialist, laboratory technicians, sampling specialist, patient identifiers, healthcare professional, professional, healthcare worker, health worker, workers. To my opinion this should be harmonized. Terminology harmonized as "health worker" to refer to personnel involved in phlebotomy or capillary blood drawing. Lenicek Krleza J. et al. ## Recommendation for capillary blood sampling ## Reviewer comments author responses ## 18. Special attention should be given to the order of presentation of certain facts in the particular chapters which consequently indicate certain recommendation of the Working Group. I suggest to the authors to reorganize the paragraph. It would be better to start at first with the known facts (In Croatia, capillary sampling...) and the recent findings (...A recent survey of clinical labs...) and then make a conclusion on whether is procedure sufficiently standardized, and consequently the need for setting the guidelines. Text edited according to the reviewer's suggestions, and a new "Recommendations" section added. ## 19. To my opinion, despite grammatically correct language the quality of the presentation can be improved by using language that is more common in laboratory and in accordance with the writing of the documents (recommendations). Specific comments are listed below. The term "popularity of" should be replaced by growing use or widespread use of…; the term "How the sampling is performed" should be replaced by: The manner in which sampling is performed or the way the sampling is performed ....; instead with use within. Using the term that you felt the need for something is not common for this type of manuscripts and gives the reader into thinking weather authors at all are standing behind the recommendations. It would be better to use expressions like we want to apply the present recommendations or similar. Instead of accepts I suggest to the authors to state The Working Group for CBS suggests the same procedure that is specified in the Croatian national recommendations... or we support the procedure… Instead of parent use accompanying person or both I suggest instead of constituents to use blood components I suggest to rephrase the sentence into: A survey of medical facilities in Croatia revealed that… I suggest rephrasing the sentence as The above recommendations could be applied also to capillary blood sampling for POCT. I suggest changing expression of estimating coagulation with coagulation testing. More details given about previous studies on differences between venous and capillary analytical results. See also our response to Comment 38. ## Reviewer 5 ## 30 In Introduction, word "increasingly" is repeated in the same section twice (line two and line five). I would suggest using some of synonyms: more and more, progressively, to an increasing extent, even more. Text edited according to reviewer's suggestion. ## 31 In Acknowledgments there are typewrite mistakes. It is not clearly stated if there is one author or more authors. In first sentence it should stand: The authors are grateful (or: The author is grateful); Laboratory should be written with capital letter. In second sentence only one author thanks Nora Nikolac, and then in third sentence there is more than one author. Text corrected by a native-speaking English editor. ## 32 Reference 13 cannot be accessed on web page. All references checked, corrected when necessary and rearranged. ## 33 Reference 14 cannot be accessed on web page, probably because of typewrite mistake and there is also another typewrite mistake -word Acessed instead of Accessed. All references checked, corrected when necessary and rearranged. ## 34 Reference 14: Croatian Chamber of Medical Biochemists. Instructions for capillary blood sampling and capillary tubes. http://www.hkmb.hr/povjerenstva/strucna-pitanja.html. Acessed (accessed) January 15th 2015.) I corrected mistake and open web page but in my opinion it is not precise enough and I was not able to find anything about capillary blood sampling. I had also problems with web pages for references 24 and 25. Title in the reference corrected and URL confirmed. To obtain information on capillary blood sampling, the user should scroll down on the same page. ## Reviewer 6 ## 35 Could the authors give some introductory sentence about steps involved in capillary blood sampling before the first paragraph on page 3, line 19? Text edited according to reviewer's suggestion and presented in new "Recommendations" section. ## 36 The recommendations are very comprehensive, but can the authors provide a written shorter version, similar to what is shown in [fig_ref] Figure 7: Steps in the skin puncture technique [/fig_ref] : Steps in the skin puncture technique? This could be used at every sampling workstation. Such text added to the Introduction. ## Reviewer 7 ## 37 Blood smear is also one of the tests mostly performed on capillary blood and I suggest including it to the manuscript (fresh drop of patient's blood or EDTA blood from microteiner is recommended?). Blood smear is including in Recommendation 24.5. ## 38 Also, laboratory should not report the results of potassium and calcium from capillary blood except at the insistence of doctors after they meet with possible deviations. Document focuses on capillary blood sampling, not on post-analytical procedures. Lenicek Krleza J. et al. ## Recommendation for capillary blood sampling Reviewer comments Author responsesIn abstract, one sentence is little clumsy: "How the sampling is performed can influence the test results". For abstract, it would be more appropriate to write: "The way of capillary sampling can influence...".or "The manner in which sampling is performed can influence...". Abstract edited and rearranged based on reviewer's suggestion. ## Reviewer 8 ## 40 Expiry dates of all supplies -should they always be checked by the person performing the skin puncture (similar to the H04-A6 document) or may they be checked in other ways? Text edited according to reviewer's suggestion and source added. ## 41 Latex allergy check -is this still valid as most countries have abandoned Latex gloves? This recommendation retained because it forms part of international standards (refs. 3 and 13) and because we are unaware of reliable evidence for or against use of latex gloves. ## 42 A notation needed that labelled capillary blood collection tube and labelled capillary tube barcodes are congruent? Rendered unnecessary because of other changes. Keywords: I suggest to include the keyword: guideline. "Recommendations" added to keywords and all text because this document is recommendation for capillary blood sampling, not gudeline." 47 Recommendation 1.2: in my opinion the weight of the patient is more important than the age. Both criteria (age and weight) recommended. ## 48 A recommend to add a checklist of what to do. Checklist of capillary blood sampling presented as [fig_ref] Figure 7: Steps in the skin puncture technique [/fig_ref]. ## Reviewer 10 49 Page 4, first paragraph: in the additional material "automatic mixing device" should be added "Automatic mixing device" added as additional material in Recommendation 1. ## 50 "Identifying the patient"-shouldn´t be the wrist band mentioned? Text edited according to reviewer's suggestion and presented as Recommendation 5. ## 51 Page 12, paragraph 3, and point (b): the mistake in the text: "on the palm-up surface of fingertips (!!) because the distance between the skin surface and bone in the newborns varies from 1.2 to 2.2 mm, so typical lancet depth can easily injure the heel (!!) bone, and because finger (!!) puncture in newborns… Text edited and mistake removed. added to simplify data presentation. ## 52 Arterialization of the puncture site: Many authors support the use of dry heating of the puncture site (not moist towel) as the wet skin make the blood drop forming more difficult. We recommend cleansing the skin puncture site after arterialization. ## 53 "Bandaging the skin…": I suppose to use the term of "accompanying person" instead of "parent" "Accompanying person" used instead of "parent". ## 57 It is not always suitable to use these fingers because of calluses, scars in certain professions e.g. brick layers, farmers hence may need to indicate that need to go to the side of the finger where skin is thinner/softer or use of the small finger Point 4. a) In my experience the small finger in larger adults is perfectly fine. We prefer to retain our recommendations because they are consistent with all available literature; the fifth finger is not recommended for puncture because of the short distance between the skin surface and bone. ## 58 The incision should be made quickly and appropriately according to the manufacturer's instructions. Sentence edited. ## 59 Page 24: Line 39: 2. excessive "milking" of the puncture site. Sentence edited. ## 60 Page 26 Line 24: The authors are grateful …. Text corrected by native English-speaking editor. ## Reviewer 12 ## 61 I think the paragraph considering who should NOT have performed capillary sampling ought to be placed earlier in the paper? We prefer not to make statements about who cannot perform capillary blood sampling, since available standards and regulations stipulate only who can perform such sampling. ## 62 The limitations would be better presented in a We prefer to present this information within the text. [fig] Figure 1a: Microcontainer labelled with a barcode. [/fig] [fig] Figure 1b: Capillary labelled with a barcode. [/fig] [fig] Figure 1c: A barcode containing at least two independent identifiers. The patient's first and last names and laboratory identification number must be present on the label. [/fig] [fig] Figure 2: Recommended procedure for immobilizing a pediatric patient during capillary blood sampling. [/fig] [fig] Figure 3: Recommendations for finger pricking.The puncture must be on the palm-up surface of the distal segment (fingertip) of the middle or ring finger (a). The puncture should be made across the fingerprint, not parallel to it (b). [/fig] [fig] Figure 4: Recommendations for heel pricking.The lateral limits of the calcaneus are marked by a line extending posteriorly from a point between the 4th and 5th toes and running parallel to the lateral aspect of the heel, as well as by a line extending posteriorly from the middle of the big toe and running parallel to the medial aspect of the heel. The light blue area indicates the recommended puncture site. The red and yellow areas indicate where puncture must not be performed. [/fig] [fig] Figure 5: Recommended steps in capillary blood collection.After site puncture, wiping and elimination of the first drop, a second drop of blood forms. The healthcare worker touches the tip of the microcollection device to the drop, and blood flows by capillary action when microcollection device is capillaries (or if microcontainer have adapter for capillary sampling) or the gravity-flow principle for microcollection device without adapter. [/fig] [fig] Figure 6a: Capillary mixing. [/fig] [fig] Figure 6b: Mixing of microcollection devices with adapter for capillary sampling. [/fig] [fig] Figure 7: Steps in the skin puncture technique. [/fig]	None	https://www.biochemia-medica.com/assets/images/upload/xml_tif/bm-25-335.pdf	Capillary blood sampling is a medical procedure aimed at assisting in patient diagnosis, management and treatment, and is increasingly used worldwide, in part because of the increasing availability of point-of-care testing. It is also frequently used to obtain small blood volumes for laboratory testing because it minimizes pain. The capillary blood sampling procedure can influence the quality of the sample as well as the accuracy of test results, highlighting the need for immediate, widespread standardization. A recent nationwide survey of policies and practices related to capillary blood sampling in medical laboratories in Croatia has shown that capillary sampling procedures are not standardized and that only a small proportion of Croatian laboratories comply with guidelines from the Clinical Laboratory Standards Institute (CLSI) or the World Health Organization (WHO). The aim of this document is to provide recommendations for capillary blood sampling. This document has been produced by the Working Group for Capillary Blood Sampling within the Croatian Society of Medical Biochemistry and Laboratory Medicine. Our recommendations are based on existing available standards and recommendations (WHO Best Practices in Phlebotomy, CLSI GP42-A6 and CLSI C46-A2), which have been modified based on local logistical, cultural, legal and regulatory requirements. We hope that these recommendations will be a useful contribution to the standardization of capillary blood sampling in Croatia.
92891283066e216dd94ff8a8f5ea23193f9de3f2	pubmed	Detection and diagnosis of periodontal conditions amenable to prevention	Detection and diagnosis of periodontal conditions amenable to prevention Gingivitis and chronic periodontitis are highly prevalent chronic inflammatory diseases. Gingivitis affects the majority of people, and advanced periodontitis is estimated to affect 5-15% of adults. # Introduction Periodontal diseases are highly prevalent chronic inflammatory conditions that affect the supporting tissues of the teeth. In broad terms, and of most relevance to the global community, these include gingivitis (i.e. plaqueinduced gingivitis) and chronic periodontitis. This paper will review the methods for detection and diagnosis of gingivitis and chronic periodontitis, these being periodontal lesions that are amenable to prevention, and will take the form of a narrative review. ## Pathogenesis of periodontal conditions Gingivitis and chronic periodontitis are highly prevalent, chronic inflammatory conditions. The last 40-50 years have witnessed a transformation in our understanding of the pathogenesis of these common conditions. The role of bacterial plaque in initiating gingival inflammation is unquestioned, and was first demonstrated in experimental gingivitis studies in the 1960s [bib_ref] Experimental gingivitis in man, Loe [/bib_ref]. Much of the 1960s and 1970s were dominated by treatment concepts that focussed exclusively on removal of calculus and "necrotic" root cementum that was believed to be infected by bacterial toxins such as lipopolysaccharide (LPS). However, ongoing research in the 1980s and 1990s resulted in increasing awareness of the importance of the inflammatory host response as an important determinant of risk for disease [bib_ref] The use of crevicular fluid prostaglandin E 2 levels as a predictor..., Offenbacher [/bib_ref] [bib_ref] Advances in the pathogenesis of periodontitis: summary of developments, clinical implications and..., Page [/bib_ref]. As technological advances have been made in the fields of microbiology, immunology and inflammation, we now recognise that inflammation is at the heart of the destructive responses that lead to the tissue breakdown that we recognise clinically as gingivitis and periodontitis. Accumulation of plaque bacteria in the subgingival environment results in diffusion of bacterial products and toxins across the junctional epithelium into the host tissues. As a result, the host mounts an immune-inflammatory response that is characterised by a complex network of cellular and molecular interactions in the host tissues. The complexities of these interactions have been described in detail [bib_ref] Host-response: understanding the cellular and molecular mechanisms of host-microbial interactionsconsensus of the..., Kinane [/bib_ref] [bib_ref] How has research into cytokine interactions and their role in driving immune..., Preshaw [/bib_ref] and our understanding of these mechanisms is likely to change and evolve with further research and technological innovations. The underlying principle is that the immune/inflammatory response to the subgingival biofilm varies greatly between individuals, and is controlled at a number of regulatory (e.g. pro-and anti-inflammatory cytokines, feedback loops), genetic, and epigenetic levels. Inflammation is intended to defend the host against the bacterial challenge, but prolonged and/or excessive inflammation results in tissue damage. Periodontal disease is now regarded as a non-resolving chronic inflammation that is initiated and perpetuated by the subgingival bacteria, but which is ineffective in removing the bacteria, and which, over time, leads to the tissue damage that we recognise as periodontitis [bib_ref] Periodontal diagnosis and treatment -where does the future lie, Chapple [/bib_ref] [bib_ref] Inflammation and periodontal diseases: a reappraisal, Van Dyke [/bib_ref]. It is important to note that gingivitis is a reversible condition, if the inflammation can be controlled. This normally is achieved by improving oral hygiene and reducing the bacterial biofilm [bib_ref] Oral hygiene in the prevention of caries and periodontal disease, Loe [/bib_ref] [bib_ref] A systematic review of the effectiveness of self-performed mechanical plaque removal in..., Van Der Weijden [/bib_ref]. If the biofilm is not controlled, gingivitis will persist, and in some patients, may progress to periodontitis [bib_ref] Mapping the pathogenesis of periodontitis: a new look, Kornman [/bib_ref]. Periodontitis is differentiated from gingivitis by the progressive breakdown of periodontal ligament fibres ("loss of attachment") resulting in increased probing depths, and resorption of alveolar bone, and the tissue damage that occurs is largely irreversible. Our current understanding of periodontitis pathogenesis is that susceptibility to disease ("disease" being the clinical manifestations that result from the persisting inflammation and tissue breakdown) appears to be largely determined by the nature of the inflammatory host response. In the classic experimental gingivitis studies of the 1960s, it was noted that inflammation developed more rapidly in some individuals as compared to others, even though plaque accumulation was similar [bib_ref] Experimental gingivitis in man, Loe [/bib_ref]. More recently, carefully controlled experimental gingivitis studies have revealed the same finding, namely that the intensity of gingival inflammation varies widely between individuals following plaque accumulation, suggesting that susceptibility to disease varies between individuals due to differences in the inflammatory host response [bib_ref] Modulation of clinical expression of plaque-induced gingivitis. II. Identification of "high-responder" and..., Trombelli [/bib_ref] , rather than being entirely due to differences in the amount and/or composition of the bacterial plaque. The importance of the host response in determining susceptibility to chronic periodontitis was clearly documented in carefully conducted longitudinal observational studies of tea plantation workers in Sri Lanka. These individuals had no access to dental care, did not routinely use conventional oral hygiene products, and presented with generalised plaque and calculus deposits. Yet, within this population, around 11% were considered to be stable, with no evidence of progression of periodontitis, another group (81%) demonstrated moderate progression of periodontitis, and 8% showed rapid disease progression [bib_ref] Natural history of periodontal disease in man. Rapid, moderate and no loss..., Loe [/bib_ref]. Longitudinal studies of patients on long term periodontal maintenance programs have also reported that a small subgroup of patients appear to be particularly susceptible to disease, with periodontitis progression occurring despite ongoing maintenance care [bib_ref] A long-term survey of tooth loss in 600 treated periodontal patients, Hirschfeld [/bib_ref] [bib_ref] Tooth loss in 100 treated patients with periodontal disease. A long-term study, Mcfall [/bib_ref]. ## Prevalence of periodontal conditions Plaque-induced inflammatory periodontal conditions are highly prevalent. However, prevalence estimates for periodontitis have changed greatly over the years, as a result of changes in the methods used to detect the presence of disease in epidemiological studies [bib_ref] Recording and surveillance systems for periodontal diseases, Beltran-Aguilar [/bib_ref]. Thus, in the 1950s and 1960s, the use of periodontal indices such as the Russell Index (which assumed continuity between gingival and periodontal inflammation) resulted in the presumption that periodontal diseases were virtually ubiquitous, with a sense of inevitability that all adults would develop periodontitis [bib_ref] Global periodontal disease epidemiology, Dye [/bib_ref]. However, more recent research has suggested that, while gingivitis and mild periodontitis are highly prevalent, advanced periodontitis is not quite as prevalent as previously perceived [bib_ref] Global periodontal disease epidemiology, Dye [/bib_ref]. Many epidemiological studies have used the CPITN (Community Periodontal Index of Treatment Need) [bib_ref] Development of the World Health Organisation (WHO) community periodontal index of treatment..., Ainamo [/bib_ref] to identify periodontitis. This method has the advantages of being quick and easy to perform, as well as being understood and used throughout the world. On the other hand, limitations include that it assesses probing depth only, and does not provide any information on loss of attachment. Furthermore, it only records the most severe score in each sextant (and therefore does not provide full information about disease extent and severity in advanced cases) [bib_ref] CPITN and the epidemiology of periodontal disease, Baelum [/bib_ref]. Inherent to the originally described CPITN scoring system was a link between CPITN score and treatment requirement; however, this link is somewhat questionable, and more recent iterations of the scoring system have renamed it as the CPI (Community Periodontal Index), with removal of the "treatment needs" component [bib_ref] Recording and surveillance systems for periodontal diseases, Beltran-Aguilar [/bib_ref]. Adaptations of the CPI (or CPITN) have also been provided by the American Dental Association and American Academy of Periodontology (the "Periodontal Screening Record", PSR), and the British Society of Periodontology (the "Basic Periodontal Examination", BPE) [bib_ref] Assessment of periodontal status with PSR and traditional clinical periodontal examination, Khocht [/bib_ref] [bib_ref] Policy for periodontal care, Smales [/bib_ref] [fig_ref] Table 1: Basic Periodontal Examination [/fig_ref]. A methodological concern in periodontal epidemiology is whether to use partial mouth or full mouth recordings of periodontal status. Clearly, partial mouth recordings are quicker to undertake than full mouth recordings, and this may be important when screening a large number of individuals. However, it is well recognised that partial mouth recordings result in underestimation of the prevalence of disease [bib_ref] Influence of CPITN partial recordings on estimates of prevalence and severity of..., Baelum [/bib_ref] [bib_ref] Effect of partial recording protocols on estimates of prevalence of periodontal disease, Susin [/bib_ref] [bib_ref] Accuracy of NHANES periodontal examination protocols, Eke [/bib_ref] [bib_ref] Effect of partial recording protocols on severity estimates of periodontal disease, Kingman [/bib_ref]. Accordingly, it has been noted that the CPI results in an underestimation of periodontal disease prevalence, though, on the other hand, it has been recognised as being well suited for identifying individuals who are (and who continue to be) periodontally healthy [bib_ref] Influence of CPITN partial recordings on estimates of prevalence and severity of..., Baelum [/bib_ref]. A major consideration is the case definitions that are used to denote a patient as a periodontitis case. Clearly, the calculated prevalence of periodontitis is fundamentally dependent on the case definition used to assign the diagnosis of periodontitis [bib_ref] Definitions of periodontal disease in research, Preshaw [/bib_ref]. Case definitions for periodontitis to be used in epidemiological studies have been proposed [fig_ref] Table 2: Case definitions for denoting periodontitis in epidemiological studies [/fig_ref] [bib_ref] Case definitions for use in population-based surveillance of periodontitis, Page [/bib_ref] [bib_ref] Advances in the progression of periodontitis and proposal of definitions of a..., Tonetti [/bib_ref] [bib_ref] Update of the case definitions for population-based surveillance of periodontitis, Eke [/bib_ref]. Clearly, while it is important to define the criteria for assigning a case of periodontitis in epidemiological studies, more comprehensive information is likely to be required by clinicians when assessing the presence, extent and severity of periodontitis in their individual patients. When taking into consideration the large number of national studies of periodontal epidemiology that have been conducted [bib_ref] Global periodontal disease epidemiology, Dye [/bib_ref] , and bearing in mind the different methodological techniques and case definitions used to define a case of periodontitis, it is generally estimated that 5-15% of adults in populations that have been studied have severe chronic periodontitis (as evidenced by having, for example, at least one periodontal pocket of ≥ 6 mm) [bib_ref] Global periodontal disease epidemiology, Dye [/bib_ref]. Prevalence estimates for moderate periodontitis (e.g. maximum probing depths of 4-6 mm) are less precise, but are probably within the range of 30-50% of adults [bib_ref] Global periodontal disease epidemiology, Dye [/bib_ref]. There is a shortage of precise data regarding the prevalence of gingivitis, which is generally considered to be very high, probably affecting the great majority (e.g. >75%) of people. A major limitation in our current understanding is that we do not have the ability to be able to recognise which sites with gingivitis will progress to periodontitis, or, which sites with periodontitis will progress further. Whereas it may be feasible to conduct studies in experimental animals to study the transition from gingivitis to periodontitis, ethical concerns preclude the same sorts of experiments from being performed in humans. Furthermore, it has also been demonstrated (in experimental animals) that even longstanding gingivitis does not necessarily progress to periodontitis [bib_ref] Plaque induced periodontal disease in beagle dogs. A 4-year clinical, roentgenographical and..., Lindhe [/bib_ref]. It is also not possible to determine, with accuracy, which sites are undergoing progressive tissue breakdown. Instead, we rely on detecting the signs of previously occurring tissue damage, through the use of periodontal probes (to detect loss of attachment and increased probing depths) and radiographs (to detect the historical occurrence of alveolar bone destruction). ## Risk assessment It is well recognised that a number of environmental exposures significantly increase the risk for periodontitis. Preeminent among these are smoking and diabetes. Smoking has long been recognised as a risk factor for periodontitis, with a 1.4 to five-fold increased relative risk for periodontitis among smokers compared to 4 Probing depth >5.5 mm (black band entirely within the pocket, indicating pocket of 6 mm or more) ## * furcation involvement Note: both the number and the * should be recorded if a furcation is detected -e.g. the score for a sextant could be 3* (e.g. indicating probing depth 3.5-5.5 mm plus furcation involvement in the sextant). The highest score is recorded for each sextant. [bib_ref] Case definitions for use in population-based surveillance of periodontitis, Page [/bib_ref] [bib_ref] Update of the case definitions for population-based surveillance of periodontitis, Eke [/bib_ref] Mild periodontitis Two or more interproximal sites with attachment loss ≥ 3 mm and two or more interproximal sites with probing depths ≥ 4 mm, not on the same tooth, or one site with probing depth ≥ 5 mm ## Moderate periodontitis Two or more interproximal sites with attachment loss ≥ 4 mm, not on the same tooth, or two or more interproximal sites with probing depths ≥ 5 mm, not on the same tooth Severe periodontitis Two or more interproximal sites with attachment loss ≥ 6 mm, not on the same tooth, and one or more interproximal sites with probing depth ≥ 5 mm non-smokers [bib_ref] Oral health risks of tobacco use and effects of cessation, Warnakulasuriya [/bib_ref]. It has also been reported, based on data from the National Health and Nutrition Examination Survey III (NHANES III) conducted between 1988 and 1994, that smoking (current smoking or former smoking) may be responsible for approximately half of periodontitis cases among adults in the United States, with the implication being that a large proportion of chronic periodontitis cases may be preventable through prevention and cessation of smoking [bib_ref] Smoking-attributable periodontitis in the United States: findings from NHANES III. National Health..., Tomar [/bib_ref]. In support of this, smoking cessation has been associated with improved outcomes of periodontal therapy [bib_ref] Effects of smoking cessation on the outcomes of non-surgical periodontal therapy: a..., Chambrone [/bib_ref] , and should form a central component of the periodontal management of all smoking patients, including patients with and without periodontitis. Diabetes is also recognised as a major risk factor for periodontitis, with poorly controlled diabetes increasing the risk for periodontitis approximately 3-fold [bib_ref] Periodontitis and diabetes: a two-way relationship, Preshaw [/bib_ref]. The precise mechanisms by which diabetes increases the risk for periodontitis are not yet fully characterised, but almost certainly relate to modified inflammatory and immune mechanisms which increase the susceptibility to the condition [bib_ref] A review of the evidence for pathogenic mechanisms that may link periodontitis..., Taylor [/bib_ref]. The level of glycaemic control is important in determining risk; thus, people with well controlled diabetes are at minimal/no increased risk for periodontitis compared to those who do not have diabetes, whereas people with poorly controlled diabetes are at much greater risk [bib_ref] Periodontitis and diabetes: a two-way relationship, Preshaw [/bib_ref]. Given the importance of factors such as smoking and diabetes in risk for periodontitis, assessing risk should form a standard component of periodontal assessment. This is undertaken as part of the history and examination, and every effort should be made to reduce or eliminate risk factors as part of periodontal therapy. A systematic approach should be employed when obtaining the history from the patient. With regards to the main systemic risk factors of smoking and diabetes, some key questions to be asked include: - do you smoke, if so, for how many years, and how many cigarettes per day? - if you previously smoked, when did you quit? And, before then, for how many years did you smoke, and approximately how many cigarettes per day? - with regards to your diabetes, how would you rate your level of diabetes control (e.g. good/poor)? Do you know your most recent HbA1c (glycated haemoglobin) measurements? In the case of a patient with poorly controlled diabetes and advanced periodontitis, it may also be useful to liaise with the patient's medical clinician so that they can also emphasise the importance of improving periodontal health (and also of maximising glycaemic control) as part of overall management. To summarise current knowledge, it is known that the accumulation of the subgingival biofilm results in a cascade of immune and inflammatory responses which leads to development of gingivitis, and in some cases, periodontitis. The onset and rate of progression of periodontitis vary greatly from person to person, and multiple factors (microbiological, environmental, immune and inflammatory) interact to determine individual susceptibility to disease. Examination of a patient with periodontitis must, therefore, not only focus on detailed assessment of the clinical condition, but must also include assessment of risk for disease. ## Detection of periodontal conditions Detection of periodontal conditions is complex and requires a high degree of skill, both as a communicator to understand the patient's problems, and as a clinical operator to detect disease. Key factors of the clinical examination will now be described. ## Clinical examination and periodontal probing The examination of the gingival and periodontal tissues should occur in a logical sequence. Most operators begin with a visual inspection of the gingival tissues to assess (somewhat subjectively) the presence or absence of gingival inflammation (by assessing the colour and degree of swelling of the tissues) as well as an initial assessment of the level of oral hygiene (assessing plaque and calculus levels). Following this, assessment of probing depths occurs. The first decision to make is the choice of periodontal probe. For epidemiological studies, the World Health Organisation (WHO) Community Periodontal Index (CPI) probe may be used, to assign a score to each sextant, dependant on the most affected site (as shown in [fig_ref] Table 1: Basic Periodontal Examination [/fig_ref]. The WHO CPI probe is specifically designed for this purpose, with a 0.5 mm ball tip (to minimise penetration of the probe into the soft tissues and also to help in the detection of calculus), a black band between 3.5 and 5.5 mm, and rings at 8.5 and 11.5 mm. However, for the individual patient in clinical practice, more detailed information may be required, particularly for patients with periodontitis, so that the precise probing depths throughout the dentition are recorded. A variety of periodontal probes are available for this purpose, including manual probes (e.g. Williams, UNC PCP-15) or computerized periodontal probes (e.g. Florida probe). On the other hand, recording a full periodontal charting for periodontally healthy patients at every visit would be excessively time consuming and laborious, and may even deter patients from attending the dentist. Recommendations regarding periodontal probing are given in [fig_ref] Table 3: Recommendations for assessment of periodontal status by means of periodontal probing WHO... [/fig_ref] , according to (in broad terms) the type of patient that is being assessed. The probing force that is used during the clinical examination clearly has the potential to influence the recorded measurements, as does the degree of inflammation in the gingival and periodontal tissues. In general terms, in the presence of inflammation, the probe tip penetrates the base of the junctional epithelium, leading to an overestimation of pocket depth, whereas in the absence of inflammation, the probe tip does not reach the base of the junctional epithelium. For this reason, it is important to note that the measured probing depth does not equate exactly to the true pocket depth, and for this reason, the term "probing depth" (or "probing pocket depth") should be used (as opposed to "pocket depth"). With regards to the optimal probing force, this should be selected to achieve a measurement of probing depth that is as accurate as possible (i.e. not significantly over-or under-estimating pocket depth) while also being as comfortable as possible for the patient (recognising that inflamed tissues in which the probe penetrates the junctional epithelium are more likely to be painful on probing compared with noninflamed tissues). It is generally recognised that around 0.20-0.25 N is the optimal probing force (equivalent to approximately 20-25 g). However, for the clinician, it is difficult to assess this amount of force, which has been described alternatively as the pressure required to blanch the tissues when the probe point is placed under the thumbnail, or, as the pressure required to depress the skin on the pad of the thumb by about 1 mm. When undertaking a screening evaluation using CPI/ BPE/PSR, a systematic approach should be adopted, and each sextant should be fully assessed before moving on to the next sextant. There is no right or wrong sequence of probing; the main issue is to be systematic so that no areas are missed. Some practitioners follow a sequence as follows: upper right, upper anterior, upper left, lower left, lower anterior, lower right. Others may prefer to go from right to left on all passes. When recording full mouth periodontal probing depths (in the case of a patient with periodontitis), a systematic approach is again used. A common approach is as follows: Probing depth measurements are recorded at 6 sites per tooth (mesio-buccal, mid-buccal, disto-buccal, mesio-palatal, mid-palatal, disto-palatal). Bleeding on probing (BOP) should also be recorded as present or absent at each site following probing, and provides (somewhat limited) information about the level of inflammation in the periodontal tissues. Whereas presence of BOP at isolated sites is not a particularly good indicator of "active" inflammation or risk of disease progression [bib_ref] Siegrist BE: Bleeding on probing. A predictor for the progression of periodontal..., Lang [/bib_ref] , absence of BOP is a reasonably good indicator of periodontal health and tissue stability [bib_ref] Periodontal disease diagnosis: current status and future developments, Chapple [/bib_ref] [bib_ref] Absence of bleeding on probing. An indicator of periodontal stability, Lang [/bib_ref]. On the other hand, persistent BOP at sites that also demonstrate increasing probing depths is a strong indicator of risk for future progression of disease [bib_ref] Diagnostic predictability of scores of plaque, bleeding, suppuration and probing depth for..., Claffey [/bib_ref]. Furthermore, in patients undergoing periodontal maintenance care, persistent bleeding on probing at successive maintenance visits is a strong indicator of risk for ongoing disease progression [bib_ref] Clinical course of chronic periodontitis. I. Role of gingivitis, Schatzle [/bib_ref]. ## Radiographic assessment For patients with evidence of periodontitis, radiographic assessment is essential to provide information regarding the pattern and extent of alveolar bone loss. Guidance is provided by relevant authorities in different countries around the world, and for the purpose of this paper, the guidance issued by the Faculty of General Dental Practice (UK) will be described. In broad terms, the use of radiography is driven by, and is secondary to, the results of the clinical examination. Recommendations adapted from those provided by the FGDP are presented in . Every effort should be made to minimise radiation dose. Therefore, available radiographs that have been taken for other purposes (e.g. caries diagnosis) should be utilised, if possible, to aid in the assessment of alveolar bone levels. Paralleling techniques should be used for intraoral periapicals, and attempts made to position sequential radiographs reproducibly over time to allow for better detection of changes in alveolar bone levels that may occur. There is no clear evidence to support any recommendations regarding the frequency of radiographs taken for periodontal assessment, other than to say that decisions regarding radiographs should be driven by the clinical findings. Thus, in a patient with a past history of periodontitis that has been treated and stabilised, and who is now in the maintenance phase of periodontal care, if there is no evidence of disease progression (e.g. as evidenced by increasing probing depths), then there is no indication to take further radiographs for periodontal assessment. Regarding radiation dose, this appears to be less (when using modern panoramic machines) with a panoramic radiograph plus a small number of supplementary periapical radiographs (taken according to the clinical situation), compared to a full-mouth series of periapical radiographs. Furthermore, with modern panoramic machines, image quality is such that no additional periapical radiographs may be required. For these reasons, there is a trend to move away from exposing full mouth series of periapical images. Therefore, when using . Recommendations for radiographic assessment of periodontal status* ## Scenario recommendation Patient in whom clinical examination indicates that it would be useful to assess all their teeth and their periodontal support Full assessment of all teeth and alveolar bone status can be achieved by: -an optimal quality panoramic radiograph alone -an optimal quality panoramic radiograph with supplementary periapical radiographs depending on the clinical situation -a complete series of periapical radiographs When determining which technique to use, consider the clinical situation, the required image quality, and the relative dose-benefit based on the radiographic equipment available. Suspected periodontal/endodontic lesion A periapical radiograph is indicated. ## Specific periodontal scenario:patient with generalised probing depths of ≤ 3-4 mm This level of probing depth is generally indicative of periodontal health. Radiographs are usually not indicated to routinely assess alveolar bone status in this situation. Specific periodontal scenario: patient with generalised probing depths of ≈ 4-5 mm (e.g. CPI/BPE/PSR scores of code 3) This level of probing depth is generally indicative of mild/moderate periodontitis. Alveolar bone levels may be adequately assessed by horizontal bitewings taken for routine caries assessment, supplemented by intraoral periapicals for selected teeth depending on the clinical situation. Alternatively, full assessment of all teeth and alveolar bone status may be undertaken as described above, if clinically indicated. Specific periodontal scenario:patient with generalised probing depths of ≈ 6 mm or more (e.g. CPI/BPE/PSR scores of code 4) This level of probing depth is generally indicative of advanced periodontitis. Full assessment of all teeth and alveolar bone status is indicated as described above. As an alternative, some authors advocate the use of vertical bitewing radiographs, supplemented by periapical views, e.g. for selected anterior teeth. Cone beam computed tomography (CBCT) Not indicated as a routine method for imaging alveolar bone levels as part of periodontal assessment. If CBCT images are obtained for other purposes, however, and they include the teeth, it is important that assessment of alveolar bone support is included in the radiographic report. * Adapted from the 2013 UK Faculty of General Dental Practice guidelines "Selection Criteria for Dental Radiography". Note: whenever periapical radiographs are obtained, a paralleling technique should be used. modern panoramic machines, it is recommended that a panoramic radiograph is sufficient to assess alveolar bone status, but this may be supplemented by selected periapical radiographs according to the specific clinical situation. Whenever radiographs are obtained, a written report should be entered into the clinical notes. This should typically include factors such as: - teeth present (including unerupted teeth)/teeth missing - bone loss, including pattern (e.g. horizontal, regular, irregular) as well as extent (usually expressed as a proportion or percentage of the root length) - presence of any specific vertical bone defects - presence of calculus (supra-and subgingival) - apical pathology - caries and enamel lucencies - ledges/overhangs of restorations - any other findings or pathology ## Other investigations that form part of periodontal assessment Periodontal probing to assess probing depths and bleeding on probing, together with radiographic assessment, remain the cornerstone of periodontal assessment. Additional measures that may be recorded, depending on the clinical situation are summarised below. ## Recession and loss of attachment Probing depths alone can sometimes be misleading in terms of assessing the cumulative effects of periodontal tissue breakdown. For example, a patient with a history of periodontitis who has been successfully treated may present with shallow probing depths yet with generalised gingival recession (indicating widespread loss of periodontal tissue support that may not be suggested by inspection of the probing depth data alone). It may also be important to measure recession in cases of localised gingival recession. Therefore, while not essential for all patients, the measurement of recession adds to the clinical information that is obtained, and may influence treatment decisions. Probing depth measurements can be summed with recession measurements to obtain loss of attachment: - Probing depth (x mm) + recession (y mm) = loss of attachment (x + y mm) ## Tooth mobility Loss of attachment and alveolar bone loss can result in increased tooth mobility. This should be assessed using rigid instruments (e.g. the ends of dental mirror handles) and a score allocated to affected teeth. Several scoring systems for tooth mobility have been proposed, but one that is in common use is shown below [bib_ref] Philadelphia: Blackston, Miller [/bib_ref] : - Grade I: mobility in excess of physiological mobility ("physiological mobility" is usually considered to be < 0.2 mm in a horizontal direction), but less than 1 mm in a horizontal direction - Grade II: horizontal mobility > 1 mm - Grade III: mobility of the crown in a vertical direction ## Furcation involvement Progression of periodontitis around multi-rooted teeth may result in horizontal loss of attachment into the furcation area. This should be assessed as part of routine periodontal assessment, bearing in mind the anatomy of multi-rooted teeth. Ideally, a curved furcation probe (e. g. the Nabers probe) should be used for this purpose. In maxillary molars, there are usually 3 roots, and therefore 3 furcations to assess (buccal, mesio-palatal, disto-palatal). In mandibular molars, there are usually 2 roots, and therefore 2 furcations to assess (buccal and lingual). The two main classification systems for assessment of furcations are those proposed by Glickman in 1953and , as shown in . ## Plaque levels/oral hygiene Given that the subgingival biofilm plays a fundamental role in initiating and perpetuating the inflammation that leads to the clinical signs that we recognise as gingivitis and periodontitis, and also that plaque control is the vehicle by which we aim to control inflammation, assessment of plaque and oral hygiene should form a standard component of periodontal assessment. It is also very important for patients to understand where plaque is accumulating so that they may direct oral hygiene efforts particularly towards those areas of concern. While a large number of plaque index scoring systems have been proposed for research purposes, they are generally not particularly useful for routine clinical practice. Instead, similar to BOP, a dichotomous "present"/"absent" approach can be taken when recording plaque at specific periodontal sites, with the possibility to then calculate a percentage of sites that are covered with plaque. This can be useful for helping to motivate patients towards improving their plaque control. Visualisation of plaque can be further enhanced, as necessary, by using plaque disclosing agents, which may be especially useful for educating children about the importance of improving oral hygiene. ## Sensibility testing In some cases, it is useful to perform sensibility testing as part of the periodontal assessment, for example, in cases of suspected periodontal/endodontic lesions. Sensibility should be assessed by a minimum of two independent methods, e.g. cold test (for example ethyl chloride) and electric pulp testing. Results should be recorded in the patient notes. ## Occlusion It may be necessary to assess for any evidence of fremitus, occlusal trauma or occlusal interferences. Occlusal trauma can be classified as primary occlusal trauma and secondary occlusal trauma. The reasons for occlusal interferences are diverse, and can include tooth/ arch relationships, developmental aspects, or iatrogenic factors. Primary occlusal trauma is said to occur in cases that are periodontally healthy, and may result in increased tooth mobility, widening of the periodontal membrane space, and tenderness, but which does not lead to periodontal tissue breakdown. Secondary occlusal trauma occurs in teeth with pre-existing periodontitis, and may exacerbate periodontal tissue breakdown. ## Assessment of periodontal status in children Gingivitis is highly prevalent in children, and periodontitis may also be evident (including both chronic periodontitis and aggressive periodontitis) [bib_ref] Periodontal diseases in children and adolescents, Clerehugh [/bib_ref]. A joint working group involving the British Society of Periodontology and the British Society of Paediatric Dentistry developed "Guidelines for Periodontal Screening and Management of Children and Adolescents Under 18 Years of Age". Early detection of periodontal diseases in children and adults is fundamentally important to enable accurate diagnosis, and implementation of correct preventive and treatment approaches. At the same time, there are some challenges associated with periodontal screening of children, such as cooperation (in the case of very young children) and also increased probing depths (false pockets) associated with the mixed dentition stage and partly erupted teeth. It is recommended that assessment of periodontal status should be started at 7 years of age, as periodontal problems below this age are very rare, and index teeth are often still unerupted. From age 7 onwards, a simplified Basic Periodontal Examination (BPE) should be performed at 6 index teeth: FDI The scoring system for the BPE in children and adolescents is the same as that used in adults [fig_ref] Table 1: Basic Periodontal Examination [/fig_ref] , except that in children of 7-11 years old, only the BPE codes of 0, 1 and 2 should be used. For children and adolescents in the age range 12-17 years old, the full range of BPE codes should be used. ## Diagnosis of periodontal conditions The periodontal diagnosis is a summation of the information from the medical and dental histories, combined with the findings of the clinical and radiographic examination. By its very nature, the diagnosis can be regarded as the clinician's "best guess" as to what condition or disease the patient has [bib_ref] Periodontal diagnoses and classification of periodontal diseases, Armitage [/bib_ref]. In broad terms, and with regards to plaque-induced periodontal conditions, the diagnosis is typically health, gingivitis, or chronic periodontitis. The most recent internationally accepted classification of periodontal conditions was published in 1999 [bib_ref] Development of a classification system for periodontal diseases and conditions, Armitage [/bib_ref] , and is summarised in [fig_ref] Table 6: Current classification of periodontal conditions* Gingival diseases and conditions [/fig_ref]. Whereas this classification system is now in widespread use (and therefore described in this paper), it is important to note that problems and difficulties in its implementation have been identified [bib_ref] U: Diagnosis of periodontitis, Van Der Velden [/bib_ref] [bib_ref] U: Purpose and problems of periodontal disease classification, Van Der Velden [/bib_ref]. These primarily result from the fact that periodontitis is a complex disease that has a multi-factorial aetiology but which has a common end-point (loss of attachment and alveolar bone loss). It is beyond the scope of this article to consider these issues in more detail, however. . Furcation classification scoring systems 4-point furcation scoring system proposed by Grade 1 furcation Incipient furcation involvement in which there is pocket formation into the "flute" of the furcation, but no horizontal loss of attachment into the furcation itself ## Grade 2 furcation Loss of attachment into the furcation, but not completely through to the opposite side of the tooth, i.e. is a cul-de-sac furcation involvement ## Grade 3 furcation Horizontal "through-and-through" involvement in which the lesion extends across the entire width of the furcation Grade 4 furcation Same as a Grade 3 furcation, but with gingival recession that has rendered the furcation region clearly visible on clinical examination 3-point furcation scoring system proposed by Grade 1 furcation Horizontal loss of attachment into the furcation of < 3 mm (approximately 1/3 the tooth width) ## Grade 2 furcation Horizontal loss of attachment into the furcation of > 3 mm (or approximately 1/3 the tooth width), but does not pass completely through the furcation, i.e. is a cul-de-sac furcation involvement Grade 3 furcation Horizontal "through-and-through" involvement in which the lesion extends across the entire width of the furcation Assigning a diagnosis is frequently very challenging, and requires an assimilation of all the available evidence and findings. Even experienced clinicians often struggle to assign a diagnosis to a particular case, and frequently will also consider multiple differential diagnoses (i.e. the possible diagnoses, usually listed in decreasing order of likelihood). It is also helpful to include assessments of the extent and severity of disease in the diagnosis. This can make the diagnosis somewhat wordy, but this is certainly acceptable, and is also very useful when describing the condition (much more so than simply referring to the "name" of the condition, with no other detail being provided). As regards the extent of disease, there are no clear "rules" on what constitutes a localised as opposed to a generalised case in the context of gingivitis or chronic periodontitis. It has been suggested that if > 30% of the teeth are affected, then the case can be described as generalised, and if < 30% of teeth are affected, it can be described as localised [bib_ref] Periodontal diagnoses and classification of periodontal diseases, Armitage [/bib_ref]. This appears to be a reasonable approach to follow in general terms, but clinicians should not become too dogmatic in applying this threshold -as mentioned above, the diagnosis should take all factors into account. It is important to note, however, that the descriptors of "localised" and "generalised" in the context of aggressive periodontitis have more specific connotations. Aggressive periodontitis is usually diagnosed in young (and otherwise healthy) adults in whom there is advanced periodontitis with rapid attachment loss and bone destruction, and a familial aggregation [bib_ref] Early-onset periodontitis, Tonetti [/bib_ref]. Localised aggressive periodontitis is probably not just a localised form of generalised aggressive periodontitis. In the case of localised aggressive periodontitis, there is a characteristic localised first molar/incisor presentation. The case definition described in the consensus report on aggressive periodontitis in the 1999 classification [bib_ref] Early-onset periodontitis, Tonetti [/bib_ref] describes interproximal attachment loss on at least two permanent teeth, one of which is a first molar, and involving no more than two teeth other than first molars and incisors. Other features include circumpubertal onset, and a robust serum antibody response to the infecting agents. In the case of generalised aggressive periodontitis, the consensus report refers to interproximal attachment loss that affects at least three permanent teeth other than first molars and incisors [bib_ref] Early-onset periodontitis, Tonetti [/bib_ref]. Other features of generalised aggressive periodontitis are that it usually affects people < 30 years of age (but may affect older individuals), there is a poor serum antibody response to the infecting agents, and there is a pronounced episodic pattern of tissue destruction [bib_ref] Early-onset periodontitis, Tonetti [/bib_ref]. With regards to severity of disease, this relates to the amount of inflammation (in the case of gingivitis) and the amount of attachment loss (in the case of chronic periodontitis). Terms such as "mild", "moderate", and "severe" are frequently used, being somewhat subjective, but also quite helpful clinically, as they are well understood by other clinicians. An assessment of severity based on mm of clinical attachment loss has been provided: 1-2 mm = slight, 3-4 mm = moderate, ≥ 5 mm = severe [bib_ref] Periodontal diagnoses and classification of periodontal diseases, Armitage [/bib_ref]. Again, this system is useful, but is sometimes not possible to be applied in a simple manner (for example, in cases with very variable attachment loss throughout the dentition). Radiographic bone loss is also useful for assigning descriptors to indicate severity of periodontitis: <1/3 bone loss = mild, 1/3 to ½ bone loss = moderate, and >½ bone loss = severe. It is important, however, to always take into consideration the full clinical picture when applying such descriptors, such as the age of the patient, presence of risk factors, degree of inflammation, probing depths, and pattern of bone loss (e.g. horizontal vs. vertical bone defects). The diagnosis may therefore form a sentence that encapsulates the key features of the case, which may describe different disease states at different locations in the same mouth. Examples of possible diagnoses for different patients could be as follows: - generalised severe gingivitis, with localised moderate chronic periodontitis (probing depths 4-5 mm) affecting interproximal sites at maxillary molars - generalised moderate chronic periodontitis (probing depths 4-5 mm) with localised severe chronic periodontitis (probing depths 6-10 mm) at maxillary and mandibular molars In many cases, it is also useful to list specifically the teeth affected by mild, moderate or severe disease, as this information, combined with the radiographic examination, will help to inform treatment decisions. # Conclusions Assessment and diagnosis of periodontal conditions that are amenable to prevention is a complex and challenging [bib_ref] Periodontal diagnoses and classification of periodontal diseases, Armitage [/bib_ref] [bib_ref] Development of a classification system for periodontal diseases and conditions, Armitage [/bib_ref] task. It is essential, however, to undertake periodontal screening in all our patients, given that the consequences of periodontal disease (attachment loss, alveolar bone loss, and ultimately, tooth loss), are largely irreversible. Key aspects relevant to the detection and diagnosis of periodontal conditions include: - for individuals without evidence of periodontitis, periodontal screening using the CPI/BPE/PSR systems or equivalent is essential, both as part of the initial assessment of new patients and as part of their regular ongoing care; - for individuals with periodontitis, full periodontal assessment is required. This includes full mouth probing and bleeding on probing assessments, together with assessment of other relevant parameters such as recession, tooth mobility and furcation involvement; - radiographic assessment is driven by the clinical situation, and is required to assess alveolar bone levels in patients with periodontitis; - for patients with treated periodontitis in the maintenance phase of care (supportive periodontal therapy), full periodontal assessment is required on an ongoing basis to ensure that any evidence of disease progression is detected; - risk assessment and management (e.g. in relation to factors such as smoking and diabetes) should form a central component of periodontal therapy. ## Competing interests Professor Preshaw received funding from Colgate Palmolive to attend and present at the Prevention in Practice conference. This was provided in the form of flights, hotel accommodation and subsistence. No one from the Colgate Palmolive Company was involved in the production, assessment or peer review of the manuscript nor was it submitted to them for approval prior to publication. Professor Preshaw has also received funding from Colgate Palmolive on an ad hoc basis for presentation of clinical periodontal and scientific information at conferences. # Declarations This article has been published as part of BMC Health Services Research Volume 15 Supplement 1, 2015: Improved access to maternal, newborn and child health services: strengthening human resources for health. The full contents of the supplement are available online at http://www. biomedcentral.com/bmchealthservres/supplements/15/S1. Publication charges for this supplement were funded by Colgate Palmolive. Published: 15 September 2015 [fig] •: buccal surfaces of upper arch (from right to left) palatal surfaces of upper arch (from left to right) buccal surfaces of lower arch (from right to left) lingual surfaces of lower arch (from left to right) [/fig] [table] Table 1: Basic Periodontal Examination (BPE) scoring codes[19] [/table] [table] Table 2: Case definitions for denoting periodontitis in epidemiological studies [/table] [table] Table 3: Recommendations for assessment of periodontal status by means of periodontal probing WHO CPI: World Health Organisation Community Periodontal Index probe UNC PCP-15: University of North Carolina PCP-15 periodontal probe (an example of a manual periodontal probe, other probes may also be used) [/table] [table] Table 6: Current classification of periodontal conditions* Gingival diseases and conditions (including plaque-induced gingivitis) Chronic periodontitis Localised aggressive periodontitis Generalised aggressive periodontitis Periodontitis as a manifestation of systemic diseases Necrotising ulcerative gingivitis and necrotising ulcerative periodontitis Abscesses of the periodontium (including gingival and periodontal abscesses) Combined periodontal/endodontic lesions Developmental/acquired conditions *Based on Armitage 1999 and 2004 [/table]	None	https://bmcoralhealth.biomedcentral.com/track/pdf/10.1186/1472-6831-15-S1-S5	None
64a8520eca76be7f99ec8d6efeb262c603e51ed9	pubmed	The difficult airway with recommendations for management – Part 2 – The anticipated difficult airway	The difficult airway with recommendations for management – Part 2 – The anticipated difficult airway Background Appropriate planning is crucial to avoid morbidity and mortality when difficulty is anticipated with airway management. Many guidelines developed by national societies have focused on management of difficulty encountered in the unconscious patient; however, little guidance appears in the literature on how best to approach the patient with an anticipated difficult airway. Methods To review this and other subjects, the Canadian Airway Focus Group (CAFG) was re-formed. With representation from anesthesiology, emergency medicine, and critical care, CAFG members were assigned topics for review. As literature reviews were completed, results were presented and discussed during teleconferences and two face-to-face meetings. When appropriate, evidence-or consensus-based recommendations were made, and levels of evidence were assigned.Principal findings Previously published predictors of difficult direct laryngoscopy are widely known. More recent studies report predictors of difficult face mask ventilation, video laryngoscopy, use of a supraglottic device, and cricothyrotomy. All are important facets of a complete airway evaluation and must be considered when difficulty is anticipated with airway management. Many studies now document the increasing patient morbidity that occurs with multiple attempts at tracheal intubation. Therefore, when difficulty is anticipated, tracheal intubation after induction of general anesthesia should be considered only when success with the chosen device(s) can be predicted in a maximum of three attempts. Concomitant predicted difficulty using oxygenation by face mask or supraglottic device ventilation as a fallback makes an awake approach advisable. Contextual issues, such as patient cooperation, availability of additional skilled help, and the clinician's experience, must also be considered in deciding the appropriate strategy. Conclusions With an appropriate airway evaluation and consideration of relevant contextual issues, a rational decision can be made on whether an awake approach to tracheal intubation will maximize patient safety or if airway management can safely proceed after induction of general anesthesia. With predicted difficulty, close attention should be paid to details of implementing the chosen approach. This should include having a plan in case of the failure of tracheal intubation or patient oxygenation. # Abstract Background Appropriate planning is crucial to avoid morbidity and mortality when difficulty is anticipated with airway management. Many guidelines developed by national societies have focused on management of difficulty encountered in the unconscious patient; however, little guidance appears in the literature on how best to approach the patient with an anticipated difficult airway. Methods To review this and other subjects, the Canadian Airway Focus Group (CAFG) was re-formed. With representation from anesthesiology, emergency medicine, and critical care, CAFG members were assigned topics for review. As literature reviews were completed, results were presented and discussed during teleconferences and two face-to-face meetings. When appropriate, evidence-or consensus-based recommendations were made, and levels of evidence were assigned. Principal findings Previously published predictors of difficult direct laryngoscopy are widely known. More recent studies report predictors of difficult face mask ventilation, video laryngoscopy, use of a supraglottic device, and cricothyrotomy. All are important facets of a complete airway evaluation and must be considered when difficulty is anticipated with airway management. Many studies now document the increasing patient morbidity that occurs with multiple attempts at tracheal intubation. Therefore, when difficulty is anticipated, tracheal intubation after induction of general anesthesia should be considered only when success with the chosen device(s) can be predicted in a maximum of three attempts. Concomitant predicted difficulty using oxygenation by face mask or supraglottic device ventilation as a fallback makes an awake approach advisable. Contextual issues, such as patient cooperation, availability of additional skilled help, and the clinician's experience, must also be considered in deciding the appropriate strategy. Conclusions With an appropriate airway evaluation and consideration of relevant contextual issues, a rational decision can be made on whether an awake approach to tracheal intubation will maximize patient safety or if airway management can safely proceed after induction of general anesthesia. With predicted difficulty, close attention should be paid to details of implementing the chosen approach. This should include having a plan in case of the failure of tracheal intubation or patient oxygenation. ## Résumé Contexte Une planification adaptée est essentielle afin d'éviter la morbidité et la mortalité lorsqu'on prévoit des difficultés dans la prise en charge des voies aériennes. De nombreuses recommandations émises par des sociétés nationales mettent l'emphase sur la gestion des difficultés rencontrées chez le patient inconscient. Toutefois, il n'existe dans la littérature que peu de suggestions sur la façon d'approcher le patient chez qui les difficultés sont prévisibles. Méthode Afin de passer en revue ce sujet et d'autres, le Canadian Airway Focus Group (CAFG), un groupe dédié à l'étude de la prise en charge des voies aériennes, a été reformé. Les membres du CAFG représentent diverses spécialités soit l'anesthésiologie, la médecine d'urgence et les soins intensifs. Chaque participant avait pour mission de passer en revue des sujets précis. Les résultats de ces revues ont été présentés et discutés dans le cadre de téléconférences et de deux réunions en personne. Lorsqu'indiqué, des recommandations fondées sur des données probantes ou sur un consensus ont été émises. Le niveau de confiance attribué à ces recommandations a aussi été défini. ## Constatations principales Plusieurs éléments permettant de prédire la laryngoscopie directe difficile sont connus. Des études plus récentes décrivent aussi les éléments permettant d'anticiper des difficultés lors de la ventilation au masque facial, de la vidéolaryngoscopie, de l'utilisation d'un dispositif supraglottique ou de la réalisation d'une cricothyrotomie. Tous ces éléments doivent être pris en compte lors de l'évaluation du patient chez qui des difficultés sont anticipées lors de la prise en charge des voies aériennes. De nombreuses études rapportent une morbidité accrue liée à des tentatives multiples d'intubation trachéale. Planifier de procéder à l'intubation trachéale après l'induction de l'anesthésie générale n'est donc recommandé que pour les patients chez qui la ou les techniques prévues ne nécessiteront pas plus de trois tentatives. Il est recommandé de prioriser d'emblée une approche vigile dans les cas où des difficultés reliées à l'utilisation du masque facial ou d'un dispositif supraglottique sont prévues. L'établissement d'une stratégie de prise en charge doit tenir compte d'éléments contextuels telles la collaboration du patient, la disponibilité d'aide supplémentaire et de personnel qualifié, et l'expérience du clinicien. Conclusion Une évaluation adaptée des voies aériennes ainsi que les éléments contextuels propres à chaque situation sont les bases qui permettent de déterminer de manière rationnelle si l'intubation trachéale vigile est apte à optimiser la sécurité du patient, ou si la prise en charge des voies aériennes peut être réalisée de manière sécuritaire après l'induction de l'anesthésie générale. Lorsqu'on prévoit des difficultés, une attention particulière doit être portée aux détails nécessaires au succès de l'approche envisagée. De plus, il convient d'avoir un plan en cas d'échec de l'intubation trachéale ou si l'oxygénation du patient s'avérait difficile. What other recommendation statements are available on this topic? Many developed countries have published national guidelines and recommendations on management of the difficult airway. Most of these recommendations emphasize management of the already unconscious patient in whom difficulty has been encountered. ## Why were these recommendations developed? Little guidance is provided by many of the existing guidelines on planning and decision-making for the patient with an anticipated difficult airway. These recommendations were developed to help address this gap. How do these statements differ from existing recommendations? These statements aim to address situations where the patient with a predicted difficult tracheal intubation can be safely managed after induction of general anesthesia or where an awake approach should be considered. Why do these statements differ from existing recommendations? These recommendations differ from existing consensus guidelines to reflect the widespread availability of recent innovations in airway management equipment and clinicians' increasing familiarity with these newer devices. Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. The authors accept that medical knowledge is an ever-changing science that continually informs, improves, and alters attitudes, beliefs, and practices. ## Contents Recommendations are not intended to represent or be referred to as a standard of care in the management of the difficult or failed airway. Application of the information provided in a particular situation remains the professional judgement and responsibility of the practitioner. When planning how to approach the anticipated difficult airway, the primary focus should be on ensuring adequate oxygenation and ventilation and not simply on intubating the trachea. Management of the anticipated difficult airway follows an assessment of the probable success of ventilation by face mask or supraglottic device (SGD) as well as direct or indirect (e.g., video) laryngoscopy, tracheal intubation and surgical airway access. [bib_ref] Predicting the difficult laryngoscopic intubation: are we on the right track? Can, Murphy [/bib_ref] Unfortunately, predicting difficulty with these measures remains an imperfect science. Furthermore, surveys suggest that clinicians' management choices vary widely even when significant difficulty is predicted. [bib_ref] Practice patterns in managing the difficult airway by anesthesiologists in the United..., Rosenblatt [/bib_ref] [bib_ref] Management choices for the difficult airway by anesthesiologists in Canada, Jenkins [/bib_ref] [bib_ref] Practice patterns for predicted difficult airway management and access to airway equipment..., Zugai [/bib_ref] There is agreement in many national consensus guidelines on the importance of performing an airway evaluation to predict difficulty with airway management. [bib_ref] The unanticipated difficult airway with recommendations for management, Crosby [/bib_ref] [bib_ref] Difficult Airway Society. Difficult Airway Society guidelines for management of the unanticipated..., Henderson [/bib_ref] [bib_ref] Practice guidelines for management of the difficult airway: an updated report by..., Apfelbaum [/bib_ref] [bib_ref] Recommendations for airway control and difficult airway management, Petrini [/bib_ref] [bib_ref] Difficult intubation. French Society of Anesthesia and Intensive Care. A collective expertise..., Boisson-Bertrand [/bib_ref] [bib_ref] Airway management. Guidelines of the German Society of Anesthesiology and Intensive Care, Braun [/bib_ref] Unfortunately, once identified, some guidelines fail to provide sufficient guidance on how to proceed, simply implying that tracheal intubation should be performed awake when difficulty is anticipated. Certainly, as highlighted by the 4 th National Audit Project (NAP4) from the United Kingdom, airway-related patient morbidity and mortality can occur following induction of general anesthesia when difficult tracheal intubation is predicted. 11 Sponsored by the Difficult Airway Society and the Royal College of Anaesthetists, the NAP4 study reported complications of airway management associated with nearly three million airway interventions in the United Kingdom during a 12-month period. Difficulty had been anticipated in most of the 43 operative patients in whom the initial attempts at tracheal intubation failed. The most common problem identified was the ''failure to plan for failure''.When difficulty is anticipated, airway management after induction of general anesthesia can be justified only when the risk of failure to oxygenate is low and when an appropriate backup plan can be quickly implemented. Historically, airway assessment has focused mainly on predictive tests of successful direct laryngoscopy. These tests had limited sensitivity and specificity, resulting in both unanticipated failures to obtain a view of the larynx [bib_ref] Predicting difficult intubation in apparently normal patients: a meta-analysis of bedside screening..., Shiga [/bib_ref] and unnecessary awake tracheal intubations. Patient safety was assigned a higher priority than comfort so awake intubations were appropriately advocated when uncertainty existed. Nevertheless, with recent innovations (e.g., video laryngoscopes) and alternative methods of providing oxygenation (e.g., supraglottic airways), it may be that more patients can be safely managed after induction of general anesthesia. This article, the second of two publications, seeks to address the approach to a patient with an anticipated difficult airway as well as implementation of the chosen approach. The first article in the series addressed difficult tracheal intubation encountered in the already unconscious patient. [bib_ref] for the Canadian Airway Focus Group. The difficult airway with recommendations for..., Law [/bib_ref] The two publications aim to provide recommendations and a cognitive framework to inform clinician decision-making in the interest of patient safety, regardless of specialty or practice environment. # Methods The methods presented are identical to those described in the companion article [bib_ref] for the Canadian Airway Focus Group. The difficult airway with recommendations for..., Law [/bib_ref] and are reproduced here for the benefit of the reader. The Canadian Airway Focus Group The difficult airway with recommendations -Part II 1121 (CAFG) was originally formed in the mid-1990s and published recommendations for the management of the unanticipated difficult airway in 1998. [bib_ref] The unanticipated difficult airway with recommendations for management, Crosby [/bib_ref] Four of the original CAFG members rejoined the current iteration, and the first author invited an additional 14 clinicians with an interest in airway management to participate. The current Focus Group includes representatives from anesthesiology, emergency medicine, and critical care. Topics for review were divided among the members, and participants conducted a literature review on their topic(s). Electronic literature searches were not conducted according to a strict protocol, but participants were instructed to search, at a minimum, Medline and EMBASE databases together with the Cochrane Central Register of Controlled Trials (CENTRAL). Search strings were determined by individual participants. A worksheet was completed for each topic with details of the search strategy, a synopsis of the relevant studies, an overall summary of findings, the perceived quality of evidence, and the author's suggestion(s) for strength of recommendation (see below). Once finished, worksheets were made available to the CAFG membership on a file hosting service. The Focus Group convened regularly by teleconference, and face-to-face meetings occurred on two occasions during the 24 months taken to complete the process. Worksheet authors presented their topics to the members, who then arrived at consensus on overall quality of evidence and any recommendations. In the event that evidence was of low quality or altogether lacking, ''expert opinion'' by consensus was sought. Finally, a draft of the completed manuscripts was distributed to all members for review prior to submission. The strength of a recommendation and assignment of level of evidence were modelled after the GRADE system, as per previously published criteria. [bib_ref] Grading strength of recommendations and quality of evidence in clinical guidelines: report..., Guyatt [/bib_ref] [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] When made, formal strength of recommendations adhere to the following descriptors: - Strong recommendation for -most patients should receive the intervention; most patients in this situation would want the recommended course of action; - Weak recommendation for -most patients would want the suggested course of action, but some would not; the appropriate choice may vary for individual patients. Three levels of evidence were applied, 14 as follows: - Level of evidence A (High) -systematic reviews of randomized controlled trials (RCTs), RCTs without important limitations, or observational studies providing overwhelming evidence; - Level of evidence B (Moderate) -RCTs with limitations, observational studies with significant therapeutic effect; - Level of evidence C (Low) -RCTs with significant limitations, observational studies, case series, or published expert opinion. When a level of evidence is not specifically supplied, recommendations reflect the consensus opinion of the authors. ## Airway evaluation: anticipating the difficult airway An airway evaluation should be performed on every patient requiring airway management (Strong recommendation for, level of evidence C). For the patient requiring tracheal intubation, an airway evaluation is performed primarily to help decide if intubation can be safely performed after the induction of general anesthesia (with or without maintenance of spontaneous ventilation) or if intubation should proceed with the patient awake. Even if a lack of patient cooperation precludes a complete airway evaluation or the option of awake intubation, performing this step serves as a ''cognitive forcing strategy'' [bib_ref] Cognitive forcing strategies in clinical decisionmaking, Croskerry [/bib_ref] to encourage appropriate planning and preparation for the airway intervention, however undertaken. A complete airway evaluation should include an assessment of not only the predicted ease or difficulty of tracheal intubation (Tables 1 and 2) but also the predicted success of fallback options to achieve oxygenation, such as face mask ventilation , SGD use , and surgical airway [fig_ref] Table 5: Predictors of difficult cricothyrotomy 54,55 • Difficulty identifying the location of the... [/fig_ref] 1 (Strong recommendation for, level of evidence C). As the number of predictors of difficulty increases, so does the probability of actually [bib_ref] Relative risk analysis of factors associated with difficult intubation in obstetric anesthesia, Rocke [/bib_ref] [bib_ref] Predicting difficult intubation, Frerk [/bib_ref] In addition to physical examination and a history of prior difficulties provided by the patient, records of previous airway interventions, imaging studies, electronic databases and letters carried by the patient should be considered if time permits and records can be sourced. Other contextual issues must also be considered, including patient cooperation, the clinician's skill and experience, availability of additional skilled help, and whether the desired equipment is accessible. [bib_ref] Context-sensitive airway management, Hung [/bib_ref] ## Options when difficult tracheal intubation is anticipated Avoiding tracheal intubation When difficult tracheal intubation is anticipated in the surgical patient, it may be feasible to proceed without general anesthesia or with general anesthesia but without tracheal intubation. However, if general anesthesia with tracheal intubation would normally occur for the procedure, a careful risk-to-benefit assessment must be undertaken before proceeding without an airway secured by a tracheal tube. The following options can be considered: Proceeding with regional or infiltration anesthesia: Regional (e.g., neuraxial or peripheral nerve block) or infiltration (local) anesthesia may be an option for surgery, with the following provisos: - Easy access to the airway during the case is advisable; - The nerve block must be compatible with the estimated duration of the surgical procedure; - Interrupting the surgery must be feasible in case an intraoperative awake intubation or re-do of the block is required; - The necessary equipment and expertise must be available to manage the airway in case complications of the block result in loss of consciousness or respiratory compromise. If regional or local anesthesia is elected in the patient with anticipated difficult tracheal intubation, the surgical safety briefing should include the anesthesiologist's planned strategy for conversion to general anesthesia, if required intraoperatively. General anesthesia using SGD or face mask ventilation: Successful use of SGDs has been reported in patients who are known or suspected to be difficult to intubate by direct laryngoscopy. [bib_ref] The intubating laryngeal mask airway after induction of general anesthesia versus awake..., Joo [/bib_ref] [bib_ref] Use of the intubating LMA-Fastrach in 254 patients with difficult-to-manage airways, Ferson [/bib_ref] [bib_ref] Intubating laryngeal mask airway for difficult out-of-hospital airway management: a prospective evaluation, Timmermann [/bib_ref] [bib_ref] Fastrach laryngeal mask and difficult intubation (French), Cros [/bib_ref] [bib_ref] The laryngeal mask airway reliably provides rescue ventilation in cases of unanticipated..., Parmet [/bib_ref] Nevertheless, the NAP4 study documented cases where inappropriate use of a SGD to avoid difficult tracheal intubation resulted in patient morbidity.If difficult tracheal intubation is predicted but intubation is not absolutely required for the safe conduct of general anesthesia, use of a SGD may be considered provided the patient is at low risk of aspiration and a plan has been made for managing intraoperative failure of ventilation or oxygenation. Deferring surgery: For the elective surgical patient with predicted difficult tracheal intubation, the option of not proceeding with surgery at that time (or at all) should be considered. This choice may be especially relevant if working in unfavourable conditions (e.g., lacking access to difficult airway equipment and/or additional skilled help), as may be the case in some remote locations. Under such Predictors of difficult face mask ventilation [bib_ref] Incidence and predictors of difficult and impossible mask ventilation, Kheterpal [/bib_ref] [bib_ref] Prediction and outcomes of impossible mask ventilation: a review of 50,000 anesthetics, Kheterpal [/bib_ref] [bib_ref] Prediction of difficult mask ventilation, Langeron [/bib_ref] [bib_ref] The incidence and risk factors of difficult mask ventilation, Yildiz [/bib_ref] [bib_ref] Prediction of difficult mask ventilation, Gautam [/bib_ref] - Higher body mass index or weight Predictors of difficult supraglottic device use* [bib_ref] Comparison of the intubating laryngeal mask airway with the fiberoptic intubation in..., Langeron [/bib_ref] [bib_ref] Limits of laryngeal mask airway in patients after cervical or oral radiotherapy, Giraud [/bib_ref] [bib_ref] Hypertrophy of the lingual tonsil and difficulty in airway control. A clinical..., Salvi [/bib_ref] [bib_ref] Failed tracheal intubation using a laryngoscope and intubating laryngeal mask, Asai [/bib_ref] [bib_ref] Impossible insertion of the laryngeal mask airway and oropharyngeal axes, Ishimura [/bib_ref] [bib_ref] The upside-down intubating laryngeal mask airway: a technique for cases of fixed..., Kumar [/bib_ref] [bib_ref] Cricoid pressure impedes insertion of, and ventilation through, the ProSeal laryngeal mask..., Li [/bib_ref] [bib_ref] Predictors and clinical outcomes from failed Laryngeal Mask Airway Unique TM :..., Ramachandran [/bib_ref] - Reduced mouth opening circumstances, airway management might be deferred until suitable equipment and/or expertise is in place. The out-of-operating room (OR) emergency: Management of the emergency patient with known or presumed difficult tracheal intubation cannot be deferred. Nevertheless, it may be possible to sustain oxygenation using nasal cannulae with high flows of humidified oxygen, noninvasive ventilation (e.g., continuous or bilevel positive airway pressure), assisted face mask ventilation, or placement of a SGD pending the arrival of additional expertise or equipment for tracheal intubation. Occasionally, this may permit an underlying condition (e.g., congestive heart failure or acute respiratory failure) to be treated to the point that tracheal intubation is no longer required. [bib_ref] High flow nasal oxygen in acute respiratory failure, Ricard [/bib_ref] [bib_ref] High-flow oxygen administration by nasal cannula for adult and perinatal patients, Ward [/bib_ref] [bib_ref] Prehospital continuous positive airway pressure for acute respiratory failure: a systematic review..., Williams [/bib_ref] [bib_ref] Humidified high flow nasal oxygen during respiratory failure in the emergency department:..., Lenglet [/bib_ref] Proceeding with tracheal intubation: options When difficulty is predicted and tracheal intubation cannot be avoided, a number of options exist for how to proceed. Further details on the following options appear in subsequent sections. Awake tracheal intubation: This can occur via the oral or nasal transglottic route, awake tracheotomy, or awake cricothyrotomy. This is generally facilitated by local anesthesia, with or without judicious sedation. Tracheal intubation after induction of general anesthesia: - Induction with ablation of spontaneous ventilation using a bolus dose of sedative-hypnotic and optimizing intubating conditions with a neuromuscular blocking agent; - Induction while maintaining spontaneous ventilation via inhalation of volatile anesthetic or infusion of a sedative-hypnotic such as propofol. Especially in out-of-OR settings for urgent or emergency cases, tracheal intubation is sometimes facilitated only by moderate to deep sedation. While often successful, this approach may result in patient apnea, suboptimal intubating conditions (including reflex glottic closure with airway instrumentation), and regurgitation/ aspiration due to gag reflex activation. Very rarely, establishing femorofemoral cardiopulmonary bypass under local anesthesia may be indicated prior to induction of general anesthesia, chiefly when disease intrinsic [bib_ref] Anesthetic management of emergent critical tracheal stenosis, Zhou [/bib_ref] [bib_ref] Extracorporeal oxygenation support for curative surgery in a patient with papillary thyroid..., Jeon [/bib_ref] [bib_ref] Emergency cardiopulmonary bypass for impassable airway, Tyagi [/bib_ref] or extrinsic [bib_ref] Femoro-femoral cardiopulmonary bypass for the resection of an anterior mediastinal mass, Sendasgupta [/bib_ref] [bib_ref] The difficult airway: cardiopulmonary bypass-the ultimate solution, Belmont [/bib_ref] to the tracheal lumen threatens complete tracheal obstruction with the onset of general anesthesia. ## Deciding on awake or post-induction tracheal intubation With anticipated difficult tracheal intubation that cannot be avoided, the clinician must decide if intubation can proceed safely after induction of general anesthesia or if it would be achieved more safely in the awake patient. Although complications up to and including loss of the airway can occur during attempted awake intubation, 71-73 an awake approach can potentially confer a safety benefit by having the patient maintain airway patency, gas exchange, and protection of the airway against aspiration of gastric contents or blood during the intubation process. The following discussion and accompanying flow diagram attempt to identify the relevant factors that must be weighed when creating a patient-specific airway strategy. Neither discussion nor flow diagram is meant to be prescriptive. Many factors impact the decision, including patient cooperation, consent, and the clinician's expertise. Two primary questions should be addressed: If general anesthesia is induced, is tracheal intubation predicted to succeed with the chosen technique(s)? Guidance to help answer this question comes from the published studies on predictors of difficult tracheal intubation. Most of these studies relate to direct laryngoscopy [fig_ref] Table 1: Predictors of difficult direct laryngoscopy17,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] [/fig_ref]. Fewer studies have been published on the predictors of difficulty using alternative techniques such as video laryngoscopy [fig_ref] Table 2: Predictors of difficult GlideScope TM and Trachlight Ò use Predictors of difficult... [/fig_ref]. Thus, if the intended ''Plan A'' or ''Plan B'' intubation technique includes the use of an alternative to direct laryngoscopy, the clinician must estimate the probability of success in his or her hands under the prevailing conditions. Data from within [bib_ref] Management of the difficult airway: a closed claims analysis, Peterson [/bib_ref] and outside the operating room (OR) 77-81 point to increasing morbidity with multiple intubation attempts. Any doubt about whether tracheal intubation will succeed in the anesthetized patient in a maximum of three attempts using direct laryngoscopy or an alternative to direct laryngoscopy would favour an awake approach. If tracheal intubation fails, will oxygenation by face mask or SGD succeed? When difficult tracheal intubation is predicted, evaluation of the probable success of fallback oxygenation by face mask or SGD ventilation is especially warranted. Predictors of difficult face mask and SGD ventilation have been studied and published. In most situations, significant predicted difficulty with both tracheal intubation and face mask or SGD ventilation should be taken as a strong signal to consider awake intubation, particularly in the cooperative elective surgical patient (Strong recommendation for, level of evidence C). It should be emphasized that overlap exists between some predictors of difficult direct and video laryngoscopy and those of difficult face mask ventilation. As such, when difficult laryngoscopy is predicted, a careful and deliberate assessment of predicted ease of face mask ventilation should occur. Consideration should also be given to the probability that successful ventilation by face mask or SGD may diminish with repeated intubation attempts. Other patient or contextual issues may impact the decision of whether to proceed with tracheal intubation before or after induction of general anesthesia, and these issues should be considered 19 (Strong recommendation for, level of evidence C). Although not an exhaustive list, if any of the following issues coincide with predicted difficult intubation, an awake approach may be most prudent: Anticipated short safe apnea time: With the onset of apnea, rapid oxygen desaturation can be anticipated in the patient with decreased functional residual capacity, increased oxygen consumption, or low starting oxygen saturation. This will shorten the available time for intubation attempts before oxygen desaturation supervenes. Patients with respiratory or metabolic acidosis may also be less tolerant of apnea. Significant risk of aspiration: When practical, awake intubation should be considered for the patient with predicted difficult tracheal intubation who is also at increased risk of regurgitation and aspiration of gastric contents. Presence of obstructing airway pathology: Significant intrinsic, extrinsic, or incipient obstructing airway pathology should prompt consideration of awake management. In the NAP4 study, a number of cases were documented where attempted post-induction tracheal intubation resulted in serious patient morbidity in the presence of obstructing airway pathology.Additional skilled help not available: Skilled assistance during the management of a difficult airway is of considerable importance. Its absence should elevate the option of awake management (although this too may necessitate additional assistance). Clinician inexperienced with planned technique or device not available: The clinician must be competent and experienced with the planned intubation technique(s) when a post-induction approach is contemplated, and the preferred device(s) must be readily available. Thus, for the patient with anticipated difficult tracheal intubation, a post-induction approach may be considered if successful intubation is anticipated with the chosen technique(s) within three attempts, successful fallback oxygenation by face mask or SGD ventilation is predicted, and other patient and contextual issues are favourable. Conversely, if there is a significant risk that tracheal intubation may require more than three attempts despite optimized conditions, face mask ventilation or SGD ventilation is also predicted to be difficult, or other patient and contextual issues are unfavourable (e.g., lack of additional skilled help), the risk of failed oxygenation is elevated and an awake approach is prudent . ## The elective surgical patient with a difficult airway The cooperative elective surgical patient must be optimized preoperatively and managed in the safest way possible. When difficult tracheal intubation is anticipated in this population, proceeding with post-induction tracheal intubation should occur only with an estimated margin of safety equivalent to that of an awake intubation (Strong recommendation for, level of evidence C). Perceived time (''production'') pressure must not be allowed to impact the decision. ## The uncooperative patient with a difficult airway A lack of patient cooperation may preclude the option of awake tracheal intubation. This subsection refers to the actively uncooperative patient (as with many pediatric patients or adults with cognitive impairment, brain injury, or hypoxemia) and not patient refusal or clinician discomfort with awake techniques. Patient refusal of an awake intubation is unusual when the technique and its rationale are advanced with confidence and empathy, along with the risks of the alternatives. All options for proceeding with anticipated difficult tracheal intubation of the uncooperative patient involve risk: the clinician's job is to manage the risk. The benefit of proceeding with tracheal intubation at that time must exceed the risk of deferring intubation. If proceeding, even with an experienced airway manager in attendance, the location of additional skilled help should be established. When significant difficulty is predicted and a lack of patient cooperation precludes the provider's usual awake intubation technique(s), one of the following options can be considered to facilitate tracheal intubation: ## Maintenance of spontaneous ventilation - Blind or bronchoscopic-aided nasal intubation (if not contraindicated), with or without use of gentle physical restraint, and application of local anesthesia as the situation permits; - Judicious sedation with a pharmacologic agent less likely to have an adverse impact on airway tone or respiratory effort (e.g., ketamine, dexmedetomidine, or haloperidol), with application of local anesthesia as the situation permits; - Induction of general anesthesia while maintaining spontaneous ventilation using inhalation of volatile anesthetic or an intravenous infusion of sedativehypnotic. ## Ablation of spontaneous ventilation Occasionally, intravenous induction of general anesthesia using a bolus of sedative-hypnotic and neuromuscular blockade (e.g., rapid sequence intubation [RSI]) must be considered in the uncooperative patient with a difficult airway if techniques maintaining spontaneous ventilation have failed or are predicted to fail. This situation demands appropriate preparation, including a ''double setup airway intervention'', whereby personnel and equipment are standing by to enable immediate cricothyrotomy in the event of failed oxygenation. See the section titled ''The double setup airway intervention''. ## The emergency patient with a difficult airway Within or outside the OR, management of the critically ill emergency patient with a difficult airway is particularly challenging. Such patients generally have limited reserves, may be hypoxemic at presentation, difficult to adequately pre-oxygenate, and can rapidly desaturate with the onset of apnea. They must be assumed to be at increased risk of aspiration of gastric contents. Outside the OR, the risk of difficult tracheal intubation is higher and is associated with greater morbidity if multiple intubation attempts are required. [bib_ref] Complications of endotracheal intubation in the critically ill, Griesdale [/bib_ref] [bib_ref] 423 emergency tracheal intubations at a university hospital: airway outcomes and complications, Martin [/bib_ref] [bib_ref] Emergency tracheal intubation: complications associated with repeated laryngoscopic attempts, Mort [/bib_ref] [bib_ref] Association between repeated intubation attempts and adverse events in emergency departments: an..., Hasegawa [/bib_ref] [bib_ref] The importance of first pass success when performing orotracheal intubation in the..., Sakles [/bib_ref] There may be difficulties with access to the patient and optimum positioning. Manual in-line stabilization of the cervical spine and cricoid pressure may interfere with insertion of the laryngoscope, laryngeal exposure, or insertion of SGDs. In some centres, nonanesthesiologists may have few opportunities for airway management. This can be compounded by a limited selection of equipment and lack of access to additional skilled help. Airway management generally cannot be cancelled or deferred, and poor patient cooperation can adversely impact both the completeness of an airway assessment and options (e.g., awake intubation) for tracheal intubation. The foregoing factors place emergency patients at higher risk of complications during attempted airway management; however, the principles outlined in the preceding sections remain applicable. While the need for tracheal intubation is often urgent in the critically ill patient, when difficulty is anticipated, there is often time to achieve topical airway anesthesia for awake intubation or to enlist additional skilled help. When rapid sequence intubation is required and difficulty is anticipated, requisite preparations should occur (see PREPARATION section below). Evidence that adverse events escalate with multiple intubation attempts in the critically ill population [bib_ref] Complications of endotracheal intubation in the critically ill, Griesdale [/bib_ref] [bib_ref] 423 emergency tracheal intubations at a university hospital: airway outcomes and complications, Martin [/bib_ref] [bib_ref] Emergency tracheal intubation: complications associated with repeated laryngoscopic attempts, Mort [/bib_ref] [bib_ref] Association between repeated intubation attempts and adverse events in emergency departments: an..., Hasegawa [/bib_ref] [bib_ref] The importance of first pass success when performing orotracheal intubation in the..., Sakles [/bib_ref] suggests that the most expert airway manager available should perform airway interventions in the emergency patient. ## Implementation -proceeding with anticipated difficult tracheal intubation ## Awake tracheal intubation Clinicians who manage difficult airways should be competent in awake tracheal intubation (Strong recommendation for, level of evidence C). For awake intubation, an antisialagogue is helpful prior to application of topical airway anesthesia, unless contraindicated. Adequate anesthesia of the pharynx, larynx, and trachea -and nasal cavity if nasal intubation is planned -can be applied topically or with nerve blocks. The semi-sitting or sitting position may provide greater airway patency and patient comfort and is recommended for the procedure when feasible. Sedation should be limited in an effort to retain airway patency and patient cooperation -amnesia is not necessarily a goal during awake intubation. Supplemental oxygen is useful and can be administered by nasal cannulae. Awake intubation in the elective surgical patient will most often proceed using a flexible intubating bronchoscope, but it can also occur with other devices alone or in combination (e.g., video laryngoscopes, optical stylets, light wands, or SGDs used as a conduit for bronchoscopic intubation). Direct laryngoscopy can be used for awake tracheal intubation (as may occur for the patient with relatively favourable airway anatomy and significant hemodynamic instability). Awake tracheotomy or cricothyrotomy performed under local anesthesia is an option and may be the safest approach in patients with symptomatic obstructing airway pathology. ## Failed awake intubation An awake intubation attempt may fail due to inadequate oropharyngeal or laryngeal airway anesthesia, excessive secretions or blood, very difficult patient anatomy, lack of patient cooperation, oversedation, or operator inexperience. If inadequate local anesthesia is the problem, before additional agent is administered, the total dose of local anesthetic already administered should be determined to avoid toxicity. If local anesthetic toxicity is a worry and the surgery is elective, the case may be deferred. The clinician must not feel compelled to proceed with post-induction intubation following failed awake intubation in elective surgical patients, as this has resulted in cases of major morbidity and death. [bib_ref] Management of the difficult airway: a closed claims analysis, Peterson [/bib_ref] In contrast, for the emergency patient, if additional expertise is unavailable for another awake intubation attempt, with appropriate preparation, post-induction tracheal intubation must sometimes be undertaken. ## Inadvertent loss of the airway during attempted awake intubation Case reports have been published of complete airway obstruction occurring during attempted awake intubation. [bib_ref] Complete upper airway obstruction during awake fibreoptic intubation in patients with unstable..., Mcguire [/bib_ref] [bib_ref] Total airway obstruction during local anesthesia in a non-sedated patient with a..., Ho [/bib_ref] [bib_ref] Complete airway obstruction during awake fibreoptic intubation, Shaw [/bib_ref] This occurs most often in the setting of obstructing airway pathology; 74 possible etiologies include natural disease progression, excess sedation, reflex glottic closure, trauma from intubation attempts, or a direct adverse effect of local anesthetic on upper airway patency. [bib_ref] The obstructed airway in head and neck surgery, Mason [/bib_ref] [bib_ref] Upper airway anesthesia induces airflow limitation in awake humans, Liistro [/bib_ref] The latter phenomenon is infrequent, but it is important to be aware of this occurrence. This does not imply that awake transglottic intubation should be avoided in all patients with obstructing airway pathology, but it does mandate readiness to proceed rapidly with surgical access if oxygenation fails. ## Post-induction tracheal intubation when difficulty is predicted Preparation When difficulty is predicted and the decision is made for tracheal intubation after induction of general anesthesia, the following preparations should occur (Strong recommendation for, level of evidence C): - The patient should be placed in an optimum position with adequate pre-oxygenation; - Equipment should be prepared for the primary intubation approach (Plan A); - A familiar alternative intubation device should also be immediately on hand (Plan B); - A suitably sized SGD should be prepared for use; - The location and availability of additional skilled help should be established; - An ''exit strategy'' plan for failed tracheal intubation should be articulated to those participating in the patient's care. Such a pre-emptive briefing should be encouraged and does not suggest an expectation of failure; rather, it increases the likelihood of a coordinated and effective response by those involved. The exit strategy is the plan to engage if tracheal intubation is unsuccessful within a maximum of three attempts. It exists to alert the clinician to avoid further potentially harmful attempts at tracheal intubation. In the adequately oxygenated patient, exit strategies include awakening the patient (if not an emergency), temporizing with face mask or SGD ventilation, obtaining more expertise or equipment for a further careful intubation attempt (if this has a high probability of success), or very rarely, a surgical airway. [bib_ref] for the Canadian Airway Focus Group. The difficult airway with recommendations for..., Law [/bib_ref] Pre-and peri-intubation oxygenation All patients with an anticipated difficult tracheal intubation and planned post-induction intubation should be preoxygenated with 100% oxygen for three minutes of tidal volume breathing, eight vital capacity breaths over 60 sec, [bib_ref] Total oxygen uptake with two maximal breathing techniques and the tidal volume..., Pandit [/bib_ref] or until F E O 2 exceeds 90% 86 (Strong recommendation for, level of evidence B). There is evidence that oxygen desaturation with apnea can be further postponed if preoxygenation is undertaken with the patient in the semi-seated (Fowler's) position or with the stretcher or table in the reverse Trendelenburg position. [bib_ref] A preliminary study of the optimal anesthesia positioning for the morbidly obese..., Boyce [/bib_ref] [bib_ref] Preoxygenation is more effective in the 25 degrees head-up position than in..., Dixon [/bib_ref] [bib_ref] Preoxygenation in the obese patient: effects of position on tolerance to apnoea, Altermatt [/bib_ref] [bib_ref] Preoxygenation with 20 degrees head-up tilt provides longer duration of non-hypoxic apnea..., Ramkumar [/bib_ref] [bib_ref] A prospective, randomised controlled trial comparing the efficacy of pre-oxygenation in the..., Lane [/bib_ref] Apneic oxygenation 92 via nasopharyngeal catheter [bib_ref] Supplementation of pre-oxygenation in morbidly obese patients using nasopharyngeal oxygen insufflation, Baraka [/bib_ref] [bib_ref] Nasopharyngeal oxygen insufflation following pre-oxygenation using the four deep breath technique, Taha [/bib_ref] or nasal cannulae 95 may also be beneficial during attempted tracheal intubation. ## Equipment choice No recommendation can be made for the use of a particular device or class of device for post-induction tracheal intubation when difficulty is predicted. Video laryngoscopes can be effective in enabling a view of the larynx and facilitating intubation when direct laryngoscopy has failed or is predicted to fail. Other classes of intubation device can be similarly effective when difficult tracheal intubation is predicted, including blind intubation with a lighted stylet or via the Fastrach TM laryngeal mask airway. Some clinicians may be facile in using the flexible bronchoscope for post-induction intubation, with or without use of a SGD as a conduit. Optical indirect laryngoscopes, such as the Airtraq TM or Bullard TM laryngoscope, are also effective and can be video enabled. Most important is the clinician's estimation that the chosen device will successfully address the anatomic reason for predicted difficulty with tracheal intubation, that he or she is experienced with its use, and that it is available. ## Ablation or maintenance of spontaneous ventilation Conditions for tracheal intubation are generally considered to be optimized with ablation of spontaneous ventilation by administration of a sedative-hypnotic and neuromuscular blocking agent. However, inhalational induction of general anesthesia has been suggested as a method to facilitate intubation when difficulty is anticipated. The theoretical safety advantage afforded by inhalational induction (or induction by infusion of a sedative-hypnotic, e.g., propofol) relates to maintenance of spontaneous ventilation and therefore oxygenation during the induction process. [bib_ref] Progress in management of the obstructed airway, Patel [/bib_ref] While inhalational induction is commonly used in the pediatric population, in adults, it can take time to attain a sufficiently deep plane of general anesthesia for airway instrumentation without provoking reflex glottic closure. Furthermore, as consciousness is lost during anesthetic induction, the activity of the upper airway dilator muscles is attenuated, rendering the pharynx vulnerable to collapse during inspiration. [bib_ref] The upper airway during anaesthesia, Hillman [/bib_ref] [bib_ref] Evolution of changes in upper airway collapsibility during slow induction of anesthesia..., Hillman [/bib_ref] The tendency of an airway to collapse is compounded in the presence of negative intraluminal pressures generated on inspiration within a narrowed airway. [bib_ref] The upper airway during anaesthesia, Hillman [/bib_ref] If airway collapse occurs during induction with spontaneous ventilation, it can be somewhat mitigated by head extension [bib_ref] Influence of head extension, flexion, and rotation on collapsibility of the passive..., Walsh [/bib_ref] and use of a nasopharyngeal airway while the patient is still in a light plane of anesthesia. [bib_ref] The obstructed airway in head and neck surgery, Mason [/bib_ref] Checking for efficacy of face mask ventilation after induction, before administration of a neuromuscular blocking agent Before administering a neuromuscular blocking agent (NMBA), confirmation that face mask ventilation is possible following the induction of general anesthesia has been advocated as a patient safety measure. [bib_ref] Is it unnecessary to confirm successful facemask ventilation before administration of a..., Xue [/bib_ref] [bib_ref] Checking the ability to mask ventilate before administering long-acting neuromuscular blocking drugs, Pandit [/bib_ref] The theoretical advantage of withholding NMBAs until after successful face mask ventilation has been demonstrated is that if significantly difficult face mask ventilation is encountered, the patient could be allowed to awaken and the airway subsequently secured awake. [bib_ref] Could 'safe practice' be compromising safe practice? Should anaesthetists have to demonstrate..., Calder [/bib_ref] However, a review by Calder and Yentis revealed that this recommendation was not based on published evidence when it was first mentioned by Stone and Gal in the third edition of Miller's Anesthesia. [bib_ref] Could 'safe practice' be compromising safe practice? Should anaesthetists have to demonstrate..., Calder [/bib_ref] Furthermore, data from three prospective studies suggest that neuromuscular blockade improves or has no effect on face mask ventilation, but never worsens it. [bib_ref] An algorithm for difficult airway management, modified for modern optical devices (Airtraq..., Amathieu [/bib_ref] [bib_ref] The effect of neuromuscular blockade on the efficiency of mask ventilation of..., Goodwin [/bib_ref] [bib_ref] The effect of neuromuscular blockade on mask ventilation, Warters [/bib_ref] Once the decision is made to proceed with tracheal intubation after the induction of general anesthesia with ablation of spontaneous ventilation, no recommendation can be made for or against the practice of checking for efficacy of face mask ventilation prior to administration of a NMBA. This applies to patients with both anticipated easy and difficult tracheal intubation. ## Use of a short-or intermediate-acting nmba No recommendation can be made on whether to use a short-(e.g., succinylcholine) or intermediate-acting NMBA to facilitate tracheal intubation when difficulty is anticipated. In a failed oxygenation ''cannot intubate, cannot oxygenate'' (CICO) [bib_ref] The emergency airway algorithms, Walls [/bib_ref] situation, there is theoretical evidence that even succinylcholine may not wear off in time to prevent hypoxic brain injury by allowing resumption of spontaneous ventilation. [bib_ref] Critical hemoglobin desaturation will occur before return to an unparalyzed state following..., Benumof [/bib_ref] In addition, an argument can be made that short-acting NMBAs may not provide sufficient time for a smooth transition to a ''Plan B'' alternative intubation technique before the return of reflex glottic closure in response to airway instrumentation. Even with rapid reversal of an intermediate-acting nondepolarizing NMBA (e.g., reversal of rocuronium's effects using sugammadex) in a failed oxygenation/CICO situation, case reports suggest that timely resumption of adequate spontaneous ventilation may not be guaranteed. [bib_ref] A persistent 'can't intubate, can't oxygenate' crisis despite rocuronium reversal with sugammadex, Kyle [/bib_ref] [bib_ref] Use of sugammadex in a 'can't intubate, can't ventilate' situation, Curtis [/bib_ref] With no assurance of a sufficiently early resumption of spontaneous ventilation with either short-acting NMBAs or rapid-reversal agents, the emphasis should not lie with the type of NMBA to use when difficulty is anticipated; rather, it should lie earlier in the decision process when deciding if awake intubation (or induction of general anesthesia with maintenance of spontaneous ventilation) will provide a greater margin of safety. ## Cricoid pressure The use of cricoid pressure remains controversial. Randomized controlled trials on its efficacy are lacking in patients at high risk of regurgitation [bib_ref] Cricoid pressure in emergency department rapid sequence tracheal intubations: a risk-benefit analysis, Ellis [/bib_ref] [bib_ref] Cricoid pressure, Brimacombe [/bib_ref] [bib_ref] No evidence for decreased incidence of aspiration after rapid sequence induction, Neilipovitz [/bib_ref] and are unlikely to be forthcoming. Recently, investigators have identified that the esophagus is not completely obstructed by cricoid pressure [bib_ref] Cricoid pressure displaces the esophagus: an observational study using magnetic resonance imaging, Smith [/bib_ref] and that the cricoid cartilage can collapse during the application of pressure, thus failing to compress the esophagus. [bib_ref] The effect of cricoid pressure on the cricoid cartilage and vocal cords:..., Palmer [/bib_ref] The maneuver is often performed incorrectly [bib_ref] Assessment of cricoid pressure application by emergency department staff, Clark [/bib_ref] ; it may attenuate lower esophageal sphincter tone, 117 hinder face mask ventilation, interfere with placement of and ventilation through SGDs, [bib_ref] Cricoid pressure impedes positioning and ventilation through the laryngeal mask airway, Aoyama [/bib_ref] [bib_ref] Cricoid pressure applied after placement of the laryngeal mask prevents gastric insufflation..., Asai [/bib_ref] and render laryngoscopy and tracheal intubation more difficult. [bib_ref] Airway obstruction with cricoid pressure, Hartsilver [/bib_ref] Furthermore, there are reports that some anesthetists have seen regurgitation despite its application. [bib_ref] The application of cricoid pressure. An assessment and a survey of its..., Howells [/bib_ref] [bib_ref] Cricoid pressure: which hand?, Cook [/bib_ref] Nevertheless, even if it results in incomplete esophageal occlusion, there is evidence that cricoid pressure still leads to compression of the postcricoid hypopharynx, constituting at least some degree of physical barrier to the passive regurgitation of alimentary track contents. [bib_ref] Cricoid pressure results in compression of the postcricoid hypopharynx: the esophageal position..., Rice [/bib_ref] In addition, there are case reports and series of patients in whom significant regurgitation has occurred upon release of cricoid pressure after successful tracheal intubation. [bib_ref] Cricoid pressure to control regurgitation of stomach contents during induction of anaesthesia, Sellick [/bib_ref] [bib_ref] Cricoid pressure is effective in preventing esophageal regurgitation, Neelakanta [/bib_ref] In the NAP4 study, aspiration was the most common cause of anesthesia-related mortality. Analysis of these cases suggests that there was a failure to employ a rapid sequence intubation technique when a significant risk of aspiration existed.As cricoid pressure is likely to have potential benefits, 127 its continued use seems prudent during rapid sequence intubation in the patient at high risk of aspiration (Strong recommendation for, level of evidence C). However, if difficulty is encountered with face mask ventilation or tracheal intubation, or if SGD insertion is needed, progressive or complete release of cricoid pressure is justified. ## Difficult tracheal intubation encountered in the unconscious patient Difficulty with tracheal intubation will inevitably be encountered in some patients once unconscious. This may be expected, especially when post-induction intubation is elected in the patient with predictors of difficulty, or it may be unanticipated. Appropriate management is addressed in the first article of this twopart series. [bib_ref] for the Canadian Airway Focus Group. The difficult airway with recommendations for..., Law [/bib_ref] The difficult airway with recommendations -Part II 1129 Obstructing airway pathology The patient with significant obstructing airway pathology may be maintaining airway patency only with considerable effort. If time permits, consultation with the attending surgeon and review of recent imaging studies (e.g., CT scans) is advisable prior to airway management. Nasopharyngoscopy may provide useful current information about the extent, location, and nature of obstructing or distorting pathology in the pharynx and larynx. [bib_ref] Preoperative endoscopic airway examination (PEAE) provides superior airway information and may reduce..., Rosenblatt [/bib_ref] Such an examination may help identify patients in whom an awake technique is appropriate. Awake bronchoscopic intubation may be feasible for oral cavity and pharyngeal pathology, although effective topical airway anesthesia may be difficult to achieve, friable tumours may bleed easily, anatomic landmarks may be obscured by edematous tissues, and bronchoscope manipulation around obstructing lesions can be challenging. Many such patients will have received radiation therapy to the upper airway or neck, rendering tissues friable or less compliant. Bulky lesions of the larynx may accommodate passage of a bronchoscope, although complete airway obstruction by the bronchoscope or the combination of the bronchoscope and tracheal tube may occur. Thus, awake tracheotomy or cricothyrotomy should be strongly considered as a primary technique for significant obstructing airway pathology. Management of mid-or lower tracheal obstruction remains controversial. [bib_ref] Progress in management of the obstructed airway, Patel [/bib_ref] [bib_ref] Airway obstruction caused by a retrosternal thyroid mass: management and prospective international..., Cook [/bib_ref] Rigid bronchoscopy and a skilled operator should be immediately available in case tracheal intubation fails to establish oxygenation. [bib_ref] The obstructed airway in head and neck surgery, Mason [/bib_ref] [bib_ref] Airway obstruction caused by a retrosternal thyroid mass: management and prospective international..., Cook [/bib_ref] Cricothyrotomy or tracheotomy cannot be relied on to rescue a more distal airway obstruction. ## Inhalational induction with obstructing airway pathology Inhalational induction has been used successfully in the setting of obstructing airway pathology. Nevertheless, apneic spells, hypoxemia, and hypercarbia can occur with this approach. [bib_ref] Progress in management of the obstructed airway, Patel [/bib_ref] Episodes of complete airway obstruction can also occur, following which the patient may not rapidly awaken as hypoxemia worsens.The use of inhalational induction in this context is controversial, with limited supporting evidence and varying expert opinion. Although the number of occasions during the study period in which the technique was used successfully is not known, the NAP4 data reveal serious episodes of failure.If awake bronchoscopic intubation or awake tracheotomy is not considered feasible in the presence of predicted difficult tracheal intubation due to obstructing airway pathology, a weak recommendation can be made for the cautious use of inhalational induction (Weak recommendation for, level of evidence C). Nevertheless, if complete obstruction occurs when using inhalational induction in this setting, an exit strategy other than awakening the patient must be in place to rescue the airway.The ''double setup airway intervention'' A ''double setup airway intervention'' refers to the immediate availability of equipment and personnel capable of performing a surgical airway in the event that oxygenation fails for any reason during attempted tracheal intubation. Elements of the double setup include identification and marking of the cricothyroid membrane location, (sometimes with application of disinfectant solution to the neck and infiltration of local anesthetic into the overlying skin), ensuring cricothyrotomy equipment is in the room, and designation of an appropriately skilled individual to perform the procedure. In experienced hands, ultrasound may be helpful to identify the cricothyroid membrane, but there is no evidence to support its use in an emergency. It should be emphasized that rapid cricothyrotomy is unlikely to succeed and cannot be regarded a prudent rescue option if access to the cricothyroid membrane is likely to be very difficult (e.g., in a patient with a very thick neck, previous neck radiation, or overlying tumour or inflammation). This situation may mandate awake tracheotomy under local anesthesia as the preferred primary technique, performed by a surgeon under controlled conditions. A double setup airway intervention should be prepared whenever the clinician considers a significant possibility of encountering a failed oxygenation situation during attempted awake or post-induction airway management (Strong recommendation for, level of evidence C). The morbidly obese patient NAP4 reported a fourfold increase in major airway events in the morbidly obese population.Variously defined as a body mass index (BMI) [ 35 or 40 kgÁm -2 , morbid obesity can portend difficulty with most aspects of airway management. Even below this level, a BMI [ 26 or 30 kgÁm -2 is an independent predictor of difficult face mask ventilation. [bib_ref] Incidence and predictors of difficult and impossible mask ventilation, Kheterpal [/bib_ref] [bib_ref] Prediction of difficult mask ventilation, Langeron [/bib_ref] [bib_ref] The incidence and risk factors of difficult mask ventilation, Yildiz [/bib_ref] [bib_ref] Prediction of difficult mask ventilation, Gautam [/bib_ref] Other conditions frequently accompanying morbid obesity, such as a thick neck, history of snoring or obstructive sleep apnea, are similarly associated with difficult face mask ventilation. [bib_ref] Incidence and predictors of difficult and impossible mask ventilation, Kheterpal [/bib_ref] [bib_ref] Prediction and outcomes of impossible mask ventilation: a review of 50,000 anesthetics, Kheterpal [/bib_ref] [bib_ref] Prediction of difficult mask ventilation, Langeron [/bib_ref] [bib_ref] The incidence and risk factors of difficult mask ventilation, Yildiz [/bib_ref] [bib_ref] Prediction of difficult mask ventilation, Gautam [/bib_ref] Studies are contradictory on whether morbid obesity or its coexisting anatomic or pathophysiologic features are predictive of difficult direct laryngoscopy; although again, a thick neck does appear to portend difficulty. [bib_ref] Morbid obesity and tracheal intubation, Brodsky [/bib_ref] [bib_ref] Prediction of difficult laryngoscopy: does obesity play a role?, Hekiert [/bib_ref] [bib_ref] High body mass index is a weak predictor for difficult and failed..., Lundstrom [/bib_ref] [bib_ref] The importance of increased neck circumference to intubation difficulties in obese patients, Gonzalez [/bib_ref] [bib_ref] Difficult tracheal intubation is more common in obese than in lean patients, Juvin [/bib_ref] [bib_ref] The extended Mallampati score and a diagnosis of diabetes mellitus are predictors..., Mashour [/bib_ref] [bib_ref] Increased body mass index per se is not a predictor of difficult..., Ezri [/bib_ref] [bib_ref] Obstructive sleep apnea is not a risk factor for difficult intubation in..., Neligan [/bib_ref] Appropriate positioning with ''ramping'' of the patient to align the external auditory meatus horizontally with the sternum will aid direct laryngoscopy. [bib_ref] A preliminary study of the optimal anesthesia positioning for the morbidly obese..., Boyce [/bib_ref] [bib_ref] Laryngoscopy and tracheal intubation in the head-elevated position in obese patients: a..., Rao [/bib_ref] [bib_ref] Laryngoscopy and morbid obesity: a comparison of the ''sniff'' and ''ramped'' positions, Collins [/bib_ref] Increased BMI is a predictor of SGD failure, [bib_ref] Predictors and clinical outcomes from failed Laryngeal Mask Airway Unique TM :..., Ramachandran [/bib_ref] and landmark identification and execution can be challenging for cricothyrotomy (e.g., with a thick neck, standard tracheotomy or cricothyrotomy cannulae may fail to reach the trachea).Additionally, physiologic factors, such as rapid oxygen desaturation and increased risk of aspiration, must be considered. Thus, an especially careful airway evaluation is warranted in the morbidly obese patient. When difficult laryngoscopy or intubation is anticipated, given the potential for difficulty with fallback oxygenation options and the potentially short safe apnea time, an awake approach may be safest. Management of the severely obese patient has recently been reviewed in more detail elsewhere. [bib_ref] Perioperative management of the severely obese patient: a selective pathophysiological review, Cullen [/bib_ref] Tracheal extubation in the patient with a difficult airway Numerous reports emphasize the risks associated with extubation and subsequent loss of the airway. 11,141-143 Such events account for a significant proportion of adverse respiratory outcomes and are sometimes catastrophic. While there has been a decrease in adverse respiratory events associated with tracheal intubation, the same has not been observed for extubation. [bib_ref] Management of the difficult airway: a closed claims analysis, Peterson [/bib_ref] Many of these outcomes can be avoided with proper planning and recognition of risk. [bib_ref] Continuous airway access for the difficult extubation: the efficacy of the airway..., Mort [/bib_ref] [bib_ref] Tracheal tube exchange: feasibility of continuous glottic viewing with advanced laryngoscopy assistance, Mort [/bib_ref] Patients are at particular risk during emergence from anesthesia, relocation to a recovery area, and discontinuation of full monitoring. In the recovery area, recognition and correction of a deteriorating airway can potentially be delayed. Recovering patients may be under the influence of medications that depress their respiratory drive, reduce muscular power, and diminish their protective reflexes. Critically ill patients are at further risk because of limited physiologic reserves. In contrast to tracheal intubation, extubation is almost always elective, and therefore careful planning is possible. This should include identification of patients at risk of failed tracheal extubation, and those with anatomic features that place them at higher risk of difficult re-intubation should this prove necessary.Examples include but are not limited to patients with a reduced functional residual capacity, increased work of breathing, reduced minute ventilation, increased dead space, swelling in or around the airway, a previously difficult airway, or an airway where accessibility is challenged. Planning for extubation begins with ensuring optimal conditions, including adequate oxygenation and minute ventilation and intact protective reflexes, and excluding probable causes of airway obstruction. The patient should be hemodynamically stable and normothermic. Recovery from any administered neuromuscular blocking agents should be confirmed with a nerve stimulator, and reversal agents should be given when indicated. Tracheal extubation of at-risk patients requires expert judgement to ensure that appropriate circumstances and resources are in place to provide continuous post-extubation oxygenation. Premature extubation during emergence is more likely to be associated with complications such as breath-holding, aspiration, laryngospasm, and hypoxemia. If tracheal intubation had been very difficult or circumstances now suggest that it would be so, shortterm maintenance of tracheal access using an airway exchange catheter [bib_ref] ANZCA Trials Group. Difficult and failed intubation in obstetric anaesthesia: an observational..., Mcdonnell [/bib_ref] is recommended (Strong recommendation for, level of evidence C). Airway exchange catheters can also be used to exchange defective or inappropriate tracheal tubes. When used to retain tracheal access after extubation, the airway exchange catheter should not be removed prematurely, as reintubation of an at-risk airway is much more likely to be associated with an adverse outcome after the device has been removed. [bib_ref] Continuous airway access for the difficult extubation: the efficacy of the airway..., Mort [/bib_ref] When properly positioned above the carina and secured, smaller gauge (e.g., 11-or 14-French) airway exchange catheters are generally well tolerated and permit spontaneous ventilation, coughing, and talking. Generally, supplemental oxygen should be applied by face mask or nasal cannulae. Although the hollow lumen of airway exchange catheters can be used for oxygen insufflation [bib_ref] The use of an endotracheal ventilation catheter in the management of difficult..., Cooper [/bib_ref] and has been used for jet ventilation, fatal barotrauma has been reported with both modalities. [bib_ref] The use of an endotracheal ventilation catheter for jet ventilation during a..., Cooper [/bib_ref] [bib_ref] Brief review: Supplementing oxygen through an airway exchange catheter: efficacy, complications, and..., Duggan [/bib_ref] When to remove an airway exchange catheter after extubation is the subject of much debate and should be individualized to the patient's respiratory reserve, potential for difficult re-intubation, and anticipated clinical course. In the intensive care setting, the majority of patients requiring tracheal re-intubation undergo the procedure within two to ten hours after extubation. [bib_ref] Continuous airway access for the difficult extubation: the efficacy of the airway..., Mort [/bib_ref] If tracheal re-intubation is required over an airway exchange catheter, success can be enhanced by using a laryngoscope to retract the tongue. Use of a video laryngoscope for this purpose holds the advantage of also allowing indirect visualization of tube passage and facilitating corrective maneuvers for any tube impingement on laryngeal structures. [bib_ref] Tracheal tube exchange: feasibility of continuous glottic viewing with advanced laryngoscopy assistance, Mort [/bib_ref] In addition, prior passage of an intermediate catheter (e.g., the Aintree catheter [Cook Medical, Bloomington, IN, USA]) over a smaller gauge airway exchange catheter may facilitate subsequent passage of the tracheal tube through the adult larynx by reducing the size discrepancy between the outer diameter of the catheter and the inner diameter of the tracheal tube. [bib_ref] Re-intubation over airway exchange catheters -mind the gap (letter), Higgs [/bib_ref] The difficult airway with recommendations -Part II 1131 ## Summary of recommendations Strong recommendation for, level of evidence B 1. All patients with anticipated difficult tracheal intubation and planned post-induction intubation should be pre-oxygenated with 100% oxygen for three minutes of tidal volume breathing, eight vital capacity breaths over 60 sec, or until F E O 2 exceeds 90%. Strong recommendation for, level of evidence C 1. A complete airway evaluation should be performed in every patient requiring airway management to assess for potential difficulty with tracheal intubation, face mask ventilation, SGD use, and surgical airway. 2. When deciding if post-induction intubation can be safely undertaken, consideration must be given to face mask ventilation, SGD or surgical airway rescue, and other patient or contextual issues (e.g., safe apnea time, aspiration risk, availability of additional skilled help, presence of obstructing airway pathology, or clinician experience) as well as to anticipated success of tracheal intubation. 3. Proceeding with post-induction tracheal intubation in the cooperative elective surgical patient with an anticipated difficult airway should only occur with an estimated margin of safety equivalent to that of an awake intubation. 4. In most situations, significant predicted difficulty with both tracheal intubation and face mask or SGD ventilation should be taken as a strong signal to consider awake intubation, particularly in the cooperative elective surgical patient. 5. Clinicians with responsibility for difficult airway management should be competent in performing awake tracheal intubation. 6. Prior to proceeding with a post-induction tracheal intubation in the patient with known or suspected difficult intubation, the clinician should prepare equipment for both primary (''Plan A'') and alternative (''Plan B'') intubation approaches. In addition, an exit strategy for failed intubation should be clear in the clinician's mind. 7. As cricoid pressure does have potential benefits and the consequences of aspiration are significant, its use is recommended during rapid sequence intubation in the patient at high risk of aspiration. 8. During attempted airway management by awake or post-induction approaches, whenever the clinician suspects a significant possibility of encountering a failed oxygenation ''cannot intubate, cannot oxygenate'' situation, a ''double setup airway intervention'' should be prepared. 9. If tracheal intubation had been very difficult or circumstances now suggest it would be difficult, shortterm maintenance of tracheal access using an airway exchange catheter is recommended upon extubation. Weak recommendation for, level of evidence C [fig] •: Strong recommendation against -most patients should not receive the intervention; most patients in this situation would not want the suggested course of action; Weak recommendation against -most patients would not want the suggested course of action, but some would; the appropriate choice may vary for individual patients. [/fig] [fig] Figure: Flow diagram: anticipated difficult tracheal intubation. SGD = supraglottic device; IV = intravenous; RSI = rapid sequence induction [/fig] [table] Table 1: Predictors of difficult direct laryngoscopy17,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] [/table] [table] Table 2: Predictors of difficult GlideScope TM and Trachlight Ò use Predictors of difficult GlideScope TM use 36,37 • Cormack-Lehane Grade 3 or 4 view at direct laryngoscopy • Abnormal neck anatomy, including radiation changes, neck scar, neck pathology, and thick neck • Limited mandibular protrusion • Decreased sternothyroid distance Predictors of difficult Trachlight Ò lighted stylet use 38,39 • Thick neck • Neck flexion deformity • Large tongue/epiglottis [/table] [table] Table 5: Predictors of difficult cricothyrotomy 54,55 • Difficulty identifying the location of the cricothyroid membrane: -Female sex -Age \ 8 yr -Thick/obese neck -Displaced airway -Overlying pathology (e.g., inflammation, induration, radiation, tumour). • Difficult access to the trachea through the anterior neck: -Thick neck/overlying pathology -Fixed cervical spine flexion deformity [/table] [table] 1: Cautious use of inhalational induction can be considered in the presence of a difficult airway or obstructing airway pathology if awake options for tracheal intubation are impractical. Philip M. Jones, MD, MSc Data acquisition, analysis, and interpretation; critically revising article. George Kovacs, MD, MHPE Data acquisition, analysis, and interpretation; critically revising article. Co-director of and royalty recipient from Airway Interventions and Management in Emergencies (AIME) course. Owner of Airway Management Education Center (the Difficult Airway Course TM Anesthesia and Emergency); and First Airway (The Difficult Airway Course: EMS TM and Fundamentals of Airway Management TM ) Viren N. Naik, MD, MEd Data acquisition, analysis, and interpretation; writing and critically revising article. Work supported by University of Ottawa Skills and Simulation Centre Jeanette Scott, MB ChB Data acquisition, analysis, and interpretation; writing and critically revising article. Shean Stacey, MD Data acquisition, analysis, and interpretation; critically revising article. Timothy P. Turkstra, MD, M. Eng Data acquisition, analysis, and interpretation; writing and critically revising article. David T. Wong, MD Data acquisition, analysis, and interpretation; critically revising article. Supported in part by the Department of Anesthesia, Toronto Western Hospital, University of Toronto [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs12630-013-0020-x.pdf	None
9d4fbb9a5f203c7aea91b7d6d0f048180ae55762	pubmed	Executive Summary - Guideline on Telecardiology in the Care of Patients with Acute Coronary Syndrome and Other Cardiac Diseases	Executive Summary - Guideline on Telecardiology in the Care of Patients with Acute Coronary Syndrome and Other Cardiac Diseases [bib_ref] Pre hospital electrocardiography: prevalence of clinically important ECG findings of a public..., Moraes [/bib_ref] [bib_ref] Utilization and impact of pre-hospital electrocardiograms for patients with acute ST-segment elevation..., Diercks [/bib_ref] [bib_ref] Reduction of treatment delay in patients with ST-elevation myocardial infarction: impact of..., Terkelsen [/bib_ref] [bib_ref] Implementation of the myocardial infarction system of care in city of Belo..., Marcolino [/bib_ref] ## Basic concepts In a health system geographically distributed like the Brazilian system, in which Basic Health Units (Unidades Básicas de Saúde, UBSs), Emergency Care Units (Unidades de Pronto Atendimento, UPAs), secondary hospitals, and ambulances are scattered throughout the country (often in remote locations), and specialized centers are located in advanced care units in large cities (such as tertiary hospitals), telemedicine offers the opportunity to improve the treatment of emergencies. The clinical ability of specialists in tertiary hospitals may be used to improve the care in Remote Care Units (Unidades Remotas de Atendimento, URAs), offering support for early diagnosis and therapy guidance for non-specialist medical practitioners providing medical care to patients in URAs [bib_ref] The Brazilian health system: history, advances, and challenges, Paim [/bib_ref] [bib_ref] Cost-benefit of the telecardiology service in the state of Minas Gerais: Minas..., Andrade [/bib_ref]. Communication channels in telemedicine include telephone lines for voice communication and connection to the internet, and for transmission of test results, ECG tracings, and images. Optionally, a video link may be used for visualization of the patient. Telemedicine in the approach to ACS [bib_ref] Improving patient access to specialized health care: the Tele health Network of..., Alkmim [/bib_ref] Situation A: A patient goes by himself to the nearest URA, or calls the prehospital care service and is taken to the URA in a standard ambulance without an electrocardiograph. The professionals at the URA take the clinical history, examine, and obtain serial ECGs from the patient. The ECG tracings are transmitted along with the clinical history to the telecardiology hub where they are interpreted by cardiologists who quickly prepare and send a report, and guide the professionals at the URA on the appropriate therapy. Situation B: A patient connects with the prehospital care service and an ambulance with an electrocardiograph and without a physician answers the call. Based on the patient's history and interpretation of the ECG, if the cardiologist at the telecardiology hub diagnoses the patient as having an ST-segment elevation MI (STEMI), he guides the medical team to administer the standard therapy (for example, aspirin and other medications) and transport the patient to a hospital that offers percutaneous coronary intervention (PCI) or to administer fibrinolytic treatment. Even if the diagnosis of STEMI is excluded, the ambulance team is oriented to follow the cardiologist's instructions about the path to be followed for that patient. Situation C: A patient calls the prehospital care service, an ambulance with a physician and an electrocardiograph answers the call, and the team obtains an ECG that is transmitted to the telecardiology hub. Based on the clinical history and interpretation of the ECG, if the cardiologist at the telecardiology hub determines that the patient has STEMI, he guides the physician to administer treatment for STEMI, such as antiplatelet and anticoagulant agents, and to follow one of these options: - If the STEMI patient can be transported to a hospital with PCI capability and the PCI can be performed within 120 minutes, or if the patient has contraindication to fibrinolytic treatment, the patient must be transported to the hospital with PCI. The ambulance physician also alerts the hospital to prepare the catheterization laboratory to treat a STEMI patient with primary PCI. - If the PCI cannot be performed within 120 minutes, the ambulance physician is instructed to first administer fibrinolytic agents, preferably within 30 minutes, and then transport the patient to the nearest hospital equipped with a catheterization laboratory to continue the therapy. - If the cardiologist in the telecardiology hub confirms that STEMI is not the diagnosis and the ambulance physician determines that the patient has ACS, after receiving the initial therapy the patient should be transferred preferably to a hospital equipped with a catheterization laboratory. If that is not possible, the patient should be transferred to the nearest hospital equipped with an intensive cardiac care unit. If the cardiologist determines that the chest pain protocol should be initiated for the patient, he or she may direct the ambulance team to transport the patient to the nearest hospital, even if the hospital is not equipped with a catheterization laboratory, for monitoring of clinical parameters, ECG, and markers of myocardial necrosis [fig_ref] Figure 1 -: Schematic representation of telemedicine for acute emergency therapy [/fig_ref]. To ensure that the transmitted information has good quality and the interaction is valuable, the patient with chest pain should receive a systematic approach, which can be achieved with several methodologies. One of these methodologies takes into account the "4D" for systematization of the diagnosis of ACS (Figure 2) 9 : - First "D": classify the chest pain (discomfort) into types A (definitely anginal), B (probably anginal), C (probably not anginal), or D (definitely not anginal). - Second "D": define whether an ST-segment elevation is present or not in the ECG. - Third "D": if the ECG does not show signs of ischemia, assess the probability of the patient having coronary artery disease (CAD) based on the presence of risk factors: age (above 45 years in men and 55 years in women), smoking, diabetes, hypertension, and family history of early CAD (below the age of 55 years in men and 65 years in women). - Fourth "D": the diagnosis of ACS must be confirmed or excluded, or the chest pain protocol should be initiated. Requirements in telemedicine for adequate diagnosis and treatment of ACS and other acute cardiac diseases [fig_ref] Figure 3 -: Recommendation grades and levels of evidence of the procedures for management of... [/fig_ref] ## Recommendation grade level of evidence Distant specialized support for guidance on the management of patients with suspected acute coronary syndrome treated in mobile and fixed emergency units. ## Iia a ## Recommendation grade level of evidence Distant specialized support for electrocardiogram interpretation for detection of ST-segment elevation myocardial infarction and coronary syndrome without ST-segment elevation in patients treated in mobile and fixed emergency units. ## I b ## Recommendation grade level of evidence Investigation of the patient, including the type of pain and the likelihood of coronary artery disease, and acquisition of an electrocardiogram for detection of ST-segment elevation myocardial infarction and coronary syndrome without ST-segment elevation in patients with suspected acute coronary syndrome treated in mobile and fixed emergency units before the teleconsultation. ## I a ## Recommendation grade level of evidence Acquisition of a prehospital electrocardiogram to refine the management and reduce the time to reperfusion in patients presenting with ST-segment elevation myocardial infarction. ## I b ## Recommendation grade level of evidence Acquisition of a prehospital electrocardiogram for the diagnosis of STsegment elevation myocardial infarction and acute coronary syndrome without ST-segment elevation to reduce mortality in these patients. ## I b ## Telecardiology in remote routine diagnosis One of the most common applications of telecardiology in remote areas is in the analysis of diagnostic tests, such as ECG, Holter, ambulatory monitoring of blood pressure (AMBP), and echocardiography. Other applications include synchronous or asynchronous teleconsulting systems or second opinions, teleauscultation, remote monitoring of blood pressure, vital signs and implantable electronic devices, and educational activities. In addition, telecardiology has important applications in the penitentiary system, in pediatrics, and in fetal cardiology. Cardiac arrhythmias and syncope [bib_ref] Incidence of atrial fibrillation in an Italian population followed by their GPs..., Scalvini [/bib_ref] [bib_ref] Mobile telemonitoring for arrhythmias in outpatients in the Republic of Georgia: a..., Kirtava [/bib_ref] [bib_ref] Atrial fibrillation with symptoms other than palpitations: incremental diagnostic sensitivity with at-home..., Brunetti [/bib_ref] Since several types of cardiac arrhythmia occur in short and unexpected episodes, its diagnosis depends on an ECG recorded during the paroxysmal episode. A standard 10-second surface ECG may not be able to detect the abnormality in the heart rhythm. In this case, long-term Guideline on Telecardiology in ACS and Other Cardiopathies Arq Bras Cardiol. 2015; 105(2):105-111 ## Figure 4 -recommendation grades and levels of evidence for the financial requirements, procedures, and clinical and team protocols in telemedicine for adequate diagnosis and treatment of acs and other acute cardiac diseases. ## Recommendation grade level of evidence Adequate support from financial resources to establish the infrastructure of the telecardiology hub and assembly of the organizational structure for operation of the telecardiology service. ## I c ## Recommendation grade level of evidence In the telecardiology hub and in the Remote Care Unit, the clinical protocols for diagnosis and treatment must be written in easy language and have simple application. The processes and work pace for each step must be documented and communicated to the team. ## I c ## Recommendation grade level of evidence The team of cardiologists at the telecardiology hub for emergency consultations, such as interpretation of electrocardiograms, conference calls, web conferences, videoconferences, or telephone calls, must be adequate to the number of calls and the number of units connected to the hub. ## I c ## Recommendation grade level of evidence Technical support and management professionals must be part of the team, and everyone should be trained, including users of the system at the mobile and fixed Remote Care Units. ## I c monitoring is recommended, such as 24-hour Holter monitoring or event recording for 2 to 4 weeks. For selected, more difficult cases, an implantable monitoring device named loop recorder may be used to record the ECG patterns during occasional but significant symptoms like syncope. The system may be useful in several situations, among others: - Detection of asymptomatic episodes of atrial fibrillation, which may require anticoagulation therapy to reduce the risk of stroke. - Quick recognition of electrode lead failure, allowing fast intervention and avoiding inappropriate shocks. - Reduction in the number of outpatient visits during long-term follow-up of patients with a pacemaker or implanted defibrillator. Heart failure (HF) [bib_ref] Utilization of telemedicine by heart disease patients following hospitalization, Morguet [/bib_ref] [bib_ref] Telemedicine and remote management of patients with heart failure, Anker [/bib_ref] Distant monitoring, or telemonitoring, is a promising strategy to improve the outcomes of HF treatment, allowing remote monitoring of patients so physicians can intervene early when evidence of clinical deterioration is present. The approaches vary from computerized systems for decision support to programs managed by nurses or physicians. A dedicated hardware or a smartphone may be used to transmit the patient's data (for example, symptoms, weight, blood pressure, and heart rate). A structured phone support, which can better guide the patient and offer specialized treatment to HF patients, has been shown to reduce the mortality and hospitalizations due to HF, improve quality of life, reduce the cost of treatment of prescriptions based on evidence, and improve the patients' knowledge and their knowledge about self-treatment. # Author contributions Conception and design of the research, Acquisition of data, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Oliveira Jr. MT, Paula LJC, Marcolino MS, Canesin MF; Analysis and interpretation of the data and Obtaining financing: Oliveira Jr. MT. ## Potential conflict of interest No potential conflict of interest relevant to this article was reported. # Sources of funding This study was partially funded by Philips Healthcare. ## Study association This study is not associated with any thesis or dissertation work. ## Recommendation grade level of evidence Use of software for electrocardiogram interpretation validated for emergency situations. IIb C ## Recommendation grade level of evidence Availability of a 12-lead electrocardiograph with a capability to transmit the tracing to the telecardiology hub, preferably with an option to print the tracing. ## I c ## Recommendation grade level of evidence Use of photographic reproduction or low-quality scanning to transmit the electrocardiogram to the telecardiology hub for preparation of the report. ## Iii c ## Recommendation grade level of evidence In the Remote Care Unit, all patients with chest pain must have a 12-lead electrocardiogram performed, which should be interpreted in less than 10 minutes from the first medical contact (FMC). ## I a ## Recommendation grade level of evidence In remote locations in which the results of the markers are not available within 60 minutes, the local availability of point-of-care equipment should be evaluated. ## I a ## Recommendation grade level of evidence Wait for the results of myocardial necrosis markers to start therapy in patients with a diagnosis of ST-segment elevation myocardial infarction. ## Iii a ## Recommendation grade level of evidence Availability of cardiac markers assessment by a point-of-care methodology in remote fixed areas where a central laboratory is not available. ## Iia b ## Recommendation grade level of evidence Internet availability for wired or wireless transmission of patients' data, electrocardiogram, and other tests. I C ## Recommendation grade level of evidence Presence of equipment for patient monitoring in the Remote Care Unit and in the mobile unit for all patients with suspected acute coronary syndrome. ## I a ## Recommendation grade level of evidence Presence of telephone equipment for routine transmissions or to allow communication during network downtime, or failure in the equipment or transmission system. ## I c ## Recommendation grade level of evidence Presence of internet connection with adequate bandwidth in the Remote Care Unit and in the telecardiology hub adapted for transmission of electrocardiograms and other additional resources, such as data and image. ## I c ## Recommendation grade level of evidence Presence of wired or wireless hardware for work and communication, suitable for the demand of both the telecardiology hub and Remote Care Unit. ## I b ## Recommendation grade level of evidence Presence of a protection system, security of local data and data to be transmitted, as well as an up-to-date anti-virus program in the telecardiology hub and Remote Care Unit. ## I c ## Recommendation grade level of evidence Recording of all the communication involving orientation or exchange of information between the telecardiology hub and the Remote Care Unit. ## I c ## Recommendation grade level of evidence In services that choose to transmit videos, or still or dynamic images, the wired or wireless hardware for work and communication should be suitable for this purpose. ## I a ## Recommendation grade level of evidence Presence in the Remote Care Unit of electrocardiogram equipment compatible with the system used in the telecardiology hub and technical stock in sufficient amount to replace and maintain the system operative. I C [fig] Figure 1 -: Schematic representation of telemedicine for acute emergency therapy. Treatment strategies using telemedicine are shown for acute coronary syndrome (ACS). ECG: surface electrocardiogram. [/fig] [fig] Figure 2 -: Care systematization for the establishment of the diagnosis in patients with chest pain. ECG: electrocardiogram; CAD: coronary artery disease; ACS: acute coronary syndrome. Chest pain (Discomfort): screen the patient and classify the pain into types A, B, C, or D Define the ECG: presence of ST-segment elevation or signs of ischemia CAD: low, intermediate, or high probability Diagnosis: confirm/exclude ACS or initiate the chest pain protocol [/fig] [fig] Figure 3 -: Recommendation grades and levels of evidence of the procedures for management of patients with ACS. [/fig] [fig] Figure 5 -: Recommendation grades and levels of evidence for the medical equipment in telemedicine for adequate diagnosis and treatment of ACS and other acute cardiac diseases. [/fig] [fig] Figure 6 -: Recommendation grades and levels of evidence for the information technology equipment and services in telemedicine for adequate diagnosis and treatment of ACS and other acute cardiac diseases. [/fig]	None	None	Cardiology is a very promising field in telemedicine. The transmission of electrocardiograms (ECG) from remote health services or ambulances to a central for analysis is already routine in the approach to acute coronary syndromes (ACS). This approach allows the obtention of expert guidance and referral to appropriate health units, with the potential of saving lives. This impact may be seen in acute myocardial infarction (MI), in which telemedicine has reduced intra-hospital mortality rates from 12.3% to 7.1%1-4.
42ee5264a72aa26528d875906c686362125f233d	pubmed	Clinical Practice Guidelines for Prenatal Aneuploidy Screening and Diagnostic Testing from Korean Society of Maternal-Fetal Medicine: (1) Prenatal Aneuploidy Screening	Clinical Practice Guidelines for Prenatal Aneuploidy Screening and Diagnostic Testing from Korean Society of Maternal-Fetal Medicine: (1) Prenatal Aneuploidy Screening In 2019, the Korean Society of Maternal-Fetal Medicine developed the first Korean clinical practice guidelines for prenatal aneuploidy screening and diagnostic testing. These guidelines were developed by adapting established clinical practice guidelines in other countries that were searched systematically, and the guidelines aim to assist in decision making of healthcare providers providing prenatal care and to be used as a source for education and communication with pregnant women in Korea. This article delineates clinical practice guidelines specifically for maternal serum screening for fetal aneuploidy and cell-free DNA (cfDNA) screening. A total of 19 key questions (12 for maternal serum and 7 for cfDNA screening) were defined. The main recommendations are: 1) Pregnant women should be informed of common fetal aneuploidy that can be detected, risks for chromosomal abnormality according to the maternal age, detection rate and false positive rate for common fetal aneuploidy with each screening test, limitations, as well as the benefits and risks of invasive diagnostic testing, 2) It is ideal to give counseling about prenatal aneuploidy screening and diagnostic testing at the first prenatal visit, and counseling is recommended to be given early in pregnancy, 3) All pregnant women should be informed about maternal serum screening regardless of their age, 4) cfDNA screening can be used for the screening of trisomy 21, 18, 13 and sex-chromosome aneuploidy. It is not recommended for the screening # Introduction The incidence of fetal aneuploidy increases with advancing age of women and percentage of advanced maternal age at or above 35 years dramatically increased from 3.8% in 1999 to.3% in 2019 in Korea.Maternal serum screening assesses the risk of the common fetal aneuploidy including Down syndrome (DS) and can be performed on all pregnant women regardless of age. Given the low percentage of pregnant women aged 35 years or older and the relatively low detection rate (DR) of maternal serum screening in the past, the invasive diagnostic testing was recommended as a primary prenatal diagnosis of DS for women at or above 35 years but invasive diagnostic testing is not primarily recommended solely based on maternal age anymore. 2,In Korea, the triple marker screening ("Triple" screening) was first introduced in 1994, and the quadruple marker screening ("Quad" screening), with enhanced diagnostic sensitivity for DS, was introduced in the early 2000s. Since the quad screening had been included in National Health Insurance coverage in 2009, it has been the primary maternal serum screening in the second trimester of pregnancy. With advances in first trimester serum screening, the combined test comprising first trimester and second trimester serum screening was introduced to Korea in 2006 and has enhanced DR of the DS. Cell-free DNA (cfDNA) screening using maternal blood is also being introduced for prenatal screening, in addition to maternal serum screening.The cfDNA screening is based on the analysis of maternal and fetal components of cfDNA in maternal blood.Fetal cfDNA was first discovered by the genotyping of the Y chromosome detected in maternal plasma and serum.It is of placental origin but represents the entire fetal genotype. It is rapidly cleared from the maternal circulation within hours of delivery, making it specific for each episode of pregnancy. 4,7,In the case of a fetus having DS, there will be a slight increase in the amount of chromosome 21-specific DNA fragments in maternal circulation. This approach forms the basis of cfDNA screening for aneuploidy in maternal blood, which can be performed in early pregnancy to reliably evaluate the DS risk and reduce the need for invasive testing such as chorionic villus sampling (CVS) or amniocentesis. Although the accuracy of this screening is dependent on the type of fetal chromosomal abnormality, it shows very high sensitivity and specificity for DS.Therefore, cfDNA screening has been widely implemented in screening for fetal aneuploidy during early pregnancy in many countries.The conventional maternal serum screening, which includes the Triple and Quad tests, is covered by the National Health Insurance scheme and is available to pregnant women at community public health service centers for free. Due to this, it has been widely performed on pregnant women for the detection of fetal aneuploidy. 11,Given the differences in the prevalence of fetal aneuploidy, patients' preferences and country-specific clinical context,a clinical practice guideline for the conventional maternal serum screening test and cfDNA screening is required, in order to reflect the needs of medical providers and consumers and to optimize the process of prenatal aneuploidy screening in Korea. There are two approaches for the development of clinical practice guidelines: de novo and adaptation process. We chose the adaptation process for this study because of the availability of good quality practice guidelines for cfDNA screening developed by other countries. # Methods ## The process of guideline development We reviewed existing guidelines and developed a Korean clinical practice guideline for maternal serum screening for fetal aneuploidy following the Adaptation Process for Developing Korean Clinical Practice Guidelines (https://www.guideline.or.kr/evaluation/sub2.php). ## Forming a treatment guideline committee To define the key questions for the clinical practice guideline, a working committee consisting of 12 maternal fetal medicine specialists and 1 methodology expert from 11 medical schools and hospitals was organized by the Korean Society of Maternal Fetal Medicine (KSMFM). The committee was responsible for the planning, literature review, screening, and evaluation of the guideline development. The process of treatment guideline development ## 1) guideline search To collect all the available forms of published clinical practice guidelines, resources including PubMed, EMBASE, and Cochrane Library was utilized. A literature search for prenatal diagnosis, fetal aneuploidy, maternal serum screening, nuchal translucency, noninvasive prenatal testing and cell-free DNA was conducted, with the inclusion of words such as 'Practice guidelines,' 'Guidelines,' 'Recommendation,' 'Level of evidence,' and 'evidence grade.' We excluded the search results which lacked recommendation, were outdated as publications before 2008, irrelevant, or for which the full texts were unavailable. Finally, 48 guidelines were selected for review. ## 2) formulating key clinical questions The committee initially produced 32 (19 for maternal serum and 13 for cfDNA screening) tentative key questions based on requirements and public opinion. The importance and urgency of the items were rated using a five-point Likert scale. A rating of 4 or more by > 90% of the respondents was regarded as necessary for the key questions, following the modified Delphi method described in previous studies. 14 Following several rounds iterative surveys, the initial 32 items were reduced to the final 19 key questions (12 for maternal serum screening and 7 for cfDNA screening test). These questions were edited and revised for coherency and grammatical clarity. ## 3) guideline assessment, selection, and adaptation To assess the quality of selected guidelines, we used the Korean Appraisal of Guidelines for Research & Evaluation II (K-AGREE II) tool which is approved by the AGREE Research Trust. Seven existing guidelines were identified to be potentially suitable for adaptation. Based on the results of the K-AGREE II evaluation, we created recommendation, in accordance with the 19 key questions, from the selected guidelines. ## 4) additional evidence searching We further reviewed the reference papers, based on which the selected guidelines were developed, in order to assess the level of evidence supporting the guidelines. ## 5) guideline development and determination of the recommendation level We wrote the guidelines and summarized evidence. Level of evidence and grades of recommendationwere determined based on the Scottish Intercollegiate Guideline Network (SIGN, https://www.sign.ac.uk/assets/sign_grading_system_1999_2012.pdf ) translated in Korean by National Evidence-based healthcare Collaborating Agency (NECA, https://www.guideline.or.kr/evaluation/file/koreaguide.pdf ). ## 6) consensus methodology on guideline adoption The subcommittee members of the KSMFM, were asked to provide their level of agreement to each draft recommendation using a Likert scale of 1-9 (where 1 denoted strong disagreement and 9 denoted strong agreement) by email. We averaged each voting score and the mean score was used to assign the item one of three groups: 1-3 (disagreement), 4-6 (neutrality), and 7-9 (agreement). Based on this score, we evaluated the degree of consensus. ## 7) assessment and review by external experts External experts were invited for a public hearing during the 24th Congress of KSMFM held in Seoul, June 2018, and their opinions on the contents, background, and evidence of our guidelines were collected. ## 8) approval After several rounds of revision within the working committee, the guideline was finalized and approved by the Korean Academy of Medical Sciences in March 2019. ## Patients for whom the guideline is applicable The primary target population applicable is all pregnant women in Korea. The major topic is maternal serum screening and cfDNA test for screening of common fetal aneuploidy. The aim was to facilitate the establishment of Korean guidelines based on an adaptation process. The literature search query used took into consideration of the target population and the potential audience. High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low-risk of bias 1+ Well-conducted meta-analyses, systematic reviews, or RCTs with a low-risk of bias 1− Meta-analyses, systematic reviews, or RCTs with a high-risk of bias 2++ High quality systematic reviews of case control or cohort studies High quality case control or cohort studies with a very low-risk of confounding or bias and a high probability that the relationship is causal 2+ Well-conducted case control or cohort studies with a low-risk of confounding or bias and a moderate probability that the relationship is causal 2− Case control or cohort studies with a high-risk of confounding or bias and a significant risk that the relationship is not causal 3 Non-analytic studies, e.g. case reports, case series 4 Expert opinion SIGN = Scottish Intercollegiate Guidelines Network, RCT = randomized controlled trial. ## Professionals for whom guideline use is recommended We considered that the audience of the guidelines would be healthcare providers responsible for the care of pregnant women. In addition, these guidelines may be used by medical students for learning purposes or by patients as a reference to obtain the latest medical knowledge. ## Principles and method of the guideline update The developed guidelines were listed on the website of the Korean Medical Guideline Information Center ('Clinical Practice Guidelines for Prenatal Aneuploidy Screening & Diagnostic Tests', https://www.guideline.or.kr/guide/view.php?number=1085&cate=A). It will be continuously reviewed and reevaluated for the feasibility within the national insurance system. The committee of the KSMFM is responsible for guideline update. # Results ## Key questions and recommendations ## Maternal serum screening Recommendation: Pregnant women should be informed of common fetal aneuploidy that can be detected, risks for chromosomal abnormality according to the maternal age, DR, and false-positive rate (FPR) for common fetal aneuploidy with each screening test, limitations, as well as the benefits and risks of invasive diagnostic testing ( Level 2++, Grade A). ## Summary of evidence: Chromosomal abnormality in which a chromosome is either missing or additionally present is known as aneuploidy. Autosomal trisomies, such as DS, are the most common, and their incidence rises proportionately to maternal age. While maternal serum screening during pregnancy can detect trisomy 21, 18, and 13, it could not screen for all chromosomal abnormalities. Maternal serum screening calculates the risk for aneuploidy by multiplying the risk for aneuploidy according to the maternal age by the likelihood ratio (LR) for aneuploidy based on serum screening test results. The cutoff for high-risk is 1:270, which is the risk for fetal DS for a woman at age 35 or above.Maternal serum screening is classified into first trimester screening and second trimester screening. The first trimester screening measures two serum biomarkers -pregnancyassociated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (hCG), and NT at 11-13 6/7 weeks of gestation and it has a DR for DS of 80-84% with a 5% FPR and positive predictive value (PPV) of 3%-4%. The second trimester screening measures four serum biomarkers-alpha-fetoprotein (AFP), hCG, unconjugated estriol, and inhibin A. The triple screening, which was first introduced in the 1990s, measures three biomarkers (AFP, hCG, and unconjugated estriol) in the second trimester, and its DR for DS was about 69% with a 5% FPR. The DR for DS was improved to 81% with a 5% FPR in the subsequently developed quad screening, which measures inhibin-A in addition to the previous three biomarkers. In recent years, integrated screening test and sequential screening test, which combines the first trimester and second trimester maternal serum screening tests, are performed. Fully integrated screening test measures NT and PAPP-A between 11 and 13 6/7 weeks of gestation ## Clinical practice guidelines for prenatal aneuploidy screening - KQ 1. What information should be given to pregnant women before performing maternal serum screening? and performs quad screening test between 15 and 21 6/7 weeks' gestation. It has the highest DR for DS at 94%-96% (5% FPR) and PPV of 5%. Serum integrated screening test, which excludes NT, has a lower DS DR of 85%-88% compared with fully integrated test. Sequential test involves two types of sequential test: stepwise sequential test and contingent sequential test. First, maternal serum screening was examined in the first trimester to identify highrisk women with reference to a risk cutoff of 1:30 and these high-risk women undergo invasive diagnostic testing in the first trimester. With the stepwise sequential test, all women who were not identified to be at high risk in the first trimester maternal serum screening undergo the quad screening in the second trimester. With the contingent sequential test, quad screening in the second trimester is performed only on the intermediate risk group (1:30-1:1,500) for DS in the first trimester maternal serum screening and omitted in the low-risk group (< 1:1,500). DR for DS is 92% (5.1% FPR) for the stepwise sequential test and 91% (4.5% FPR) for the contingent sequential test. Whereas maternal serum screening enables noninvasive screening of fetuses with elevated risks for trisomy 21, 18, and 13, it cannot detect all chromosomal abnormalities. In other words, being identified as low-risk in the maternal serum screening simply means that these women have a low-risk for the detectable chromosomal abnormalities and not that their chromosomes are all normal. While integrated test has the highest DR for DS among maternal serum screening tests, it has some limitations including not presenting the results of the first trimester screening, having to complete the second trimester screening, and having to undergo both blood samples in a same facility, which may raise issues pertaining to patient adherence. During the counseling for maternal serum screening for fetal aneuploidy, the healthcare providers must also inform women of the benefits and risks of invasive diagnostic testing. One benefit of invasive diagnostic testing, namely CVS and amniocentesis, is that they reveal the numeral and structural anomalies of all chromosomes, but they have a risk for fetal loss. The rate of fetal loss prior to 24 weeks' gestation due to amniocentesis between 15 and 22 weeks of gestation was reported to be 0.13%, and CVS in the first trimester was higher at about 1.2%. Counseling about the limitations of maternal serum screening should be recorded, and the women's decision should be fully respected. Recommendation: It is ideal to give counseling at the first prenatal visit, and counseling is recommended to be given early in pregnancy (Level 2++, Grade A). Summary of evidence: Women should be given sufficient time to understand the information about fetal aneuploidy screening and invasive diagnostic testing offered during counseling and make their own informed decision. In the first trimester, serum screening would be performed in addition to NT measurement at 11-13 6/7 weeks, and it would be ideal to give counseling about fetal aneuploidy screening and invasive diagnostic testing before the antenatal visit for NT measurement, so that fetal aneuploidy screening could be performed at the appropriate timing and women can make their own choices. systems.However, considering the high frequency of miscarriage in early pregnancy, the National Health Insurance system, and relatively high access to healthcare in Korea, it would be more appropriate to set the timing of counseling as any time before the NT measurement in the first trimester instead of at the first prenatal visit. Recommendation: All pregnant women should be informed about maternal serum screening regardless of their age (Level 2++, Grade A). ## Summary of evidence: As the incidence of fetal aneuploidy increases with increased maternal age, advanced maternal age at 35 years or older itself was considered an indication for invasive prenatal testing in the past.The risk for fetal aneuploidy in twin pregnancy differs not only by maternal age but also by zygosity. Dizygotic twins are at an elevated risk for fetal DS compared to single fetuses of women at the same maternal age, and thus the risk for aneuploidy is comparable between twin pregnancy aged 32 years or older and singleton pregnancy aged 35 years older. In recent years, the increased use of assisted reproduction techniques (ARTs) have led to an increase in twin pregnancies, and the incidence of both dizygotic twins and monozygotic twins have risen. Zygosity may be diagnosed based on the use of ART or chorionicity, but chorionicity alone is not sufficient to accurately determine zygosity, as 33% of monozygotic twins are dichorionic. Moreover, because the risk of fetal loss due to invasive diagnostic testing was known to be higher for twins than for singletons, assessing fetal risk for DS using maternal serum screening is recommended over using maternal age alone in twin pregnancies as well. Performing invasive diagnostic testing without screening should be limited to cases involving intrauterine fetal death or structural abnormality of one fetus. Summary of evidence: Performing first trimester and second trimester serum screening independently of one another without using them as a part of combined test increases FPR without increasing the DR for fetal aneuploidy. Because the quad screening has a lower DR for fetal aneuploidy with higher FPR compared to the first trimester maternal serum screening including NT, first trimester screening is superior to the quad screening when performed independently. Therefore, both healthcare providers and pregnant women must be aware of the fact that the risk for FPR may increase without better DR for fetal aneuploidy if a woman who was low-risk in the first trimester maternal serum screening undergoes the quad screening in the second trimester at a different facility. ## Recommendation ## Recommendation: Healthcare providers should explain that the result indicating high-risk does not confirm fetal abnormality and offer counseling about cfDNA screening or invasive diagnostic testing (Level 2++, Grade A). ## Summary of evidence: In the maternal serum screening, the individual risks for trisomy 21 and 18 are analyzed, and the woman is classified as high-risk if a certain threshold of risk is met. It should be explained to the woman that the result indicating high-risk does not confirm fetal abnormality and that it is an outcome of a combined analysis of the existing risk for fetal aneuploidy according to maternal age and the serum test results. Further, after informing the woman of the accuracy of each serum screening test and confirming that they have understood the test results, healthcare providers should explain the pros and cons of further tests to be considered in detail. Healthcare providers should first recommend invasive diagnostic testing to high-risk women and explain the method, safety, and cost. Women should be informed that CVS could be performed prior to 14 weeks' gestation and amniocentesis could be performed after 14 weeks' gestation and should undergo testing accordingly. CVS can detect chromosomal abnormality at a rate of 98%-99%, with < 1% mosaicism, < 1% risk of maternal cell contamination, and 0.5%-1.2% procedure-related fetal loss rate. The accuracy of genetic amniocentesis performed in the second and third trimesters was reported as 99.8%-99.9%, and while the procedure-related fetal loss rate was 1/200, that is, 0.5%, but recent reports showed lower fetal loss rate at 0.06%-0.13%. Amniocentesis is not recommended in the first trimester due to increased risk of amniotic fluid leakage and equinovarus.While fetal chromosomal abnormality can be diagnosed only based on invasive diagnostic testing, some women prefer noninvasive 'blood' test as an alternative due to concerns about fetal safety from invasive testing. Maternal serum screening should not be performed again in these women, as doing so would be not cost-effective. screening. Also, women should be well informed that the cfDNA screening could delay the diagnosis for fetal chromosomal abnormality in true positive cases because women with high-risk in the cfDNA screening must be taken invasive diagnostic testing. Women should be well informed that cfDNA screening is not a diagnostic test. screening or cell-free DNA screening, MSAFP must be performed in the second trimester in such cases. NTD is a different congenital abnormality from fetal aneuploidy, so healthcare providers should give information about MSAFP screening to women prior to 21 6/7 weeks of gestation even if they decided not to undergo the fetal aneuploidy screening. If MSAFP screening is chosen, the results must be analyzed after adjusting for ultrasound-based gestation age, body weight, insulin-dependent diabetes mellitus, race, and a number of fetuses. Using a cutoff of 2.5 MoM for MSAFP in the second trimester, 73%-83% of open NTD was diagnosed. Recommendation: Invasive diagnostic testing for fetal chromosomal abnormality and detailed ultrasonography to examine structural anomalies should be performed (Level 2++, Grade A). ## Summary of evidence: NT can be measured between 11 and 13 6/7 weeks of gestation, with the highest accuracy between 11 and 12 weeks. Chromosomal abnormality was found in 35% of cases with NT between 3-8 mm, and various structural abnormalities were associated although fetal karyotype was normal. NT increases by 15%-20% depending on gestational age, so recent DS screening programs calculate the risk by converting the values into MoM for the specific gestational age. According to a single center study about gestational age and NT thickness in Korea by Chung et al. in 2004, the ethnic difference was not significant, and as no past studies have reported a racial difference in NT, it would be acceptable to directly apply foreign criteria. If NT is ≥ 99th percentile or 3 mm or greater between 11 and 13 6/7 weeks of gestation regardless of gestational age, the likelihood of aneuploidy is high at 1:6, and even if combined with maternal serum screening, only 8% of these cases have the risk for DS lowered to 1:200. Most of these cases still are at high-risk and need to consider invasive diagnostic testing, based on which it would be appropriate to recommend invasive prenatal testing without serum screening. Moreover, enlarged NT to 3 mm or higher was only observed in 0.5% of the cases, so the overall medical cost would not increase much. An enlarged NT (≥ 3.0 mm) can detect fetal DS with a 69%-75% DR with 5.0%-8.1% FPR. Regarding cystic hygroma, 51% of the cases are accompanied by chromosomal abnormality, and 34% with normal karyotype are accompanied by major heart and skeletal anomalies. Therefore, when cystic hygroma is observed, clinicians should recommend invasive diagnostic testing and perform detailed ultrasonography to identify other structural anomalies. Recommendation: Detailed ultrasonography for structural abnormality and fetal echocardiography should be performed in the second trimester and women should be informed of the possibility of genetic syndrome undetected through fetal karyotyping and increased risk for poor perinatal outcomes (Level 2++, Grade A). ## Summary of evidence: Enlarged fetal NT is also associated with the genetic syndrome and fetal structural anomalies such as heart, abdominal wall, and musculoskeletal system in addition to fetal chromosomal abnormality. Survival rate decreases with increasing NT thickness, where survival rate decreases from 96.3% when NT < 3.5 mm to 44.4% when NT ≥ 6.5 mm, and the incidence of fetal abnormality and genetic syndrome also increase with increasing NT thickness. The incidence of cystic hygroma was reported to be 1/285 first-trimester pregnancies and of them, 51% have chromosome abnormality. Among cystic hygroma with normal karyotype, 34% had fetal structural abnormality and intrauterine death occurred in 8% of normal karyotype, and 4% of survivors were reported to have cerebral palsy and developmental disorder. Cystic hygroma has poorer prognosis compared to a simple enlargement of NT, where the risks for fetal aneuploidy, heart anomaly, and perinatal death are 5 times, 12 times, and 6 times higher, respectively. Therefore, if normal karyotype is confirmed in a fetus with enlarged NT or cystic hygroma in the first trimester, a detailed ultrasonography and fetal echocardiography should be performed in the second trimester to examine for structural anomalies. Clinicians should inform women with enlarged NT or cystic hygroma of the risk for undiagnosed genetic syndrome and risk for poor perinatal outcomes. ## Recommendation: In cases with an isolated minor marker related to aneuploidy in the second trimester ultrasound, prenatal aneuploidy screening is recommended if it was not performed. If fetal aneuploidy screening was performed in the first or second trimester and the result was low-risk, an additional test is not recommended (Level 2++, Grade B). ## Summary of evidence: Ultrasonographic minor markers are generally normal variants identified on second trimester but can be associated with fetal DS. 20,21 They are relatively common enough to be found in 10% of normal pregnancies and do not mean fetal abnormalities or affect prognosis in absence of fetal aneuploidy. Because the LR of DS differs for each minor marker, each minor marker should be assessed in consideration of the woman's overall clinical situation. According to Nyberg et al.,an analysis of the LR of nuchal fold thickening, echogenic bowel, short femur, echogenic intracardiac focus, and renal pelvis dilation for DS revealed that nuchal fold thickening had the highest LR (LR 11), followed by echogenic bowel (LR 6.7), with the remaining minor markers having a LR of 1. the strongest association with DS, highlighting the need for detailed ultrasonography and counseling to evaluate for the presence of other minor markers in cases showing nuchal fold thickening in the second trimester ultrasound. One study reported that echogenic bowel could result from swallowing blood in the amniotic fluid and that it does not increase the risk for DS. Echogenic intracardiac focus is reported to occur in up to 30% of Asian pregnant women, which should be taken into consideration when applying it as a minor marker in Korean women. While nasal bone hypoplasia improves DR of DS when combined with other minor markers, additional test is not recommended solely based on nasal bone hypoplasia. Thus, if minor markers other than nuchal fold thickening are detected alone, it is desirable to perform fetal aneuploidy screening if it had not been previously performed and an additional test is not recommended if the fetal aneuploidy screening result was low-risk. When adjusting for the risk of existing maternal serum screening using minor markers, the relative LRs of positive and negative findings should be applied systematically, and if the marker is present alone, it has little impact on the existing maternal screening test. In particular, if cfDNA screening was already performed and its result was low-risk, the detection of a single minor marker does not warrant additional test or risk readjustment. Choroid plexus cyst was excluded from the list of minor markers of DS. Recommendation: Pregnant women should be informed that maternal serum screening tests have lower accuracy in twin pregnancies than in singleton pregnancies (Level 2++, Grade B). ## Summary of evidence: The risk for fetal aneuploidy in twin pregnancy is affected by the number of fetuses and zygosity. When assessed according to maternal age, the risk for fetal DS is equal between monozygotic twin pregnancy and singleton pregnancy but increases in dizygotic twin pregnancy, as each of the dizygotic twin has a risk for fetal aneuploidy. However, data on maternal serum screening is relatively lacking for twin pregnancies compared to singleton pregnancies, and as maternal serum screening assesses the overall risk present in pregnancy as opposed to assessing the risk for each fetus, it has a lower accuracy for twin pregnancies compared to singleton pregnancies. According to the cohort study by Neveux et al.,the DR for fetal DS with triple screening is 73% in monozygotic twin pregnancy, 43% in dizygotic twin pregnancy, and 53% overall with 5% FPR, which were lower than that in singleton pregnancy. According to Wald et al.'s study,integrated test detected DS in 93% in monochorionic twins, 78% in dichorionic twins, and 80% in all twin pregnancies with 5% FPR, but the results were not confirmed with a prospective study. Based on the fact that integrated test that combines NT and maternal serum screening enhances the DR while lowering the FPR in singleton pregnancies, the same strategy is currently used for twin pregnancies; however, this method has not been prospectively validated, so pre-and post-test counseling is essential when performing maternal serum screening in twin pregnancy. Recommendation: Maternal serum screening is not recommended when fetal demise or major structural abnormality is identified in one fetus in twin pregnancies. In such cases, ## Clinical practice guidelines for prenatal aneuploidy screening - KQ 11. Can maternal serum screening be recommended in twin pregnancies with an equal accuracy with that in singleton pregnancies? - KQ 12. Is maternal serum screening appropriate when fetal demise or major structural abnormality is identified in one fetus in twin pregnancies? invasive diagnostic testing can be considered to diagnose for fetal chromosomal abnormality (Level 2++, Grade B). ## Summary of evidence: Multifetal pregnancy is associated with a higher incidence of miscarriage and fetal anomaly compared to a singleton pregnancy, and there are cases in which one fetus dies in utero or has structural abnormalities while the co-twin is normal. Vanishing twin, which refers to the loss of one embryo early in pregnancy, occurs in 10%-40% of all twin pregnancies, and this can impact the concentration of serum biomarkers even after a prolonged period. Concentrations of serum biomarkers were compared between vanishing twin and singleton pregnancy in consideration of same gestational age and maternal age, and the results showed that the vanishing twin group had 21% higher PAPP-A in the first trimester and 10% higher AFP and 13% higher inhibin A in the second trimester. The concentrations of PAPP-A and AFP levels showed a negative correlation with time interval between the occurrence of fetal demise and blood sampling, so PAPP-A value was similar to that of singleton pregnancy after 4 weeks, but it was found that the concentrations of hCG and inhibin A did not change over time. Therefore, maternal serum screening would lead confusion with its results in cases involving a vanishing twin and is not recommended. Similar to the consideration of invasive diagnostic testing in a singleton pregnancy with structural abnormality, it is appropriate to consider invasive diagnostic testing in twin pregnancies involving one fetus with structural abnormality. ## Cell-free dna screening Recommendation: All pregnant women can be informed and offered the choice of cfDNA screening, although the first priority for these tests should be the high-risk group (Level 2++, Grade B). ## Summary of evidence: The cfDNA screening shows similar sensitivity and specificity in both low and high-risk groups. 24 -28 Given the low PPV of this test in low-risk group and the possibility of 'no call' from inadequate sample, in terms of cost-effectiveness, it is not recommended for all pregnant women. Recommendation: cfDNA screening can be used for the screening of trisomy 21, 18, 13 and sex-chromosome aneuploidy. It is not recommended for the screening of microdeletion (Level 2++, Grade B). ## Summary of evidence: The cfDNA screening demonstrates high reliability in detecting trisomy 21, 18, and 13. While this method shows the highest sensitivity (99.3%) and specificity (99.8%) for trisomy 21, the sensitivity is 97.4% and specificity is 99.8% for trisomy 18. The sensitivity is 91% and specificity is > 99% for trisomy 13 and monosomy X. In the high-risk group, aged 40 or older, PPV is 87%, 68%, and 57% for trisomy 21, 18, and 13, respectively. 17,18,29 -The false positive rate of cfDNA screening for common trisomy is 1%, and even < 1% for trisomy 21. The performance of this screening may be affected by placental mosaicism, vanishing twin, maternal copy number variations and maternal malignant tumor. The DR for monosomy X is over 90% and false positive rate is 1%. 18,32 -34 In a study using prospectively collected samples, PPV for monosomy X was 48.4% (30%-67%).It should be conveyed that there can be a false positive result for sex chromosome abnormality, which may have varied clinical implication in the presence of maternal sex chromosome mosaicism.The cfDNA screening for microdeletions is not recommended because the PPV ranges from 3.8 to 17%, which precludes practical implication. 36 Recommendation: 1) It should be clarified that a 'low-risk' result does not mean the absence of chromosomal abnormality. 2) A mother with a result of 'no call' should be offered the invasive test, rather than a retest (Level 2++, Grade B). ## Summary of evidence: Although it shows good performance in the screening of trisomy 21, 18, and 13, several studies have reported false positive and false negative cases. 37,38 Therefore, confirmative diagnosis should be made only after the invasive test has been performed. Likewise, women with a negative result should be informed that it does not rule out all abnormalities in fetal chromosomes.In cases of a failure to obtain result ('no call'), the woman is more likely to have fetal aneuploidy such as trisomy 18 and 13. 28,The success rate of the repeat test is reported to be as low as 45%-50% or as high as 80%-90%, depending on the study setting.Considering the higher risk of abnormal result and the anxiety of women who have to wait for the test to be repeated, we do not recommend repeating cfDNA screening in women with 'no call' result. This 'no call' result is more common in women with obesity, with the prevalence being 20% when the bodyweight is > 113 kg (250 lb) and 50% when it is > 159 kg (350 lb).Thus, cfDNA screening would not be the optimal fetal aneuploidy screening test in pregnancy for women with severe obesity. 43 ## Recommendation: The cfDNA screening cannot be offered as a first-line aneuploidy screening test for all women because it is not cost-effective in low-risk pregnancy (Level 2++, Grade B). ## Summary of evidence: On an average, cfDNA screening shows better performance in detecting chromosomal trisomy compared to the conventional maternal serum screening test.However, PPV of cfDNA screening is lower in the low-risk group compared to the high-risk group. There is also the possibility of 'no call,' when the amount of placenta-derived cell-free DNA in maternal blood is not sufficient for the test. Comparing to the analytebased tests, which are frequently positive for a large range of chromosomal abnormalities, cfDNA screening is specific for individual aneuploidies.Of abnormal result from invasive diagnostic testing,.9% of all abnormalities detected by invasive diagnostic testing were considered undetectable by the current cfDNA screening.Given the high cost of cfDNA screening, it is not cost-effective to recommend this test for all pregnant women. ## Recommendation: The optimal timing for cfDNA screening is 10 weeks of gestation and beyond (Level 2++, Grade A). ## Summary of evidence: The proportion of fetal component in cfDNA in maternal blood has been known to remain constant between gestational weeks 10 and 22, regardless of maternal ethnicity or age. 46 Recently, some reports have shown that the proportion of fetal component is closely associated with gestational age; fetal component in cfDNA increases by 0.1% per week during gestational weeks 10-21 and by 1% after gestational week 21. 47,For most pregnant women, the proportion of fetal component is > 4% after gestational week 10, which is sufficient for cfDNA screening. The test is likely to fail to yield a result before gestational week 9, with only 72.6% success rate.Therefore, it is recommended that cfDNA screening be performed after gestational week 10. Recommendation: Cell-free DNA screening is not recommended for women with multiple gestations, since the accuracy in multiple pregnancy is not as high as that in singleton pregnancy (Level 1+, Grade B). ## Summary of evidence: Twin pregnancy generally shows lower fetal component in cfDNA of maternal blood than singleton pregnancy (7.4% vs. 10% or 8.7% vs. 11.7%). 49,The failure rate was also shown to be higher in twin pregnancy. 50,51 Therefore, cfDNA screening is not recommended in twin pregnancy because of poorer performance compared to a singleton pregnancy. Recommendation: Women with a high-risk result should be offered the option of having an invasive test. It should be urged that no irreversible obstetric procedures be undertaken without a confirmative diagnostic test (Level 2++, Grade B). ## Summary of evidence: Given the false positive and false negative cases and the varied accuracy, depending on the type of aneuploidy, cfDNA screening should not be regarded as a confirmative test. 37 -40,52 According to a study of 31,030 women, the PPV for all types of trisomy was 82.9% and for trisomy 21 it was 90.9%.Therefore, drawing conclusions of fetal aneuploidy, based on a high-risk result without any invasive testing, should be avoided. ## Clinical practice guidelines for prenatal aneuploidy screening - KQ 5. When can cfDNA screening be performed during pregnancy? Is there an optimal timing for cfDNA screening? - KQ 6. Is the result of cfDNA screening also valid in multiple pregnancy, as it is in singleton pregnancy? - KQ 7. What are the recommendations for women whose result is high-risk in cfDNA screening? ## Summary Our guidelines aim to define an optimal application of maternal serum screening and cfDNA test as a fetal aneuploidy screening test; however, the ultimate decision should be made by the women and physicians. The purpose of this guideline is to reduce an unnecessary invasive test and the misinformation on the termination of pregnancy. This guideline provides evidence for a cost-effective strategy for prenatal aneuploidy testing and a reference for reimbursement by the national health insurance. Based on this guideline, we will be able to establish more effective prenatal care system and programs to improve maternal fetal health, as well as a research basis of maternal fetal medicine.	None	None	In 2019, the Korean Society of Maternal-Fetal Medicine developed the first Korean clinical practice guidelines for prenatal aneuploidy screening and diagnostic testing. These guidelines were developed by adapting established clinical practice guidelines in other countries that were searched systematically, and the guidelines aim to assist in decision making of healthcare providers providing prenatal care and to be used as a source for education and communication with pregnant women in Korea. This article delineates clinical practice guidelines specifically for maternal serum screening for fetal aneuploidy and cell-free DNA (cfDNA) screening. A total of 19 key questions (12 for maternal serum and 7 for cfDNA screening) were defined. The main recommendations are: 1) Pregnant women should be informed of common fetal aneuploidy that can be detected, risks for chromosomal abnormality according to the maternal age, detection rate and false positive rate for common fetal aneuploidy with each screening test, limitations, as well as the benefits and risks of invasive diagnostic testing, 2) It is ideal to give counseling about prenatal aneuploidy screening and diagnostic testing at the first prenatal visit, and counseling is recommended to be given early in pregnancy, 3) All pregnant women should be informed about maternal serum screening regardless of their age, 4) cfDNA screening can be used for the screening of trisomy 21, 18, 13 and sex-chromosome aneuploidy. It is not recommended for the screening of microdeletion, 5) The optimal timing of cfDNA screening is 10 weeks of gestation and beyond, and 6) cfDNA screening is not recommended for women with multiple gestations. The guideline was reviewed and approved by the Korean Academy of Medical Sciences.
78c90c938458c164068ea2b6727c6184aea60cfe	pubmed	Update of guidelines on laparoscopic (TAPP) and endoscopic (TEP) treatment of inguinal hernia (International Endohernia Society)	Update of guidelines on laparoscopic (TAPP) and endoscopic (TEP) treatment of inguinal hernia (International Endohernia Society) and Other Interventional Techniques formulated and circulated for approval by all the involved experts.References (in parentheses graduation of evidence)1. Eccles M, Mason J (2001) How to develop cost-conscious guidelines. Health Technol Assess 5(16):1-69. Reviews # Introduction Guidelines are the bridge between science and clinical practice . Science is a dynamic process and it is continuously evolving. Consequently, there is a continual development of new insights necessitation updates of existing guidelines. For this update, the authors concentrated on studies with level of 1 and 2 evidence. All references are marked with the level of evidence, according to the Oxford classification. In general ''Recommendation Grade D'' does not constitute a recommendation, but in some instances it is shown in the text to indicate lack of quality data. We recommended all readers to download the original statements and recommendations , for fully appreciation of the Update Guidelines on Laparoscopic Hernia Surgery. Updates should include issues that were not yet sufficiently covered in the original guidelines or those which have gained increased clinical importance. For this reason, the Update includes four new chapters: single port surgery, convalescence, costs and training. The update process was started in March 2013. All the authors were requested to commence revision of their chapters between January 2009 and September 30th 2013. An Update Consensus Conference was held on October in Windhoek/ Namibia, following which, the first versions of the updates were presented to the delegates and extensively discussed. Based on these discussions the definite update was Comments An update of the Cochrane report analyzing open hernia repairs, non-mesh and mesh repairs, was published in 2012 (search until October 2011) including 7,843 hernia operations in 17 studies . The overall infection rates were 3.1 % in the prophylaxis group and 4.5 % in the control group (OR 0.64, 95 % CI 0.50-0.82). The subgroup with mesh had infection rates of 2.4 and 4.2 % in the prophylaxis and control groups, respectively (OR 0.56, 95 % CI 0.38-0.81). The recommendation in this report was: ''Antibiotic prophylaxis for elective inguinal hernia repair cannot be universally recommended for open hernia repair. Neither can the administration be recommended against when high rates of wound infection are observed.'' The three other meta-analyses are all performed on mesh repairs and all except one study is included in the Cochrane report . They all conclude that antibiotic prophylaxis is beneficial for protection of surgical site infections in open mesh repair. References (in parentheses graduation of evidence) Comments Due to the present structure of the guidelines some of the fundamental technical key points of TAPP repair like the mesh choice, mesh size, slitting/non-slitting and fixation /non fixation are discussed in depth in other chapters. These key points do influence obviously the patient's outcome and represent an important part of the TAPP's best practice. In several instances Recommendation Grade D is mentioned. In general ''Recommendation Grade D'' is no recommendation at all, due to weak evidence. Nevertheless it is used in this text to demonstrate that some important data are still missing. Which is the safest and most effective method of establishing pneumoperitoneum and obtaining access to the abdominal cavity? New statements-identical to previous except statement below. 1B In thin patients (BMI \ 27), the direct trocar insertion is a safe alternative to the Veress needle technique (stronger evidence). New recommendations-identical to previous except recommendation below. Grade C The direct trocar insertion (DTI) can be used in order to establish pneumoperitoneum as a safe alternative to Veress needle, Hasson approach or optical trocar, if patient's risk factors are considered and the surgeon is appropriately trained (new recommendation). What kind of trocars should be used? Is there any relation between the trocar type and risk of injury and/or trocar hernias? New statement-identical to previous except statement below. Level 2B Use of 10-mm trocars or larger may predispose to hernias, especially in the umbilical region or in the oblique abdominal wall (Stronger evidence). New recommendation-identical to previous except recommendation below. Grade B Fascial defects of 10 mm or bigger should be closed (Stronger evidence). ## Is clinical examination efficient enough? What is the role of TAPP and other techniques in reliable assessment? New statements-identical to previous (but additional references, see comment). New recommendations-identical to previous. Peritoneal closure New statements-identical to previous. New recommendations-identical to previous except statement below. ## Grade b A thorough closure of peritoneal incision or bigger peritoneal tears should be achieved (Stronger evidence). ## Comments After more than two decades of practicing TAPP repair, the technique per se is standardized to a great extent. Although only minimal changes in evidence levels and no completely new insights were to be expected in the time frame of the last 3 years, the content of the guidelines must be periodically scrutinized, re-examined and if necessary corrected. In order to reinforce the validity of existing recommendations and to improve the adoption of it by the world-wide surgical community it was sometimes necessary to interpret the evidence to make it fit better to everyday life. In paragraph ''Which is the safest and most effective method of establishing pneumoperitoneum and obtaining access to the abdominal cavity?'' there is a new input of stronger evidence (1B) and 2B concerning the direct trocar insertion. Nevertheless the authors defend their recommendation Grade A ''When establishing pneumoperitoneum … extreme caution is required''. Because of the potential risk of a major injury the recommendation based on the statement ''the direct trocar insertion is a safe alternative to the Veress needle technique'' is intentionally downgraded to grade C: The direct trocar insertion (DTI) can be used in order to establish pneumoperitoneum as a safe alternative to Veress needle, open access or optical trocar, if patient's risk factors are considered and the surgeon is appropriately trained. The paragraph ''What kind of trocars should be used? Is there any relation between the trocar type and risk of injury and/or trocar hernias?'' reached stronger evidence for to refrain from the use of cutting trocars in order to diminish the local trauma and prevent the development of possible trocar hernias. The recommendation Grade C ''Trocar sites with fascial defects of 10 mm or larger can be closed'' was upgraded to Grade B ''Fascial defects of 10 mm or bigger should be closed. The recommendations concerning clinical examination and anticipation of undiagnosed contralateral hernias gained additional support and insight from literature . The previous recommendation on peritoneal closure already connoted verbally the importance of the task, although assigned to Grade C. To emphasize the fact the recommendation was upgraded to Grade B. References (in parentheses graduation of evidence) New recommendations-identical to previous except recommendation below. Grade D As alternative the primary closure of direct inguinal hernia defects with a pre-tied suture loop can be used (new recommendation). ## Comments Each of the M2 or M3 direct defects, according to the European Hernia Society (EHS), were systematically closed prior to the introduction of the prosthetic mesh . Grasping and inversion of the attenuated transversalis fascia at its apex, using a laparoscopic forceps and plication of the transversalis fascia by placing a tight endoloop of polydioxanone (PDS) at its base. In total, endoloops of PDS were used to close the weakened transversalis fascia in 76 cases (30 M3, 44 M2 and two M1). Only one patient (1.3 %) complained of a residual seroma formation, which was still clinically present at 3 month post-operatively, but was not symptomatic. There were only two minor postoperative complications, which occurred in the same patient and were not related to the endoloop technique. Finally, no patient complained of chronic groin pain and there was no hernia recurrence after a median follow up of 18 months. How should a large indirect sac be handled? New statement-identical to previous except statement below. Transection of a large indirect sac does not lead to significant differences in postoperative pain, length of hospital stay and recurrence, but to a significant higher seroma rate (new statement). New recommendation-identical to previous except recommendation below. ## Grade c A large indirect sac may be ligated proximally and divided distally without the risk of a higher postoperative pain and recurrence rate, but with an increased postoperative seroma rate (new recommendation). Comments 520 TEP repairs with indirect inguinal sac were performed in 498 patients. The patients were classified into two groups: the transected sac group with 269 patients (275 cases) and the completely reduced sac group with 230 patients (245 cases) . Statistical analysis between the two groups showed no significant differences in postoperative pain, length of hospital stay, and recurrence, except for postoperative seromas, which were more frequent in the transected sac group (24 of 275) than the completely reduced sac group (6 of 245; p = 0.002). Should a drain be used after a TEP repair? Should seromas be aspirated? New statement-identical to previous except statement below. Drain after TEP significantly reduces the incidence of seroma formation with increasing the risk of infection or recurrence (new statement). New recommendation-identical to previous except recommendation below. Grade C A closed-suction drain can be used to reduce the risk of seroma formation without increased risk of infection (new recommendation). ## Comments In 929 patients (1,753 hernias), drain was put in 849 patients (1,607 hernias) and no drain was put in 80 patients (146 hernias) . Follow-up ranged from 9 to 45 months. Seroma formation was significantly lower in the drain group reviewed eight trials that included a total of 373 patients . They found no difference between the groups in postoperative pain reduction following endoscopic TEP inguinal hernia repair. The intensity of pain was not significantly different between the bupivacaine treatment group and the control group. No bupivacaine-related complications were reported. They concluded, that extraperitoneal bupivaciane treatment during endoscopic TEP inguinal hernioplasty is not more efficacious for the reduction of postoperative pain than placebo. ## Comments Postoperative/persistent pain Bansal et al. randomized 314 patients into two groups (TEP, TAPP) and recorded the postoperative pain score at 6 h, 24 h, 1 week and 6 weeks as well as parenteral analgesic requirement. TAPP group was associated with a significantly higher pain score at 6 h, 24 h, 1 week and 6 weeks. Parenteral analgesic requirement was also found to be significantly higher in the TAPP group. Zanghi et al. prospectively studied 439 patients undergoing TEP or TAPP repair. Postoperative pain score was higher in the TAPP group on 1, 7, 30 and 90 days postoperatively. Visceral injury In the RCT done by Bansal et al. , no major intraoperative complications with no hollow viscus, bladder injury, or major vascular injury were seen. None of the patients in either group had any life-threatening complications during the postoperative period in form of deep vein thrombosis (DVT) and pulmonary embolism (PE) or myocardial infarction (MI). ## Deep infection No incidence of deep infection were seen postoperatively in level 1 and 2 studies . Port site hernia No incidence of port site hernia were seen postoperatively in level 1 and 2 studies . Seroma Bansal et al. found a significantly higher incidence of postoperative seroma in the TEP repair group. Postoperative seroma were managed by observation only. Scrotal edema Bansal et al. found a significantly higher incidence of postoperative scrotal edema in the TAPP repair group. Operative time TAPP repair group was associated with a significantly longer operative time compared to the TEP group . In the population based study by Gass et al. , TEP repair was associated with a significantly longer operating time compared to TAPP group. Hospital stay In the meta analysis by Bracale et al. , there was a significantly longer postoperative hospital stay in the TAPP group. Bansal et al. did not find any significant difference in the postoperative hospital stay between TAPP and TEP repair. Gass et al. also found a significantly longer hospital stay in the TAPP group. Conversion rate Bansal et al. had a single conversion in the TEP group, because the anatomy could not be defined due to adhesions between peritoneum, posterior rectus sheath, and abdominal wall fascia, which lead to peritoneal laceration leading to conversion. However, the repair could be accomplished after conversion to TAPP. Gass et al. found that unadjusted and risk-adjusted analyses of conversion rates revealed significantly higher rates for the TEP group, as is reflected by a high odds ratio. Complication rate Gass et al. found that patients undergoing TEP had a statistically significant increased rate of intraoperative complications and postoperative surgical complications. General postoperative complications were not statistically different between the two methods. Recurrence rate Bansal et al. had one recurrence in TAPP group (0.3 %), where mesh was found to have migrated into the dilated internal inguinal ring at reoperation and forming part of the sac. No recurrences were seen in the TEP repair group. Overall satisfaction No difference in the overall satisfaction was found between TEP and TAPP in level 1 and 2 studies . Quality of life In the study by Bansal et al. , both the TEP and TAPP groups showed significant improvement in quality of life from the preoperative period to 3 months postoperatively. The TEP group showed significant improvement in all domains, whereas the TAPP group showed significant improvement in all domains except those of vitality and social functions. However, both groups were comparable postoperatively in terms of quality of life. ## Comments Ferzli et al. reviewed their experience with 1,890 TEP hernia repairs. Ninety-four large scrotal hernias were identified of which, nine cases (9.5 %) required conversion to an open procedure due to an incarcerated and indurated omentum. Six of these (6.4 %) underwent a combined laparoscopic and open repair with good results and no recurrence at 6 months. They conclude that a combined laparoscopic and open approach can greatly assist in the visualization and dissection of the preperitoneal space, thereby facilitating reduction of the hernia and placement of the mesh. Siow et al. retrospectively reviewed their experience with TAPP in the treatment of incarcerated scrotal hernias. They were able to successfully treat 20 patients using either a pure TAPP technique or TAPP combined with a limited open technique. TAPP for incarcerated and strangulated inguinal hernia No new statements or recommendations. ## Tep for incarcerated and strangulated inguinal hernia New statement-identical to previous except statement below. 3 Laparoscopic hernia repair for incarcerated inguinal hernia has been successfully and safely performed in the pediatric population (new). New recommendations-identical to previous except recommendations below. Grade C Laparoscopic hernia repair for incarcerated inguinal hernia may be successfully and safely performed in the pediatric population by surgeons with laparoscopic expertise (new). ## Comments Nah et al. performed a retrospective study of pediatric patients with incarcerated inguinal hernias and found a trend toward fewer complications in the group whose repair was performed laparoscopically rather than open, although this was not statistically significant. They also found a higher statistically significant incidence of contralateral hernias that were repaired at the time of repair of the incarcerated hernia. Esposito et al. reviewed their experience with 601 children who underwent laparoscopic inguinal hernia repair 46 (7.6 %) of whom presented with incarceration. The authors were able to successfully treat these patients with laparoscopic repair with a recurrence rate of 4.3 %. Chan et al. reviewed their experience with laparoscopic approach to the incarcerated pediatric inguinal hernia repair. They were able to safely and successfully treat 16 patients with incarcerated hernias using laparoscopy. Choi et al. conducted a retrospective analysis of 945 patients who underwent TEP repair of their inguinal hernia and 66 had an incarcerated hernia. There was no difference in outcome between the incarcerated and reducible groups but operative times were longer and seroma formation was greater in the incarcerated group. Yang et al. retrospectively reviewed 188 patients who underwent emergency surgical repair of strangulated groin hernias; 57 received laparoscopic and 131 received open repairs. They found that more laparotomies were performed in the open group (19 vs. 0), the wound infection rate was significantly higher in the open group (12 vs. 0), and the mean hospital stay was shorter in the laparoscopic group Shah et al. found no difference in complication rate in their retrospective review of 172 patients who underwent either open versus laparoscopic inguinal hernia repair for recurrent inguinal hernia. They did find a significantly lower incidence of re-recurrence in the laparoscopic group. Sevonius et al. reviewed the Swedish hernia registry and found that the risk of reoperation for re-recurrence in 19,582 hernia repairs for recurrent hernia is significantly reduced if the laparoscopic or open pre-peritoneal repair were used for the repair of the recurrence (p \ 0.001). Bignell et al. prospectively studied 120 patients who underwent TAPP inguinal hernia repair versus open hernia repair. They demonstrated a slightly lower severity of chronic groin pain after laparoscopic inguinal hernia repair for bilateral and recurrent inguinal hernias versus open repair but with no significant improvement in quality of life. Yildiz et al. reviewed 26 male pediatric patients who underwent laparoscopic repair of recurrent hernia. Thirteen were treated with laparoscopic surgery (with Schier's intracorporeal ''N'' suture closure) and 13 with open surgery (with high ligation technique). They found a statistically shorter length of the operation time in laparoscopic repair group. ## Tapp / tep inguinal hernia repair after failed tapp / tep No new statements or recommendations. Comments van den Heuvel and Dwars reviewed 2,594 TAPP inguinal hernia repairs (TAPP). Of these, 53 repairs were attempted for recurrent hernias after a previous posterior repair in 51 patients. Two repairs had to be converted to an open technique. One case resulted in ligation of the vas deferens. Four patients developed port site hernias. There were no serious postoperative events. At follow-up (mean of 70 months) no recurrences were found. Uchida et al. retrospectively reviewed 28 patients who underwent TEP repair of a contralateral inguinal hernia out of 215 who had undergone previous TEP inguinal hernia repair. Complications in this group were few. Three patients required conversion to an anterior approach and, in four, the inferior epigastric artery and vein were divided. TAPP and TEP repair in patient after previous transabdominal radical prostatectomy No new statements or recommendations ## Pitfalls of tapp and tep repair for recurrent inguinal hernia No new statements or recommendations. ## Tapp and tep repair and the occult synchronous hernias New statements-identical to previous except statement below. Women are at increased risk of having an occult synchronous femoral hernia (New). New recommendation-identical to previous except recommendation below. Grade C When performing inguinal hernia repair in women, extra effort should be undertaken to reveal and treat occult synchronous femoral hernia (New). ## Comments Putnis et al. performed a retrospective review of 362 patients who underwent 484 TEP inguinal hernia repairs. They found a total of 18 cases of synchronous femoral hernias with a statistically higher incidence of femoral hernia in females (37 %) compared to males (3 %) (p \ 0.001). They suggest that all women presenting with an inguinal hernia also have a formal assessment of the femoral canal. Henrikson et al. looked at 461 patients undergoing laparoscopic hernia repair for the incidence of occult synchronous femoral hernia. They found a significantly higher incidence of unsuspected femoral hernia in patients undergoing repair for recurrence 2 %) compared to the group undergoing primary repair (8/211, 3.8 %), p = 0.02. Furthermore, 38.1 % of women operated on for a recurrent inguinal hernia, presented with an unsuspected femoral hernia at surgery as opposed to 6.6 % of the men, p = 0.003. Dulucq et al. prospectively performed 337 laparoscopic inguinal hernia repairs in 263 patients. These patients were all assessed for occult concomitant hernia. 44 unexpected hernias were encountered and repaired with minimal complication: 6 Spiegelian hernias, 19 obturator hernias and 19 femoral hernias. Nah et al. performed a retrospective study of pediatric patients with incarcerated inguinal hernias and found a trend toward fewer complication in the group whose repair was performed laparoscopically rather than open, although this was not statistically significant. They also found a higher statistically incidence of contralateral hernias which were repaired at the time of repair of the incarcerated hernia. References (in parentheses graduation of evidence) ## Search machines PubMed and the Cochrane Database of Systematic Reviews specialized register and reference lists of the included studies were searched for studies for potential inclusion. New publications A total of 81 new studies were identified (compared with former literature search covering 1966 to January 2009) and none of them were relevant. No new statements or recommendations. ## References (in parentheses graduation of evidence) No references. . However, these papers are disregarded by reason that they are not comparing mesh types in TAPP. TEP The TEP search resulted in n = 34 hits. Excluding n = 3 articles (listed in TAPP search), n = 1 (3 %) article correlate to level 1B . In a one-year follow up midterm results are described in this RCT. Overall n = 3 meta-analysis are available . Since the publication of the IEHS Guidelines in 2011, n = 3 prospectively randomized trials and n = 1 registry study have been published concerning azoospermia . New statements-identical to previous except statement below. ## Level 1 a The statistical significance that lighter meshes with larger pores results in improvement of quality of life is not consistent in recently published meta-analyses. Subset analysis revealed no higher risk of recurrence after using lightweight meshes in laparoscopic inguinal hernia repair (New). ## Level 2b The middle-and long-term results of prospective studies in men do not support the hypothesis that bilateral inguinal hernia repair with alloplastic mesh prosthesis causes male infertility or decreasing the sperm motility (New). New recommendations-identical to previous except recommendation below. ## Grade b A monofilament implant with a pore size of at least 1.0-1.5 mm (usually meaning low-weight) consisting of a minimum tensile strength in all directions (including subsequent tearing force) of 16 N/cm appeared to be most advantageous; however, this assumption mainly summarizes personal and published clinical and experimental experiences (stronger evidence). The application of large pore polypropylene meshes in endoscopic hernia repair is harmless concerning azoospermia and should therefore further used (New). ## Comments A clear recommendation cannot be made based on currently published RCT's even if level 1A evidence is available. Two of three meta-analyses found no significant differences in terms of early postoperative pain, recurrence rate or return to work . The reduced incidence of chronic groin pain is only in one meta-analysis significantly lower after LM implantation. Li et al. evaluated a publication bias by using Egger's test but mixed different techniques in hernia repair. Regardless of the addition of non-randomized but controlled trails, there is no difference in the development of chronic groin pain within 6 months between both mesh types. Interestingly, out of a total of 16 RCT's which are used for the structured review by Currie et al. , Li et al. and Sajid et al. , only n = 6 were cited in the three published meta-analysis [fig_ref] 1: Ferzli GS, Rim S, Edwards ED [/fig_ref]. In addition only Sajid includes data from Champault and independently from the discussion if Champault study is prospective randomized or not, it influenced substantial this meta-analysis. Therefore the value is arguable. However, based on a slight trend to improved quality of life after using large pore and so called lightweight meshes, the authors upgrades the existing recommendation from Grade D to Grade B even if the present meta-analysis are not statistical consistent. The lack of consistency of the results of published RCT''s suggests that, on one hand, the mesh-choice only slightly influence the clinical outcome and, on the other hand, the classification in heavy and light meshes does not allow sufficient differentiation. On this account, a modified implant classification with primary regard to the local scarring formation than the implants weight should be done in future to allow better comparability of RCT's . Concerning azoospermia as an important parameter regarding quality of life, a Belgian prospective study showed significant early postoperative sperm-motility disorders in the light-mesh group and could not be noticed in long-term examinations . A Swedish registry study compared patients receiving meshes with such without mesh implantation . This study could exclude, independently of the mesh type, a higher risk of infertility. References (in parentheses graduation of evidence) New statements-identical to previous except statement below. 1 Cutting a slit in the mesh to allow the structures of the funicel to pass does not compromise testicular perfusion and testicular volume (New). New recommendations-identical to previous except recommendations below. ## Grade b Based on available evidence we recommend not to cut a slit in the mesh although cutting does not compromise testis perfusion (New). ## Comments We identified one new randomized trial . In this trial [1] 40 patients undergoing TEP were randomized to a slit or no slit. Doppler ultrasound was performed preoperatively, day 5 and after 6 months. There were no significant differences in testicular perfusion and volume. Finally, one case-control study with a retrospective design compared 78 patients undergoing TEP with a slit mesh with 300 patients undergoing TEP with a no-slit mesh. Number of patients included was not based on a power analysis. Patients had a 12 9 15 cm polypropylene mesh. Clinical recurrences were seen in 0.6 % in the slit group and in 6 % in the no-slit group (p \ 0.01). Followup after 3 years was either with telephone interview or clinical examination and the study quality was questionable since significant bias may have been involved in patient selection for slit versus no-slit. There is no convincing evidence to support use of a slit or to use no-slit in the mesh for laparoscopic inguinal hernia repair. One study found some of the recurrences to be associated with insufficient closure of the mesh slit. This could argue against slitting the mesh. We routinely do not cut a slit in the mesh as it does not bring any technical advantage for the surgeon or better clinical results for the patient. References (in parentheses graduation of evidence) ## Search machines PubMed and the Cochrane Database of Systematic Reviews specialized register and reference lists of the included studies were search for studies for potential inclusion. New publications A total of 10 new studies were identified as Level 1. Four studies on non-fixation versus mechanical fixation were identified. Three were meta-analysis and the last one by Sajid et al. reported on eight RCTs that was used for the analyses. One RCT was published after this meta-analysis and was included in this analysis . Five studies on glue fixation versus mechanical fixation were identified. Two were meta-analysis and the last one by Sajid et al. reported on 5 RCTs and were used in this analyses. Another five new RCTs have been published since and have been included in this analysis. New statements-identical to previous except recommendations below. Level 1A Fixation and non-fixation of the mesh in TEP are associated with equally risk of postoperative pain or recurrence (New). ## Level 1b Fibrin glue fixation is associated with less chronic pain than stapling. New recommendations-identical to previous except recommendations below. Grade A If TEP technique is used, non-fixation has to be considered in all types of inguinal hernias except large direct defects (MIII, EHS classification) (stronger recommendation). ## Grade b In case of TAPP repair non-fixation should be considered in types LI, II, and MI, II hernias (EHS classification). For fixation, fibrin glue should be considered to minimize the risk of acute postoperative pain (modified recommendations). ## Comments Sajid et al. reported in the meta-analysis on no difference between non-fixation versus mechanical fixation for both early (overall effect Z = 0.75 p = 0.45) and chronic pain (Z = 0.43 p = 0.67) . The RCT of Garg et al. , published after this meta-analysis, confirmed the same results. This evidence is the background for the new statement Level 1A. Sajid et al. reported in their second meta-analysis no difference between glue fixation and mechanical fixation for early pain (Z = 1.27, p = 0.20). There was a significant difference for chronic pain (Z = 3.27, p = 0.001) . Three studies reported on early pain after the meta-analysis . They all concluded that early pain was significantly less in the glue group. Four studies reported on chronic pain after the meta-analysis demonstrating no difference between glue and mechanical fixation . This led to the decision to exclude the former recommendation to consider fibrin glue to minimize the risk of chronic pain. Concerning the use of self-fixating meshes up to now only one randomized controlled trial comparing fixation by fibrin glue versus micro-hooks is published 2012 without any significant difference concerning postoperative pain in a follow up of 3 months . For information Cochrane Colorectal Cancer Group specialized register reported an on-going meta-analysis of mesh fixation techniques for laparoscopic inguinal hernia repair . New publications A total of 13 new studies were identified as Level 1. There is one new systematic review comparing open versus TEP and TAPP for acute and chronic pain and one systematic review comparing TEP and TAPP for acute pain . ## References (in parentheses graduation New statements-identical to previous except statements below. Level 1A There is no difference of chronic pain after TEP and TAPP (stronger evidence). Fixation and non fixation of the mesh in TEP are associated with equally risk of postoperative pain (see chapter ''Fixation'') (new). ## Level 1b Fibrin glue fixation is associated with less chronic pain than stapling (see chapter ''Fixation'') (new). ## Level 2a Age below median (40-50 years) is a risk factor for acute pain (stronger evidence). Age below median (40-50 years) is a risk factor for chronic pain (stronger evidence). Severe acute postoperative pain is a risk factor for chronic pain (stronger evidence). New recommendations-identical to previous except recommendations below. ## Comments Four new RCT compared TEP and TAPP for pain of which three analyzed only chronic pain . While there was no difference for chronic pain, two RCT reported less acute pain after TEP. There were identified 9 new RCT including 3,780 patients comparing open repair with TEP/TAPP repair. Two of these trials analyzed only chronic pain. All seven studies reported less acute pain after TAPP/TEP. Eight trials found significant less chronic pain after TAPP/TEP. One systematic review identified young age as risk factor for acute pain and one RCT reported more chronic pain in younger patients. One systematic review and one RCT identified severe acute postoperative pain as risk factor for chronic pain. ## Comments Mesh erosion into the bladder after LIH is rare, probably occurring in well less than 1 % of cases. The literature dealing with this complication is made up almost exclusively of case reports and therefore the complication is under reported so that the exact incidence is not known . ## Urinary retention No new statements or recommendations. Comment One reference is confirming previous statement . ## Urinary infection no new statements or recommendations miscellaneous cord and testicular problems No new statements or recommendations. Ischemic orchitis /testicular atrophy No new statements or recommendations. ## Sexual dysfunction No new statements or recommendations. Comments Post herniorrhaphy inguinal, genital or ejaculatory pain occurs in a small percentage of men after groin hernia repair. In a Danish study comprised of men undergoing a laparoscopic inguinal hernia repair who were registered in the Danish Hernia Database, dysejaculation occurred in 3.1 % . Some pain in the groin or genitals was reported during sexual activity in 10.9 % and in 2.4 % the impaired sexual activity was moderate or severe. The incidence is probably underestimated because of the reluctance of patients to discuss their sexual function. The cause is not completely understood. There is no consistently effective therapy but alpha receptor blockers to decrease contractility of the Vas and neurolytic agents such as Pregabalin have been tried. Erectile dysfunction is another complication which men occasionally report after inguinal herniorrhaphy but its direct relationship makes little anatomical sense and the incidence is unknown Infertility New statement ## Level 2b Inguinal hernia repair with mesh is not associated with an increased risk of, or clinically important risk for, male infertility. (new). ## New recommendation Grade B Groin hernia repair using mesh techniques may continue to be performed without major concern about the risk for male infertility. (new). ## Comments Although animal studies have suggested a strong correlation between mesh inguinal hernia repairs and structural damage to elements of the spermatic cord and testicle , this has not translated into a clinically significant infertility rate after open or laparoscopic inguinal hernia repair . A concern that the light weight meshes might have a greater adverse effect on sperm motility, seen 1 year after total extraperitoneal inguinal hernia repair (TEP) in one study , could not be confirmed at 3 years follow up . References (in parentheses graduation of evidence) New statements-identical to previous except statements below. ## Level 1b Minimally invasive open approaches (i.e., Kugel) may offer a cost advantage over laparoscopic approaches. (new). ## No new recommendations Comments Recent literature does not support a change to previous recommendations. Bender, et al. randomized 40 patients to either Kugel or TEP repair of unilateral hernias. There were no significant differences in operative time, length of stay, return to activity, or serum inflammatory markers. Cost was US$546 lower with Kugel. Hamza, et al. randomized 100 patients to open pre-peritoneal, Lichtenstein, TAPP, or TEP. Laparoscopic approaches were associated with less pain and faster return to activity. Ozmen et al. compared flow dynamics and cross-sectional area of femoral vessels following either TEP or Stoppa procedures. There was no evidence of DVT or significant changes in flow characteristics as a result of mesh placement in either technique. ## Davide lomanto Search terms: Inguinal Hernia, Laparoscopy/methods, Surgical instruments, Single port, Single port access, Single port laparoscopic hernia repair is a safe and feasible alternative to traditional multiport technique although has not been showed to be superior or more effective. Single port laparoscopic hernia repair may offer a better cosmetic outcome and patient's satisfaction. Single port laparoscopic hernia repair has no increased risk compared with standard multiport technique. Homemade ports, as an alternative to commercially available ports, provides a feasible and safe alternatives ## Recommendations Grade B Single port laparoscopic inguinal hernia repair is safe and feasible alternative options to conventional laparoscopy in selected cases but further RCTs are needed. Both TAPP and TEP can be performed with equal results in selected cases. ## Comments In the last few years, minimally invasive surgery has continued to develop by further reducing surgical aggression and scars hence Natural Orifice Transluminal Endoscopic Surgery (NOTES) came into light. This new approach created a lot of enthusiasm but still several issues and challenges have arisen and need to be resolved before a full clinical acceptance . While improving on these procedures, the idea of reducing the number and size of ports, so-called single incision access surgery came into limelight. In the beginning by using multiple fascial punctures and later using dedicated devices that were ad hoc developed and marketed. Through a small wound incision between 1.5 and 2.5 cm, the single port device can be inserted and allow multiple access for telescope and instrumentations to carried out the surgery. Early reports of different procedures have been published and the cosmetic advantage offered by the single port endo-laparoscopic surgery (SPES) make this approach attractive option for patients who require additional benefit of cosmesis. Further clinical studies involving large series of patients, are needed to confirm the benefits and advantages of SPES over standard procedure. Some case reports and cohort studies have been published on single port inguinal hernia repair . Two RCT Trials has been published recently from high volume centers in which safety, efficacy and improved cosmesis was confirmed with an overall outcome similar to standard technique . # Introduction Since intra-abdominal pressure plays a triggeringalbeit not causative-role in inguinal hernia development, the avoidance of physical strain has been traditionally recommended after surgical repair. However, intraabdominal pressure-the putative link between physical strain and recurrence-has not been objectively established as a risk factor for recurrence yet . Recommendations for periods of physical inactivity after groin hernia repair are very variable and typically rather long (4-6 weeks) , and mostly just expert opinions rather than the result of systematic research . Presently available guidelines are based on cohort or case-control studies of low evidence . There are a precious few reports of clinical trials on this issue , and reliable, evidence-based recommendations for a requirement of physical inactivity after hernia repair are notably absent . Since the most current guideline recommends some caution in patients doing heavy lifting (''Probably a limitation on heavy weight lifting for 2-3 weeks is enough'') without specifying either the probability or the threshold of ''heavy'', physicians may decide to err on the side of caution rather than recommend a too-early return to work. Therefore, one of the key outcome parameters of hernia surgery is based on arbitrary decisions rather than representing an objective feature of procedural quality, diminishing the informative value of the published results. Moreover, there is insufficient evidence to support the surgeon while making a decision of quite substantial impact: False recommendations may lead to unnecessary recurrences with potentially hazardous consequences for the patient on the one or economic penalties for patient and/or society due to unnecessary vocational downtime on the other hand. The issue of convalescence is of particular importance in the context of endoscopic hernia repair since reduced postoperative pain and shorter periods of recovery are some of the key advantages of this approach. Due to the relative paucity of pertinent published evidence, the literature search for the issue of convalescence was not limited in terms of publication dates and evidence levels. A meticulous analysis of all published evidence yielded no indication for a relationship between postoperative physical strain and risk of hernia recurrence. The only randomized controlled trials (RCTs) on the issue were performed in the same hospital in Nottingham and published about 30 years ago . After an initial 3-week period of physical inactivity, patients received different recommendations for the ensuing time (immediate full occupational and recreational activity vs. activity according to the GP's recommendation or reduced strain for an additional 3 months , respectively). GPs recommended extended periods of restrained activity, and immediate full workload had no adverse effects. On the contrary, the only recurrences observed by Taylor et al. occurred after the extended reduced activity. In a number of retrospective studies, patients were advised to resume full physical activities early after the operation, and did so without any negative impact on the recurrence rates, which were well under 1 % . In addition, a sizeable number of RCTs compared different hernia repair techniques and employed return to work and/ or activities of daily living (ADL) as endpoints; these trials uniformly failed to demonstrate a relationship between early rehabilitation on the one and hernia recurrence on the other hand . On the contrary, there are some studies showing the opposite tendency: In a prospective comparison of different recommendations for convalescence presented by Bay-Nielsen et al. , three groups of patients treated with the Liechtenstein procedure received the following advice: - immediate full activity without strain limits (n = 1,069). - reduced activity for 3-4 weeks (n = 1,306) or - no specific recommendations (8,297 reference patients from the Danish Hernia Database). There were no significant differences between groups in terms of hernia recurrence, but alas, the recurrence rate in the first group was only half as high (0.7 %) as in the others (1.6 and 1.4 %, respectively). This difference is hardly attributable to the early resumption of activity but probably reflects a better standard of care in the study center; however, it underlines the absence of an increased recurrence risk due to early rehabilitation when the surgical procedure was faultless. The importance of the latter point is emphasized by a relatively broad spread of recurrence incidence between centers that suggests procedure-related prognostic factors; for instance, the German Quality Assurance Office and the European Hernia Society reported recurrence rates of as low as 0 % and as high as 19 % in contemporary series surveys. In conclusion, groin hernia recurrence is obviously surgeon-and not burden-related. Obviously, the following recommendations only address the issues that are specific for groin hernia repair; general rules and precautions of convalescence after ambulatory or day-case surgery certainly apply to those patients as well. Is post-surgery physical strain related to groin hernia recurrence? Statements Level 1B There is no evidence for an increase in recurrence risk due to physical strain (including heavy lifting) after groin hernia surgery irrespective of the method of surgery. Level 3 Immediate return to work (within 1-3 days) is not associated with hernia recurrence. Immediate resumption of activity of daily living (ADL) (within 1-3 days) is not associated with hernia recurrence. Short convalescence is not associated with a higher recurrence risk, and some studies even show an inverse relation ## Recommendations Grade B Patients should be actively assured that physical activity of any kind does not jeopardize the stability of groin hernia repair. Patients should be encouraged to resume work and ADL after 1 day. What are the limiting factors for the resumption of work and physical activities after groin hernia repair? Statements Level 2A Pain is an important limiting factor for the resumption of work and physical activities after groin hernia repair. Level 3 Patients' attitude toward convalescence is heavily influenced by their surgeons' recommendation. Return to work is heavily influenced by the type of sickleave compensation. ## Recommendations Grade C Effective pain control is a prerequisite of early return to work and ADL. ## Grade b Patients should be counseled with regard to availability and side effects of analgesics. ## Comments The published literature shows a wide variety of periods of sick-leave and return to ADL; the difference between the lowest and highest published figures amounts approximately to a factor of 10 (return to work 5-50 days, resumption of ADL 3-30 days) . This clearly demonstrates the absence of objective criteria for recommendation, and a broad spread like that can hardly reflect the consideration of recurrence risk alone. Careful analysis of the limiting factors for return to work and ADL shows three issues of relevance: - Within series of patients with identical recommendations by the surgeon, pain is the single most important reason stated for extended periods of inactivity . - Between series, there are two important factors - recommendation given by the surgeon (and the resulting expectation of the patient) . - type and generosity of sick-leave compensation ]. An American case-control comparison between patients covered by ''worker's compensation'' or private health insurance, respectively , graphically corroborates the importance of socio-economic circumstances: not only did the former group return much later to work (33.5 ± 4.6 vs. 12.6 ± 2.3 days), but it also reported persistent pain for a sixfold period (111.0 ± 42.2 vs. 17.8 ± 7.9 days). Whereas the latter point cannot be easily influenced by the surgeon, the two former points show clear and broad avenues to shorter periods of convalescence: Clear recommendation of very short periods (1-3 days) of physical inactivity and generous analgesics prescription, obviously under consideration of patient-and work-specific side effects and risks. The importance of the patient's expectation-that is easily influenced by the surgeon-is confirmed by the observation that dispositional pessimism as a personality trait significantly delays return to work after hernia repair . The fact that early postoperative pain is an important precursor of chronic pain after hernia repair corroborates the recommendation of a generous analgesics prescription regimen. This issue is of particular relevance since there are clues that chronic pain after hernia repaira relatively frequent residuum -is promoted by early resumption of physical activities in patients who experience early postoperative pain . What period of physical inactivity, if any, is recommended after groin hernia repair? No specific period of inactivity needs to be recommended. The typical stability of mesh reconstructions of 50-150 N would allow a reconstruction size of 35-100 cm 2 under consideration of the maximal physiologic intra-abdominal pressure of 14,000 N/m 2 ; therefore, even without the stabilizing effect of peri-reconstructional soft tissue a properly executed mesh reconstruction is immediately stable and withstands pressure peaks due to coughing, pressing or heavy lifting. Tolver et al. counseled patients about a 1-day expected convalescence, leading to a resumption of work and ADL after 3-5 days without any negative consequences. Even this recommendation is, strictly speaking, debatable, but its consequent application would lead to an enormous reduction of socio-economic consequences of groin hernia. Statements ## Level 1b No specific period of physical inactivity is required after groin hernia repair. ## Recommendations Grade B The patient's individual wish after counseling is to be respected and facilitated, e.g., by generous analgesics prescription; however, extended periods of sick-leave are usually not necessary and should not be supported In which way, if any, does convalescence pertain to the choice of surgical procedure? It is widely accepted and has been shown in numerous original articles and reviews that endoscopic hernia repair is associated with less postoperative pain and a reduced period of vocational and recreational downtime [bib_ref] Laparoscopic versus open inguinal hernia repair: randomised prospective trial, Stoker [/bib_ref] [bib_ref] Randomized trial of TEP laparoscopic hernioplasty versus Bassni inguinal hernia repair, Tanović [/bib_ref] [bib_ref] Laparoscopic vs open inguinal hernia repair. A randomized, controlled trial, Tanphiphat [/bib_ref] [bib_ref] Randomised controlled trial of laparoscopic versus open mesh repair for inguinal hernia:..., Wellwood [/bib_ref]. Due to the aforementioned substantial variation of actual periods of return to work and ADL, the benefit cannot be determined exactly; however, the differences are sufficiently pronounced and homogenous to warrant the recommendation of endoscopic techniques with regard to convalescence. Statements Level 1A Postoperative pain is less pronounced after endoscopic as compared to open hernia repair. Endoscopy hernia surgery is associated with shorter vocational downtime and earlier resumption of ADL as compared to open hernia repair. ## Recommendations Grade B With respect to convalescence, endoscopic hernia repair is preferable over open techniques. ## Comments All recommendations given in this chapter only apply to the conventional ''heavy'' (or small pore) mesh techniques since convalescence data for lightweight (or large-pore) mesh are not yet available. However, since there appear to be no differences in recurrence risk depending on mesh pore size [bib_ref] Systematic review and meta-analysis of the use of lightweight versus heavyweight mesh..., Sajid [/bib_ref] we provisionally assume that the recommendations are also applicable to large pore mesh techniques. For conservative treatment of refractory Sportsman's hernia, radiofrequency denervation of both ilio-inguinal nerve and inguinal ligament must be considered, in the short term, an alternative to anesthetic/steroid injection. (new). ## Comments One paper with level of evidence 2 has been published since 2009 based on the diagnostic procedures of sportsmen hernias . Regarding treatment two level 1 studies are available: Comin has published a study comparing radiofrequency denervation of both the ilio-inguinal nerve and inguinal ligament to desensitize the groin region and enable the athlete to become pain-free. This therapy was compared with local anesthetics (Bupivacaine) and steroid (Trimacinolone) injection, showing that the use of radiofrequency denervation is safe and efficacious at least in the short term, being superior to unaesthetic/steroid injection. Regarding surgery, Paajanen et al. compared conservative treatment to endoscopic mesh repair on 60 patients with a diagnosis of chronic groin pain and suspected sportsman's hernia. Operative repair was more effective than non-operative treatment to decrease chronic groin pain after 1 month and up to 12 months of follow-up. Of the 30 athletes who underwent operation, 90 % returned to sports activities after 3 months of convalescence compared to 27 % of the 30 athletes in the non-operative group. ## Search machines PubMed/Ovid MEDLINE/Ovid EMBASE/Web of Science/Scopus. ## Publications Following the above MESH terms, 46 abstracts resulted from the search and were reviewed. Of those, 24 full papers were reviewed. Seven papers were excluded as they only described mathematical models underlying virtual reality (VR) simulation for hernia repair. Five meta-analysis and systematic reviews, two randomized controlled trials, prospective cohort studies were included. Introduction Laparoscopic inguinal hernia repair (LIHR) is an advanced laparoscopic procedure with a long learning curve, up to 250 procedures to proficiency . showed that simulation training leads to improved outcomes for patients undergoing laparoscopic inguinal hernia repair . Simulation training tools and programs exist for both general laparoscopic task training and for procedure specific training. In the United States, surgeons now have to obtain a cognitive and general technical skills certification, the fundamentals of laparoscopic surgery (FLS), to be eligible for certification by the American Board of Surgery. Beyond general task training, laparoscopic inguinal hernia specific trainers have been developed. Concepts exist on the low-tech box trainer platform, cadaveric tissue or the high tech virtual reality platform . Low cost trainer boxes for laparoscopic inguinal hernia repair have been developed . They have face validity and improve skills . On review of the literature to date, no studies were encountered using computer simulated inguinal hernia repair for training. Along with the technical skills trainers, surgical educators have been interested in developing training curricula and assessment tools specific to inguinal hernia repair . In addition, pathways to teach cognitive components and surgical decision making have been evaluated . After review of the above studies, we can make the following statements regarding levels of evidence and recommendations. # Statements Level 1A Simulation training improves trainee satisfaction, trainee knowledge, time and process measure of skills, behaviors, compared to no training and to non-simulation training. Level 1A Computer simulation and box trainers improve operative performance. Box training is as effective as computer simulation and results in higher learner satisfaction Level 1B Cognitive training plus mastery learning on box trainers improves patient outcome Level 2B GOALS-GH is an objective and valid measure of skills required to perform LIHR (TAPP and TEP). Training on fresh frozen cadaver has higher face validity than training on a VR trainer. ## Recommendations Grade A A simulation trainer should be available to all learners to improve operative performance. At the current time, box trainers are preferred over computer-assisted simulation for inguinal hernia repair. ## Grade b A proficiency-based curriculum for the available trainer tool should be established to improve patient outcomes. A validated assessment tool should be used to assess proficiency. ## Comments A recent study linked surgical skill to patient outcome after bariatric surgery for surgeons in practice, underlining the increased focus on technical proficiency even beyond the training phase. Here we reviewed the literature to provide recommendations how to set up deliberate practice opportunities for trainees to become experts . It is clear that beyond the presence of a training tool, a cognitive and technical training curriculum is vital to improve surgeon skills and patient outcomes. Faculty involvement does not have to be extensive, as research on feedback in other surgical areas suggests . Faculty feedback is moderately effective for learner skills training. Terminal feedback is more effective than concurrent feedback for learners' skills retention (level 2A evidence). A small prospective study reported that providing video-based cognitive and technical instruction along with training parameters and a feedback session after a 6-week period increased practice frequency and improved skills . Operation time is a cost-relevant factor. Time for anesthesia is a cost-relevant factor. Experience and quality of performance are cost-relevant factors. Simulator-training may improve quality of performance. ## Level 2c Hernia surgery is cost-effective. It may be superior to ''watchful waiting'' in the long run. Laparoscopic hernia surgery offers a higher cost-utility compared to open. Hospitals costs for laparoscopic hernia repair may be similar or lower compared to open but there is a large variation in cost per QALY generated by individual providers. In hospitals with a high case load costs are lower. ## Recommendations Grade A Non-disposable trocars and instruments must be considered. Non-fixation techniques should be considered. Use of no or indigenous balloon must be considered. Operative performance and education of the surgeons must be improved. To shorten the learning curve of traineesurgeons, simulator training should be introduced. ## Grade b In hernia disease surgery might be superior to ''watchful waiting''. From the point of cost-utility laparoscopic inguinal hernia repair may be considered. To enhance the case load centralization of hernia surgery should be considered. ## Comments Cost calculations in treatment of inguinal hernias are difficult to perform mainly due to the multitude of factors having some influence on the costs. In 2006 a large randomized controlled study (RCT) showed that at 2 years ''watchful waiting'' (WW) is a cost-effective treatment option for men with minimal or no groin hernia symptoms . But 7 years later the same group of authors found a long-term crossover rate of 68 % and concluded that although WW is a reasonable and safe strategy, symptoms will likely progress and an operation will be needed eventually . In accordance with this long-term result a large register study from UK recently published demonstrated that hernia surgery offers value for money . Moreover these authors found laparoscopic repair more cost-effective and providing less money per quality adjusted live years (QALY) in comparison to open surgery. Two previously published comprehensive reviews reported similar results . With regard to hospital costs only nearly all RCT's show higher costs for the laparoscopic repair (TAPP, TEP) . But the reliability of some of these studies should be scrutinized. Long operating times ([60 min) , high recurrence rates for laparoscopic repair (10 %) and high conversion rate (6-10 %) reported indicate lack of experience. Moreover studies not mentioning the kind of instruments and materials are useless for cost calculations. In contrast to these RCT's when analyzing routine administrative highly standardized, patient-level cost data (collected in 15 German hospitals participating in the national cost data study) Wittenbecher et al. 2013 found lower costs for TEP/ TAPP and concluded that laparoscopic approaches are not necessarily associated with higher hospital resource consumption than open mesh repair. These conflicting data demonstrate clearly that cost calculations in hernia surgery are complex because of the nearly countless number of cost-relevant variables. These factors may be dependent on the patient, the pathology of the hernia, type of anesthesia, case load of hernias per year, type of procedure, skills of the surgeon, operating time, materials, meshes, type of fixation or no fixation, complications, setting in which operation is performed (ambulatory, size of hospital/institution, country, region), number of postoperative visits/home care, time of sick leave, outcome (recurrence rate, quality of life), salaries of the personnel, depreciation of equipment, and an appropriate share of the costs of the most relevant support departments: administration, house keeping, cleaning, sterilization, equipment maintenance. According to that apparently countless number of factors the published data with regard to costs show a huge range from about 126 US-$ to more than 4116 US $ . Moreover even within one institution there is a large variation in costs generated by individual providers . Only a few of these factors may be influenced by the surgeon. Operating time, quality of the surgical intervention as well as the choice of instruments and materials are directly under the responsibility of the surgeon . In most of the papers it is stated that the higher costs found in laparoscopic surgery is mainly a reflection of the greater use of expensive disposable equipment and longer operating time for laparoscopic hernia repair . Multiple sensitivity analyses demonstrated that when use of disposable trocars, graspers, preperitoneal balloon, and stapling devices (''tacker'') were included, direct costs and charges were significantly higher for laparoscopic hernia repair. On the other hand, in a large volume laparoscopic surgery center with minimal use of disposable instruments and avoidance of preperitoneal balloon and tackers for mesh fixation, the actual direct costs of laparoscopic repair are comparable to open repairs . Controversially discussed are the use of low-cost meshes and the use of indigenous dilatation balloons for further cost reduction. But without doubt experience is a significant factor for decreasing operating time as well as the rate of complications, recurrences and long-term complaints like chronic pain . In so far surgical performance is directly correlated to quality of life and QALY'S. Different to the results of the calculations of hospital costs (direct) nearly all RCT's, systematic reviews, and meta-analysis prove that the societal costs(indirect) are less after laparoscopic repair mainly due to more rapid recovery and a shorter time of sick leave when compared to open surgery. In summary, up to now due to the higher hospital costs worldwide acceptance of laparoscopic hernia repair is low despite less pain and more rapid recovery in comparison to open surgery. Therefore cost containment measures are to consider like increase of the case load (more rapid depreciation of equipment costs, large experience) , shortening of the learning curve and improvement of surgical performance by standardizing the technique and systematic training . Other recommendations are using nondisposable trocars and instruments , avoidance of ''tacker'' fixation and implantation of low-cost meshes . [fig] 1 Chapter 2: Langeveld HR, van't Riet M, Weidema WF, Stassen LP, Steyerberg EW, Lange J, Bonjer HJ, Jeekel J (2010) Total extraperitoneal inguinal hernia repair compared with Lichtenstein (the LEVEL-Trial): a randomized controlled trial. Ann Surg 251(5):819-824. (1B) 2. Bittner R, Schmedt CG, Leibl BJ, Schwarz J (2011) Early postoperative and one year results of a randomized controlled trial comparing the impact of extralight titanized polypropylene mesh and traditional heavyweight polypropylene mesh on pain and seroma production in laparoscopic hernia repair (TAPP). World J Surg 35(8):1791-1797. (1B) 3. Bittner R, Leibl BJ, Kraft B, Schwarz J (2011) Oneyear results of a prospective, randomised clinical trial comparing four meshes in laparoscopic inguinal hernia repair (TAPP). Hernia 15(5):503-510. (1B) 4. Sanchez-Manuel FJ, Lozano-García J, Seco-Gil JL (2012) Antibiotic prophylaxis for hernia repair. Cochrane Database Syst Rev 2012 Issue 2. Art. CD003769. doi: 10.1002/14651858.CD003769.pub4. (1A) 5. Mazaki T, Mado K, Masuda H, Shiono M (2013) Antibiotic prophylaxis for the prevention of surgical site infection after tension-free hernia repair: a Bayesian and frequentist meta-analysis. J Am Coll Surg 217(5):788-801. (1A) 6. Li JF, Lai DD, Zhang XD, Zhang AM, Sun KX, Luo HG, Yu Z (2012) Meta-analysis of the effectiveness of prophylactic antibiotics in the prevention of postoperative complications after tension-free hernioplasty. Technical key points in TAPP repair Jan F. Kukleta, Reinhard Bittner Search terms: ''Inguinal hernia'', ''TAPP repair'', ''TAPP'', ''TAPP technique'', ''hernia repair'', ''endoscopic repair''. Filters: Engl., Ger., Ital., French, Port., Span. RCT, Meta-analysis, multicenter study, systematic review, controlled trial. Search machines PubMed, Medline and reference lists of articles selected for inclusion. New publications Of 1,684 papers involved with ''endoscopic repair'', to ''TAPP Hernia'' with 355 and TAPP repair with 305. Of the 176 contributions to ''TAPP technique'' 37 were published in the last 3 years. (18 RCT's, 3 meta-analysis and 16 reviews). [/fig] [fig] 1: Ferzli GS, Rim S, Edwards ED (2013) Combined laparoscopic and open extraperitoneal approach to scrotal hernias. Hernia 17(2):223-228. (3) 2. Siow SL, Mahendran HA, Hardin M, Chea CH, NikAzim NA (2013) Laparoscopic transabdominal approach and its modified technique for incarcerated scrotal hernias. Asian J Surg 36(2):64-68. (3) 3. Nah SA, Giacomello L, Eaton S, de Coppi P, Curry JI, Drake DP, Kiely EM, Pierro A (2011) Surgical repair of incarcerated inguinal hernia in children: laparoscopic or open? Eur J Pediatr Surg 21(1):8-11. (3) 4. Esposito C, Turial S, Alicchio F, Enders J, Castagnetti M, Krause K, Settimi A, Schier F (2013) Laparoscopic repair of incarcerated inguinal hernia. A safe and effective procedure to adopt in children. Hernia 17(2):235-23. (3) 5. Chan KW, Lee KH, Tam YH, Sihoe JD, Cheung ST, Mou JW (2011) Laparoscopic inguinal hernia repair by the hook method in emergency setting in children presenting with incarcerated inguinal hernia. J Pediatr Surg 46 (10):1970-1973. Comparison of lichtenstein and laparoscopic transabdominal preperitoneal repair of recurrent inguinal hernias. Int Surg 96(3):233-238. (1B) 10. Shah NR, Mikami DJ, Cook C, Manilchuk A, Hodges C, Memark VR, Volckmann ET, Hall CR, Steinberg S, Needleman B, Hazey JW, Melvin WS, Narula VK (2011) A comparison of outcomes between open and laparoscopic surgical repair of recurrent inguinal hernias. Surg Endosc 25(7):2330-2337. (3) 11. Sevonius D, Gunnarsson U, Nordin P, Nilsson E, Sandblom G (2011) Recurrent groin hernia surgery. BJS 98(10):1489-1494. (2C) 12. Bignell M, Partridge G, Mahon D, Rhodes M (2012). Prospective randomized trial of laparoscopic (transabdominal preperitoneal-TAPP) versus open (mesh) repair for bilateral and recurrent inguinal hernia: incidence of chronic groin pain and impact on quality of life: results of 10 year follow-up. Hernia 16(6): 635-640. (2B) 13. Yildiz A, Ç elebi S, Akin M, Karadag Ç A, Sever N, Erginel B, Dokucu AI (2012) Laparoscopic herniorraphy: a better approach for recurrent hernia in boys? Pediatr Surg Int 28(5):449-453. (3) 14. van den Heuvel B, Dwars BJ (2013) Repeated laparoscopic treatment of recurrent inguinal hernias after previous posterior repair. Surg Endosc 27(3):795-800. (3) 15. Uchida H, Matsumoto T, Endo Y, Kusumoto T, Muto Y, Kitano S (2011) Repeat laparoscopic totally extraperitoneal hernia repair after primary laparoscopic totally extraperitoneal hernia repair for inguinal hernia. J Laparoendosc Adv Surg Tech A 21(3):233-235. (3) 16. Putnis S, Wong A, Berney C (2011) Synchronous femoral hernias diagnosed during endoscopic inguinal hernia repair. Surg Endosc 25: 3752-3754. (3) 17. Henriksen NA, Thorup J, Jorgensen LN (2012) Unsuspected femoral hernia in patients with a preop-terms: ''Hernia, Inguinal [MESH] (''size'' or ''recurrence''), ''clinical trial'', randomized controlled-''meta-analysis''. [/fig] [fig] Chapter 7: Heavy or light weight mesh in TAPP and TEP-functional outcome and quality of life Dirk Weyhe, F. Koeckerling, Uwe Klinge Search terms: ''TAPP'' AND ''mesh'', TEP AND ''mesh'', ''Biocompatibility'' AND ''mesh'', ''groin pain'' AND ''mesh'', ''inguinal hernia'' AND ''mesh'', ''Quality of life'' AND ''mesh'', ''azoospermia'' AND ''mesh'', ''sperm-motility'' AND ''mesh'' Search machines Pubmed, Medline, and Cochrane Library. New publications TAPP In total, n = 26 hits were found from February 2009-October 2013. Excluding n = 2 (review a.o.), n = 23 publications were classified according to the evidence criteria. The result was n = 3/23 articles fulfilled the criteria of Level IB (13 %) based on Oxford hierarchy of evidence [/fig] [table] Grade A: If TEP technique is used non fixation has to be considered in all types of inguinal hernias except large defects (L III, [/table]	None	https://link.springer.com/content/pdf/10.1007/s00464-014-3917-8.pdf	None
2e3f29bbe4f62421eebf83a3b1204bb0cbd64833	pubmed	Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life	Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first-and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' e e e of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained. # Introduction - These guidelines apply to children with HIV-1 infection in Europe. - Thresholds for starting antiretroviral therapy (ART) have changed as continuing improvements in treatment mean that the objectives of ART should increasingly be optimizing health status for a full and productive adult life rather than just survival. - New drugs have been incorporated into the guideline as first-and second-line options. The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines have been updated from those of 2009 [bib_ref] PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1..., Penta Steering Committe [/bib_ref] , and make recommendations based on a shift in aims of treatment away from minimization of short-term morbidity and mortality towards optimizing immune status and general health for a full and productive adult life. This mirrors the general trend in global treatment guidelines that now include higher CD4 thresholds for ART initiation and an increased number of clinical indications in both adults and children [bib_ref] British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral..., Williams [/bib_ref]. The aim is to provide a practical guide to treatment rather than a comprehensive review of all the evidence on ART in children. More detailed information for resource-rich and resource-poor settings is available from recently updated USand World Health Organization (WHO)paediatric guidelines. Special considerations for children in resource-limited settings where background rates of concomitant infections and malnutrition are much higher are not considered here, and the reader is referred to WHO guidelines. Differences from the WHO and US Department of Health and Human Services (DHHS) guidelines will be referred to where relevant in the document and are summarized in . Licensing of newer drugs in children and the availability of more appropriate formulations have allowed inclusion of a larger number of drug options at different ages. These drugs, with limited data on long-term toxicity, are included with the caveat that clinicians should be vigilant for signs of adverse effects and fully counsel children and families regarding what is known and unknown about long-term use of newer drugs. Much of the new paediatric data (published since 2009) that have been used to inform the 2015 PENTA guidelines have come from non-European settings and therefore must be considered with caution when applied to European cohorts. As with previous versions of the guidelines, there remains a paucity of data from randomized controlled trials (RCTs) on which to base European paediatric ART guidelines. Therefore, we continue to rely on cohort studies, extrapolation from adult data, and expert opinion. Wherever possible, children should be entered into clinical trials. The guidelines have been developed using a similar method to that used for the adult European AIDS Clinical Society (EACS) guidelines [bib_ref] Rating evidence in treatment guidelines: a case example of when to initiate..., Sabin [/bib_ref]. A panel of experts reviewed the published literature and formulated the main recommendations. The full PENTA Steering Committee then reviewed and refined the recommendations until consensus was reached. This approach has recently been criticized by some. Latest WHO and British HIV Association (BHIVA) guidelines have now moved to using the structured Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [bib_ref] Rating evidence in treatment guidelines: a case example of when to initiate..., Sabin [/bib_ref]. It is the opinion of PENTA that the paucity of RCT evidence means that the GRADE system would not provide sufficient additional benefit to the guidelines' development to justify its use and therefore the writing group has elected to continue using the less formalized system described above. PENTA guidelines seek to optimize treatment for children in Europe. However, particularly during adolescence, care may need to be individualized. This document should not be seen as a standard for litigation as individualization of case management and departure from this guidance may be necessary and indicated. Significant changes since the 2009 guidelines include: - decreased frequency of laboratory monitoring in clinically stable children both on and off ART; - consideration of ART initiation in all children aged [bib_ref] PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1..., Penta Steering Committe [/bib_ref] [bib_ref] British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral..., Williams [/bib_ref] years in order to minimize the risks of disease progression or death; - consideration of ART initiation at higher CD4 thresholds in children > 5 years of age in order to optimize potential for immune reconstitution; - additional clinical indications for ART initiation at all ages; - addition of newer protease and integrase inhibitors to first-line preferred and alternative third agent options, respectively; - update on specific guidance in the context of hepatitis B and C virus and tuberculosis (TB) coinfection in light of new ART options at younger ages; - a summary of new drugs [including new fixed dose combinations (FDCs)] that can be considered for second-and third-line options and of the 'pipeline' of new drugs likely to become available; - an emphasis on the needs of older children and adolescents as they approach transition to adult care; - an updated drug dosing table including all currently recommended licensed antiretroviral drugs for children.. Diagnosis, baseline investigations and pretreatment monitoring ## Summary of recommendations - If a woman is diagnosed with HIV infection, all of her children potentially at risk of infection should be tested for HIV irrespective of age. - Children under 18 months of age at risk of perinatally acquired HIV infection should be tested using blood DNA or RNA polymerase chain reaction (PCR) with subsequent confirmatory repeat PCR if positive. - Post-exposure prophylaxis (PEP) should be given for 4−6 weeks to all babies born to HIV-infected mothers according to local guidelines. ## - babies born to hiv-infected mothers should have an hiv RNA PCR test at birth and at least two further separate PCR tests (the first 2 weeks after cessation of PEP, and the second at least 6 weeks after cessation of PEP). For babies with high risk of transmission, an additional PCR test midway through PEP is recommended. - Breast feeding is not recommended. In circumstances in which the mother is choosing to breast feed against recommendations, the baby should have regular screening PCR tests. Two negative HIV RNA PCR tests (2 and 6 weeks after cessation of breast feeding) are required to confirm that the baby is not infected. - Children over 18 months of age can be tested using serological assays with subsequent confirmatory PCR if positive or equivocal. - A negative serological test in children who have had a positive HIV RNA PCR test does not exclude ongoing HIV infection. - A detailed history of any possible previous ART given to the child and/or mother (or other likely source of infection) should be documented. - The genotypic HIV resistance profile should be documented at baseline. - The human leucocyte antigen (HLA) B5701 genotype should be confirmed negative before using abacavir (ABC). - Clinical assessment should be carried out 3−4-monthly in children who are stable off ART, with frequency of laboratory monitoring dictated by age, clinical status and proximity to thresholds for ART initiation [minimum 6-monthly HIV viral load (VL) and CD4 count]. - Local guidelines for bacillus Calmette−Guérin (BCG) immunization of babies of HIV-infected mothers should be followed. HIV-exposed infants at low risk of HIV transmission (maternal VL < 50 HIV-1 RNA copies/ml at or after 36 weeks of gestation) with high risk of TB exposure may receive BCG vaccination at birth, prior to definitive diagnosis/exclusion of HIV infection. ## Prophylaxis against opportunistic infections - Prophylaxis against Pneumocystis jirovecii pneumonia (PJP) should be given to all HIV-infected infants from age 1 month and to older children with low CD4 counts: in children aged 1-4 years, CD4 count < 500 cells/μL or < 15%; in children aged ≥ 5 years, CD4 count < 200 cells/μl or < 15%. Co-trimoxazole is the drug of first choice (see for dosing). - Routine primary prophylaxis against other infections is not recommended. ## When to start art ART is recommended: - in all children under 1 year of age; - in all children with significant disease [WHO stage 3 or 4 or Centers for Disease Control and Prevention (CDC) stage B or C]; - in asymptomatic children over 1 year of age based on age-specific CD4 count thresholds; - to be initiated before the CD4 count reaches the CD4 treatment threshold; - in those with hepatitis C virus (HCV) or active TB coinfection. ART should be considered: - in asymptomatic children over 5 years of age at CD4 counts of 350-500 cells/μl, to potentially optimize CD4 count in adulthood; - in children with high VL (> 100 000 copies/ml); - in asymptomatic children aged 1-3 years irrespective of immune status and VL; - in sexually active adolescents, to minimize the risk of onward transmission; - in the presence of any significant HIV-related clinical symptoms; - in hepatitis B virus (HBV) coinfection irrespective of immune status. 6. Which ART regimen to start as first-line therapy - Children should start effective (at least three drugs) ART, usually a dual or triple nucleoside reverse transcriptase inhibitor (NRTI) backbone together with either a ritonavir-boosted protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI). - Children exposed to nevirapine (NVP) during failed prevention of mother-to-child transmission (PMTCT) (or in whom perinatal NVP exposure cannot be excluded) should be started on a boosted PI-containing regimen as transmitted resistance may lead to failure of NVPcontaining ART. - Children aged < 3 years not exposed to NVP during failed PMTCT may be initiated on either NVP or ritonavirboosted lopinavir (LPV/r)-containing ART. We recommend that NVP should be given together with three NRTIs [ABC, lamivudine (3TC) and zidovudine (ZDV)] in all infants and in children aged 1-3 years with VL > 100 000 copies/ml or signs of central nervous system (CNS) involvement as an induction-maintenance strategy, unless any of these drugs are contraindicated (such as ABC in HLA B5701-positive children). - In children aged > 3 years, either NNRTI or boosted PI-based ART is acceptable for initial therapy. Factors such as availability of age-appropriate formulations, palatability, dosing frequency and adherence should be considered when choosing NNRTIs or boosted PIs. - The preferred NNRTI is NVP in children aged < 3 years not exposed to NVP during failed PMTCT, and efavirenz (EFV) in children aged > 3 years. The preferred PI in children aged < 6 years is LPV/r, in children aged 6−12 years it is ritonavir-boosted atazanavir (ATV/r), and in children aged > 12 years it is ATV/r or ritonavir-boosted darunavir (DRV/r). - Integrase inhibitor (INSTI)-based ART may be an alternative regimen in children over age 12 years. - The preferred first-line NRTIs are ABC/3TC in children aged < 12 years, and tenofovir/emtricitabine (TDF/FTC) or ABC/3TC (if VL < 100 000 copies/ml) in children aged > 12 years. - Age, HLA B5701 genotype, previous drug exposure, resistance profile, coinfections, available formulations and likely adherence should be taken into account when choosing a first-line regimen. - See [fig_ref] Table 4: Recommended first-line antiretroviral therapy [/fig_ref] (later) for details of recommended first-line ART regimens. ## Adherence and hiv knowledge - Adherence to treatment is paramount and should be discussed at each clinic visit. - Every effort should be made to simplify a regimen to support adherence (e.g. using once-daily regimens, FDCs, and 'forgiving' regimens with higher barriers to resistance). Simple adherence aids should be used when appropriate. - Children should know of their HIV diagnosis before adolescence. - Monitoring for psychological, neurocognitive and mental health issues should be routine, allowing early supportive and therapeutic intervention. ## Monitoring on art - The aim of ART is to achieve an undetectable VL (< 50 copies/ml) and CD4 reconstitution. - Laboratory monitoring for drug toxicity should be performed initially within 2-4 weeks of starting a new drug, then at least every 6 months if there are no ongoing toxicity concerns. - After starting ART, VL should be checked early (at around 1 month) to confirm that VL is decreasing (this can coincide with toxicity monitoring). - VL and CD4 count can then be monitored approximately every 3-4 months once the patient has been established on treatment. - Once CD4 cells are reconstituted and VL has been < 50 copies/ml consistently for over 1 year, CD4 parameters can be monitored less frequently (every 6-8 months, i.e. at alternate clinic visits). - More frequent clinical and laboratory monitoring is required: - in infancy; - if adherence is poor; - soon after starting or changing therapy (e.g. liver function tests should be performed within 2 weeks); - in the context of ongoing drug toxicity; - when giving medications with significant drug interactions with ART such as antituberculous therapy. ## Drug toxicities and interactions - Toxicities depend on the individual drugs and ART combination and should be assessed at each clinic visit. - Drug interactions should be considered when starting new medications in a child on ART. Use http://www.hiv -druginteractions.org/ to check drug interactions and toxicities. - See (later) for common ART-associated toxicities. ## Coinfections ## Hepatitis b virus and hepatitis c virus - Liver disease in children with HBV or HCV coinfection should be managed jointly with paediatric experts in viral hepatitis. - HCV coinfection is an indication for starting ART. - For HBV coinfection, if treatment of HIV infection is not indicated and there is no evidence of liver disease, HIV treatment should be considered but may be deferred. ## Tuberculosis - All HIV-infected children exposed to an individual with infectious TB and all children with evidence of latent TB infection should have preventive TB treatment (once active TB disease has been excluded). - In children with active TB disease, TB treatment should be started at TB diagnosis. ART should be started, as soon as practicable, and within 2 and 8 weeks of TB treatment in children with severe and moderate immunosuppression, respectively. ART may be deferred at higher CD4 counts until TB treatment is completed. - There is significant interaction between ART and TB therapy. Therapeutic drug monitoring (TDM), where available, should be used in the context of potential significant interactions. - Children with TB coinfection should be managed in consultation with an expert in the treatment of paediatric TB. A specialist in drug-resistant TB (DRTB) should be involved in the management of DRTB contacts and cases. - See [fig_ref] Table 6: Antiretroviral therapy [/fig_ref] (later) for ART choices in children with TB. ## Opportunistic infections - We recommend that ART should be initiated as early as possible, apart from in the context of cryptococcal meningitis, where evidence in adults has shown that delaying ART may be associated with reduced mortality. 11. When to switch, resistance testing and second and subsequent ART regimens ART regimens may be changed because of treatment failure, because of toxicity or for simplification. ## Stopping treatment and treatment interruption - Treatment interruptions cannot be routinely recommended and starting ART currently means lifelong therapy. - Judicious use of planned treatment interruptions may be considered in circumstances when ART needs to be stopped such as because of toxicity or adherence difficulties, while the latter is being addressed. - Stopping NNRTIs when HIV is fully suppressed requires a replacement or staggered stop to reduce the risk of developing NNRTI resistance as a result of the longer half-life of NNRTIs. A replacement stop is preferable. ## Adolescence, mental health and transition - Adolescents commencing first-line therapy should be started on boosted PI-based ART and subsequently switch to NNRTI-based ART once adherence has been established and VL is consistently < 50 copies/ml. - Multidisciplinary monitoring for signs of psychological distress and mental health disorder should be routine as children progress through adolescence towards transition. - Early and ongoing support from clinical psychologists with specialist paediatric knowledge is recommended. ## Pipeline and upcoming trials See [fig_ref] Table 8: The paediatric antiretroviral pipeline Phase II/III [/fig_ref].. PCR tests become more reliable 14-21 days after birth. The purpose of the initial test at birth is thus to allow rapid identification of those that are already positive so that a confirmatory test and treatment can be initiated without delay. Later tests are essential for excluding HIV infection in babies who test negative at birth. In the absence of breast feeding, at least two separate negative HIV RNA PCRs after stopping PEP are required to confirm that an exposed baby is uninfected (the first 2 weeks after cessation of PEP, and the second at least 6 weeks after cessation of PEP). For babies born with high risk of transmission, an additional PCR test midway through PEP is recommended to allow earlier identification of infected infants. The use of fourth-generation pointof-care antibody/antigen testing for diagnosis of HIV infection in children under 18 months of age is not recommended in view of low sensitivity for distinguishing between HIV infection and positive serology from maternal antibody [bib_ref] Performance of the first fourth-generation rapid human immunodeficiency virus test in children, Bhowan [/bib_ref]. Some less prevalent HIV subtypes may escape detection by PCR (e.g. HIV A, C-H and O) [bib_ref] Impact of human immunodeficiency virus type 1 (HIV-1) genetic diversity on performance..., Swanson [/bib_ref]. Those using PCR for diagnosis should know the sensitivity of the assay being used for the likely subtype being tested for. Expert advice should be sought if there is any doubt about the interpretation of results. However, initiation of ART in infants should not be unduly delayed by referrals to an expert centre. ## Diagnosis, baseline investigations and pretreatment monitoring Babies of HIV-infected women may subsequently become infected after initial negative tests if they are breast-fed. Breast feeding is not recommended in highincome countries, where alternative feeding is safe and practical. If in exceptional circumstances an uninfected baby is breast-fed, the mother should be on effective ART. Two confirmatory PCR tests, 2 and 6 weeks after cessation of breast feeding and PEP, are required to confirm that the baby is not infected. It is important to note that HIVinfected children who have commenced ART may become seronegative by standard commercial testing after loss of passively acquired maternal antibodies, especially after early ART initiation (< 3-6 months of age) . A negative serological test in this context does not exclude ongoing HIV infection as the HIV DNA PCR test remains positive. Infants and children > 18 months of age who present with symptoms consistent with HIV infection and unknown maternal HIV status should initially have an HIV antibody test. If this is positive, they will require a confirmatory PCR test. It is recommended that all previously untested children of HIV-infected women should be tested for HIV whatever their age, as infected children may remain asymptomatic throughout childhood and adolescence [bib_ref] Vertically acquired HIV diagnosed in adolescence and early adulthood in the United..., Judd [/bib_ref]. All siblings at risk of perinatally acquired infection (irrespective of age) should also have an HIV test. Adult physicians and family doctors should routinely ask all HIV-infected men and women in their care if they have children and refer those at risk for testing. ## Baseline assessments once diagnosis has been confirmed Once a diagnosis of HIV infection has been confirmed, children should be assessed clinically, including assessment of growth and development, to allow staging of HIV infection according to WHO (or CDC) classifications. To plan future ART, it is important to document whether the child has been exposed to previous ART, in utero, through breast feeding, as PEP or as therapy (e.g. in their country of origin). If available, the antiretroviral history of the mother or other source case should also be documented. In view of the possibility of transmitted drug resistance [bib_ref] Perinatal acquisition of drug-resistant HIV-1 infection: mechanisms and long-term outcome, Delaugerre [/bib_ref] [bib_ref] Effect of transmitted drug resistance on virological and immunological response to initial..., Wittkop [/bib_ref] and unreported prior ART exposure, HIV genotypic resistance testing is recommended at baseline (including reverse transcriptase, protease and integrase resistance testing when available). If available, the results of resistance testing of the source case, as close as possible to the time of transmission, should also be documented. Baseline viral co-receptor [C-C chemokine receptor type 5 (CCR5)] tropism testing is not indicated, as CCR5 receptor antagonists are not currently recommended as first-line therapy. Other baseline investigations [fig_ref] Table 4: Recommended first-line antiretroviral therapy [/fig_ref] , syphilis, TB and Chagas (in those at risk)], full blood count, haemoglobinopathy screen (in risk groups), bone profile, and tests of liver and renal function. Baseline echocardiography in those at risk of cardiomyopathy should be considered. HLA B5701 testing, where available, is recommended at baseline prior to starting ABC [bib_ref] HLA-B5701 screening for hypersensitivity to abacavir, Mallal [/bib_ref]. See baseline investigations at http://www.chiva.org.uk for further guidance. A full vaccine history should be taken and if necessary serology performed to confirm immunity and to aid in decision making around catch-up and boosting [bib_ref] Guidance on vaccination of HIV-infected children in Europe, Menson [/bib_ref]. Local BCG practices for babies of HIV-infected mothers should be followed. In areas of low TB incidence or if there is high risk of HIV transmission, BCG vaccination should be postponed until an infant is confirmed as HIV negative. HIVexposed infants at low risk of HIV transmission (maternal VL < 50 copies/ml at or after 36 weeks of gestation) with high risk of TB exposure may receive BCG vaccination at birth, prior to definitive diagnosis/exclusion of HIV infection [bib_ref] British HIV Association guidelines for the management of HIV infection in pregnant..., Taylor [/bib_ref]. The very low risk of HIV transmission with an undetectable maternal VL means that in these circumstances the risk of severe TB from not vaccinating is greater than the risk of HIV-related BCG complications. In resource-poor settings with high TB prevalence, BCG vaccination is given to all infants prior to determination of HIV status. Early ART in this context has been shown to minimize the risk of BCG-related complications [bib_ref] Early antiretroviral treatment reduces risk of bacille Calmette-Guerin immune reconstitution adenitis, Rabie [/bib_ref]. In those presenting outside the neonatal period, a baseline chest radiograph allows assessment for respiratory complications, including lymphoid interstitial pneumonitis and TB. Infants and children with advanced HIV disease should have an ophthalmic examination for evidence of retinitis, and a blood CMV PCR test (if available). Infants and children with evidence of neurological involvement should undergo baseline neuroimaging. Additional baseline immunological assessment for evidence of TB infection is recommended [tuberculin skin test (TST) and/or interferon gamma release assay (IGRA)]. Children not yet requiring ART (see treatment criteria below) should have clinical monitoring at intervals of no longer than 3-4 months. Routine monitoring should include clinical examination and measurement of growth parameters. Monitoring for HIV disease progression and complications using CD4 count/percentage and VL, renal and liver function and urinalysis is recommended on a 6-monthly basis, and should be performed more frequently in younger children and those approaching treatment thresholds. Annual assessment of neurodevelopment, blood pressure, nutrition (including lipids) and puberty is also recommended. Vitamin D should be assessed and managed according to local guidelines as in HIV-uninfected children. Less frequent assessment of these parameters has been suggested in adult guidelines [bib_ref] British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral..., Williams [/bib_ref]. However, in view of the possibility of more rapid disease progression in children, the frequency of laboratory monitoring should remain as recommended above for children not receiving ART. ## Prophylaxis against opportunistic infections - Prophylaxis against Pneumocystis jirovecii should be given to all HIV-infected infants from age 1 month and to older children with low CD4 counts (see criteria below). Co-trimoxazole is the drug of first choice (see for dosing). - No routine primary prophylaxis against other infections is recommended. Prophylaxis with co-trimoxazole is highly effective at preventing potentially life-threatening infection with P. jirovecii, and also at reducing bacterial infections [bib_ref] Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a..., Chintu [/bib_ref]. In view of their susceptibility to severe P. jirovecii infection, all HIV-infected infants should receive prophylaxis from 4 weeks of age until their first birthday, regardless of CD4 and VL. HIV-exposed babies at high risk for transmission should also commence P. jirovecii prophylaxis at 4 weeks of age and continue until HIV infection has been excluded. Co-trimoxazole is the first-choice drug unless contraindicated. Co-trimoxazole has not previously been recommended before the age of 4 weeks because of the theoretical risk of kernicterus with sulphonamide administration in neonates. Hard evidence for this is lacking [bib_ref] Cotrimoxazole and neonatal kernicterus: a review, Thyagarajan [/bib_ref] and it is unclear what the relative risks of this are compared with the risks of P. jirovecii infection in young infants in whom the diagnosis of HIV infection is made before 4 weeks of age. Children aged 1 to 4 years should receive prophylaxis against P. jirovecii if they have a CD4 count below 500 cells/μL or 15% of total lymphocyte count. Children aged 5 years and above should receive prophylaxis against P. jirovecii if they have a CD4 count below 200 cells/μl or 15%, and it should be considered when they are approaching these thresholds [bib_ref] Revised classification system for human immunodeficiency virus infection in children less than..., Caldwell [/bib_ref]. While intermittent dosing (3 days a week) is sufficient for P. jirovecii prophylaxis, daily co-trimoxazole prophylaxis according to weight bands, as in the current WHO guidelines, simplifies recommendations with the additional benefit of protecting against bacterial infections. This option is also therefore endorsed by these guidelines. Daily co-trimoxazole prophylaxis may also be considered for children travelling to countries with a high prevalence of bacterial infections and/or malaria, irrespective of their CD4 count/percentage and current treatment status [bib_ref] A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa, Bwakura-Dangarembizi [/bib_ref]. The use of co-trimoxazole in this context may also have additional benefit as antimalarial prophylaxis [bib_ref] Safety and efficacy of co-trimoxazole for treatment and prevention of Plasmodium falciparum..., Manyando [/bib_ref] , although specific malaria prophylaxis appropriate to the regions being visited should always be prescribed. Once ART has been started and the CD4 count has risen, the risk of P. jirovecii infection decreases [bib_ref] Withdrawal of Pneumocystis jirovecii prophylaxis in HIV-infected children under highly active antiretroviral..., Urschel [/bib_ref] [bib_ref] The rate of serious bacterial infections among HIV-infected children with immune reconstitution..., Nachman [/bib_ref]. Most paediatricians stop co-trimoxazole in children over 1 year of age living in well-resourced settings 6 months after CD4 count recovery. The AntiRetroviral Research for Watoto (ARROW) trial has reported additional benefits of continuing co-trimoxazole prophylaxis after immune reconstitution in children in resource-poor settings. It is likely that these additional benefits are related to antibacterial, antimalarial and anti-inflammatory effects. The findings of this trial are therefore less likely to be of relevance in most European settings [bib_ref] A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa, Bwakura-Dangarembizi [/bib_ref]. Prophylaxis against other infections has been suggested for those with very low CD4 counts. There is insufficient evidence to make any recommendations for routine primary prophylaxis, but specific guidance is available [bib_ref] Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and..., Siberry [/bib_ref]. Prophylaxis against TB can be considered for children visiting countries highly endemic for TB (see Section 10 below). The most important means to reduce susceptibility to all opportunistic infections is prompt initiation of ART when indicated. ## When to start art ## Art is recommended: - in all children under 1 year of age; - in all children with significant disease (WHO stage 3 or 4 or CDC stage B or C); - in asymptomatic children over 1 year of age based on age-specific CD4 count thresholds; - to be initiated before the CD4 count reaches the CD4 treatment threshold; - in those with HCV or active TB coinfection. ## Art should be considered: - in asymptomatic children over 5 years of age at CD4 counts of 350-500 cells/μl, to potentially optimize CD4 count in adulthood; - in children with high VL (> 100 000 copies/ml); - in asymptomatic children aged 1-3 years irrespective of immune status and VL; - in sexually active adolescents, to minimize the risk of onward transmission; - in the presence of any significant HIV-related clinical symptoms; - in HBV coinfection irrespective of immune status. ## Children under 1 year of age ART should be started as soon as possible in all HIVinfected children under 1 year of age irrespective of clinical or immunological status. Evidence for this comes from the South African randomized controlled Children with HIV Early Antiretroviral Therapy (CHER) trial [bib_ref] Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected..., Cotton [/bib_ref] [bib_ref] Early antiretroviral therapy and mortality among HIV-infected infants, Violari [/bib_ref] , which showed a 4-fold reduction in mortality among asymptomatic infants starting ART before 3 months of age compared with those starting at a CD4 percentage < 25% or WHO stage 3 or 4. In addition, in Europe, a 4-fold reduction in HIV progression/mortality was observed among infants starting ART at less than 3 months of age compared with later in a large infant cohort meta-analysis [European Infant Collaboration (EIC)] [bib_ref] deferred antiretroviral therapy: evidence from the Children with HIV Early Antiretroviral Therapy..., Goetghebuer [/bib_ref]. Additional CHER trial substudies have added further evidence of the clinical [bib_ref] Early antiretroviral treatment reduces risk of bacille Calmette-Guerin immune reconstitution adenitis, Rabie [/bib_ref] , immunological [bib_ref] Effect of HIV infection status and anti-retroviral treatment on quantitative and qualitative..., Madhi [/bib_ref] and neurodevelopmental [bib_ref] Early antiretroviral therapy improves neurodevelopmental outcomes in infants, Laughton [/bib_ref] benefits of early ART initiation in infants. Data from European cohorts have also shown that virological, clinical and immunological benefits from early treatment are sustainable outside the trial setting [bib_ref] treatment response and duration of first-line regimens, Judd [/bib_ref] [bib_ref] Five-year follow-up of children with perinatal HIV-1 infection receiving early highly active..., Chiappini [/bib_ref]. Further analysis of laboratory parameters from the EIC has demonstrated an association between early infant ART, more rapid control of viraemia and a higher CD4 count up until 12 months of age [bib_ref] Shortand long-term immunological and virological outcome in HIV-infected infants according to the..., Goetghebuer [/bib_ref]. Universal treatment of all infants with HIV infection, although challenging, is an achievable goal. The risks of drug resistance and early toxicity are markedly outweighed by improvements in short-term mortality and disease progression, especially prevention of irreversible HIV encephalopathy. Infants should be reviewed at a minimum of monthly intervals up to 6 months of age in order to increase ART dosing in line with growth. Symptomatic infants presenting with severe illness (including opportunistic infections) should start ART as soon as possible. Debate remains about whether ART should be started immediately or deferred until treatment for the presenting illness has started and the child is clinically stable. There is no evidence to inform this, and it is recommended that ART be started as soon as the child is stable (ideally within 2 weeks of diagnosis). Expert pharmacist advice should be obtained if there is a complex treatment for a coinfection (e.g. TB) as drug interactions may interfere with effectiveness and/or cause side effects. See Section 10 below for further specific information on coinfection. ## Children over 1 year of age -general principles Starting ART is recommended in all children over 1 year of age with HIV-related symptoms, and in asymptomatic children with CD4 counts or percentages below or approaching recommended age-related thresholds. Starting ART should also be considered in those with a high HIV RNA VL (> 100 000 copies/ml), as they are more likely to progress rapidly to symptoms or have a rapid fall in CD4 values [bib_ref] Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in..., Palumbo [/bib_ref] [bib_ref] Prognostic Markers Collaborative Study Group. Short-term risk of disease progression in HIV-1-infected..., Dunn [/bib_ref]. The evidence for clinical benefit of ART in children with AIDS/CDC category C disease is so strong that parental refusal to treat is a child protection issue. CDC clinical category B covers a wide range of disease severity. A retrospective study from the USA demonstrating a significant reduction in rate of progression of disease adds further weight to the recommendation that children with category B or C disease should be treated irrespective of their CD4 count/percentage [bib_ref] Timing of antiretroviral therapy initiation and its impact on disease progression in..., Sturt [/bib_ref]. PENTA now recommends that treatment should be initiated for all children in WHO stage 3 or 4 (CDC category B or C) and considered in all children with HIV-related symptoms (WHO stage 2; CDC category A). CD4-guided treatment thresholds in asymptomatic children are based predominantly on analysis of paediatric and adult cohort data and extrapolation from the adult Simple Trial Comparing Two Strategies for Management of Anti-Retroviral Therapy (SMART study) [bib_ref] Prognostic Markers Collaborative Study Group. Short-term risk of disease progression in HIV-1-infected..., Dunn [/bib_ref] [bib_ref] Current CD4 cell count and the short-term risk of AIDS and death..., Dunn [/bib_ref]. Only one randomized trial [Pediatric Randomised Early versus Deferred Initiation in Cambodia and Thailand (PREDICT)] has addressed the question of when to start ART in children over 1 year of age. Thai children aged 1-12 years (median age 6.4 years), with CD4 percentage 15-24%, were randomized to start immediate ART or defer ART until the CD4 percentage dropped below 15%. Rates of progression and death were unexpectedly low in both groups during 144 weeks of follow-up. As a result, the study was underpowered to detect a difference in the primary endpoint of AIDS-free survival. Analysis of secondary endpoints did, however, demonstrate better height-for-age Z scores in the immediate treatment group [bib_ref] Early versus deferred antiretroviral therapy for children older than 1 year infected..., Puthanakit [/bib_ref]. The evidence for absolute age-related CD4 thresholds for starting ART remains as for the PENTA 2009 guidelines, as follows. (1) Analysis of adult data Data from the SMART trial clearly showed that adults with CD4 counts between 250 and 350 cells/μL have significantly better outcomes on ART than off ART. Adult (US and European) guidelines strongly recommend ART initiation at CD4 cell counts below 350 cells/μl [bib_ref] British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral..., Williams [/bib_ref]. that the short-term risk of disease progression was very similar in young adults (around 20 years old) and children aged 5 years and older [bib_ref] Current CD4 cell count and the short-term risk of AIDS and death..., Dunn [/bib_ref]. Absolute CD4 count, rather than percentage, should therefore be used to determine treatment thresholds in children from the age of 5 years. These should follow the same CD4 threshold recommendations for treatment recommended in adult guidelines. ## (3) analyses of child data Analyses from the HPPMCS cohort demonstrated that CD4 counts are highly prognostic of disease progression at all ages after infancy. However, to obtain a uniform progression risk with the thresholds for adults and children aged 5 years and over, thresholds between 1 and 5 years of age would have to change approximately every 6 months or less. This would require too many age bands for a workable guideline, and the historical data on which progression risks are based are not robust enough to warrant ignoring the importance of practical guidance and the desirability of general concordance with other international guidelines. Therefore, only two age bands between 1 and 5 years have been selected. CD4 count as well as CD4 percentage thresholds should be taken into account. In the HPPMCS data, 10-20% of CD4 percentages and CD4 counts are discordant in terms of ART initiation thresholds adopted for these PENTA guidelines. However, these values are frequently concordant on a subsequent blood sample. If consistent discordance is observed, and particularly if the count is below the threshold although the percentage is not, then initiation of ART is strongly recommended [bib_ref] Discordance between CD4 cell count and CD4 cell percentage: implications for when..., Dunn [/bib_ref]. The prognostic significance of plasma HIV RNA for shortterm risk of disease progression is much weaker than CD4 count or percentage [bib_ref] Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in..., Palumbo [/bib_ref] [bib_ref] Prognostic Markers Collaborative Study Group. Short-term risk of disease progression in HIV-1-infected..., Dunn [/bib_ref]. However, ART is recommended in asymptomatic children with VL persistently above 100 000 copies/ml, even if they do not meet CD4 count criteria. Rapid clinical, virological or immunological failure may occur, but, in general, ART does not need to be started quickly except in infants or in an older child seriously ill with advanced HIV disease. Time spent preparing and educating the family, particularly about adherence, is very important. Starting ART needs to be supported and promoted by the caregivers if it is to succeed. It is preferable not to start ART at the first clinic visit. Older children should preferably know why they are taking treatment, and timing of full or partial naming of HIV diagnosis in relation to starting ART is an important consideration. These CD4 thresholds are for children without coinfection. See Section 10 for guidance in the context of HBV/HCV, TB and opportunistic infections. ## Children aged 1-3 years As in the previous PENTA guidelines [bib_ref] PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1..., Penta Steering Committe [/bib_ref] , CD4 thresholds for absolute indication to start treatment outside the infant period are based on data extrapolated from adults and analysis of HPPMCS data. The age bands (1−< 3, 3−< 5 and ≥ 5 years) provide harmony with DHHS guidelines (which are also largely based on HPPMCS data)but contrast with new WHO guidelines which group all children aged 1-5 years together. The PENTA 2009 guidelines defined thresholds based on an individual child's risk of progression to AIDS or death over the subsequent 1 year (derived from HPPMCS data using the on-line PENTA calculator available at http://www.hppmcs.org/). The absolute treatment thresholds aimed to maintain the overall risk of mortality below 2% and the AIDS progression risk below 5% (acknowledging that progression risk is higher and more variable in the first few years after infancy). The ongoing success of ART means that we should continue to expect better clinical outcomes for children, and in 2015 these rates of disease progression are no longer deemed acceptable. Looking more closely at the calculated risks, using a threshold of < 1000 cells/μl and < 25%, between 1 and 3 years, risk of progression at these thresholds increases dramatically at younger ages [fig_ref] Table 2: Percentage risk of progression to AIDS or death in the next 12... [/fig_ref]. For these reasons, while we recommend keeping the 2009 CD4 thresholds in this age range, it is also recommended that ART should be considered in all children aged 1-3 years in order to minimize risk of progression and death and to minimize potential deleterious effects of ongoing viral replication on the child's rapidly developing brain and immune system. ## Children aged 3-5 years As mentioned above, the levels of risk deemed acceptable in previous versions of the PENTA guidelines (2% mortality and 5% AIDS) should be lowered in the light of the ongoing success of ART, and the absolute CD4 threshold for ART initiation in children aged 3-5 years has been increased to 750 cells/μl and 25% accordingly . This is in line with current US and WHO guidance. ## Children aged > 5 years For older children, the recommended absolute threshold for ART initiation remains at a CD4 count of 350 cells/μl, in line with current European adult guidelines [bib_ref] British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral..., Williams [/bib_ref]. However, ART should be considered below 500 cells/μl, in line with current US and WHO guidelines, in order to potentially optimize ultimate CD4 count in adulthood (see below). Treatment should certainly be initiated before the CD4 count reaches 350 cells/μl rather than letting it fall below this value. The ongoing Strategic Timing of Antiretroviral Treatment (START) trial comparing ART initiation at > 500 cells/μl versus < 350 cells/μl will report in 2016. ## Other indications for art initiation irrespective of immunological or virological status - Coinfection with HCV or TB - Autoimmune manifestations (e.g. thrombocytopenia) - Malignancy - Growth or puberty delay - Neurocognitive delay - Prevention of transmission in sexually active adolescents - Pregnancy - Primary infection (e.g. after nosocomial or sexual transmission) - Child and family wish to start treatment (following full discussion of risk/benefit) Percentage risk progression to AIDS or death in the next 12 months associated with absolute thresholds at age 3-5 years at (a) previous thresholds and (b) updated thresholds ## Consideration for starting antiretroviral therapy to optimize immune function in adulthood The aim of treatment in paediatric HIV infection should extend beyond survival to maximizing long-term outcomes and quality of life. Current treatment goals should thus include normal growth and physical, pubertal, neurological and psychological development and immune reconstitution, while minimizing long-term drug toxicity and viral drug resistance. To date, studies with such long-term outcome data have been lacking, but in the field of immune reconstitution, mathematical models may allow us to begin to use predicted long-term outcomes for treatment initiation decisions. A number of studies indicate that, even with good adherence, long-term immunity may remain suboptimal after starting ART. The reasons for this are likely to be multifactorial and include: a depleted/inadequate immunological memory for childhood infections and vaccinations; destruction/skewing of B-and T-cell repertoires; and persistently low CD4 counts in relation to healthy agematched children (reviewed in [bib_ref] Suboptimal immune reconstitution in vertically HIV infected children: a view on how..., Cotugno [/bib_ref]. Mathematical modelling of data from large European and African cohorts indicates that CD4 cell recovery depends strongly on both the age and CD4 count at ART initiation [bib_ref] Predicting patterns of long-term CD4 reconstitution in HIV-infected children starting antiretroviral therapy..., Picat [/bib_ref] [bib_ref] Age and CD4 count at initiation of antiretroviral therapy in HIV-infected children:..., Lewis [/bib_ref]. The important predictions from these studies are as follows. ## 1) children under 5 years of age have very good potential for recovering their CD4 counts, even when counts are low at ART initiation. 2) In contrast, with every year that passes after the age of 5 years, the potential for long-term CD4 count recovery to the normal range diminishes [fig_ref] Figure 1: Predicted long-term CD4 count following antiretroviral therapy [/fig_ref]. Current PENTA guidelines recommended a uniform threshold for children over 5 years old and continuing at the same threshold through adulthood (CD4 count < 350 cells/μl). These mathematical projections raise the concern that this approach may substantially compromise longterm CD4 recovery in adulthood, particularly for children older than 10 years at ART initiation. The reasons for the effects of age and initial CD4 count on immune reconstitution are only partially understood. They are likely to be attributable to a combination of declining thymic output from its peak at 1 year of age and irreversible immune injury. Whatever the causes, it would appear logical to strive to initiate ART at combinations of age and CD4 counts that are most likely to achieve a better long-term reconstitution. The absolute thresholds for ART initiation represent the lowest CD4 thresholds for ART initiation to prevent disease progression; however, these may not be optimal thresholds for CD4 recovery in adulthood. Although [fig_ref] Figure 1: Predicted long-term CD4 count following antiretroviral therapy [/fig_ref] represents extrapolations in time and from available data, it can be used as a guide to help indicate how delay in ART initiation may adversely influence eventual CD4 recovery. With current treatment regimens, which are less toxic and easier to take, there is a theoretical case for starting ART at any CD4 count in older children, especially those over 5 years old. Another long-term consideration when starting ART in children, irrespective of CD4 count, is the possible benefit of minimizing HIV viral reservoirs in order to optimize the potential for achieving eventual 'functional HIV cure' . Recent reports in both adults and children have indicated Predicted long-term CD4 count following antiretroviral therapy (ART) initiation at thresholds of 250, 350, 500, 750 and 1000 cells/μL (curves), using models derived from the AntiRetroviral Research for Watoto (ARROW) study. Delaying treatment in children younger than 5 years (to the left of the vertical line) results in relatively small differences in long-term expected CD4 count. In contrast, children aged over 5 years (right of the vertical line) are predicted to experience a steady deterioration in long-term CD4 count as ART is initiated at increasingly older ages (and a constant CD4 threshold). Dashed lines show that a 6-year-old delaying treatment until the age of 13 years, with a CD4 count of 350 cells/μL throughout, may expect the long-term CD4 count to be lowered by 151 cells/μL: from 770 to 619 cells/μL. that early and sustained full suppression of HIV may limit viral reservoirs [bib_ref] Long-term antiretroviral treatment initiated in primary HIV-1 infection affects the size, composition..., Buzon [/bib_ref] [bib_ref] Dynamics of the resting CD4(+) T-cell latent HIV reservoir in infants initiating..., Persaud [/bib_ref] and that a longer cumulative time spent with ongoing viral replication is associated with a larger viral reservoir. How this may relate to future 'cure' is yet to be determined, but it should also be borne in mind when considering ART initiation in young children who may see the advent of new curative treatments within their lifetime. We therefore recommend that the CD4 thresholds indicate the lowest limits below which a child should not be allowed to fall before starting treatment. Where resources allow and families are motivated, discussions should be had with children, young people and their families about the option of starting treatment at higher CD4 counts with the aim of optimizing long-term immune recovery, while always balancing possible long-term toxicity effects of ART and the potential for viral drug resistance if adherence is poor. With an increase in the number of indications for ART, and in the context of less robust evidence for clinical benefit, optimal adherence is essential so as not to compromise future treatment options though development of resistance to first-line drugs. ## Comparison of penta guidelines with dhhs and who guidelines for hiv-infected children and adults As can be seen from , PENTA and US guidelines are generally in agreement; however, DHHS guidelines advise that ART initiation should be considered for any child irrespective of immune and clinical status. Furthermore, the CD4 thresholds are higher for children over 5 years of age. This is in line with recent updates to adult DHHS and WHO guidelines, which give a universal ART threshold of 500 cells/μl, while DHSS recommend that asymptomatic adults should be considered for treatment at any CD4 count. The latter is in part based on cohort data demonstrating a possible benefit with respect to non-AIDS-related morbidity for all patients on ART as well as a known decrease in the risk of onward sexual transmission (summarized in. These most recent changes to the adult US guidelines have been debated extensively; the strength of the evidence on which they are based is relatively weak [bib_ref] Rating evidence in treatment guidelines: a case example of when to initiate..., Sabin [/bib_ref] [bib_ref] When to start antiretroviral therapy: the need for an PENTA 2015 paediatric..., Lundgren [/bib_ref] [bib_ref] When to start antiretroviral therapy: as soon as possible, Franco [/bib_ref]. It is the opinion of PENTA that extrapolation of these adult data to guide treatment for children is inadvisable at present. Results of large randomized trials comparing higher versus lower treatment thresholds in adults are expected in 2016 [http://clinicaltrials.gov/show/ NCT00867048 (START); http://clinicaltrials.gov/show/ NCT00495651 (TEMPRANO)]. This evidence will clarify the wider risks and benefits of starting treatment at higher CD4 counts. Current European/UK adult guidelines are more conservative [bib_ref] British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral..., Williams [/bib_ref]. The absolute CD4 threshold for ART initiation remains at 350 cells/μl, with a number of exceptions where starting at higher thresholds is indicated (end organ involvement, hepatitis/TB coinfection, pregnancy, discordant couples or primary infection). The PENTA 2015 guidelines are in line with European adult guidance, with the additional option that, for older children, ART initiation at CD4 counts > 350 cells/μl, to optimize immune reconstitution/CD4 count in adulthood, should be considered. WHO guidelines have harmonized and simplified adult and child recommendations as far as possible, recommending starting ART in all children under 5 years of age, and in older children with CD4 counts < 500 cells/μl. Treatment is recommended for all children under 5 years old for mainly programmatic reasons alongside extrapolation of data from adult cohort studies suggesting clinical benefit to treating irrespective of immune status, while accepting that neither data from PREDICT [bib_ref] Early versus deferred antiretroviral therapy for children older than 1 year infected..., Puthanakit [/bib_ref] nor data from a causal modelling study from a large paediatric cohort study [bib_ref] When to start antiretroviral therapy in children aged 2-5 years: a collaborative..., Schomaker [/bib_ref] indicate clinical benefit. It is suggested that, by simplifying guidance and making treatment universal, access to ART for children will increase in resource-poor settings where it remains inadequate. This is fortunately not as relevant for the majority of European countries, so for this reason universal treatment is still only recommended by PENTA for those under 1 year of age, for whom the evidence-based health benefits are incontrovertible. ## Which art regimen to start as first-line therapy - Children should start effective (at least three drugs) ART, usually a dual or triple NRTI backbone together with either a ritonavir-boosted PI or an NNRTI. - Children exposed to NVP during failed PMTCT (or in whom perinatal NVP exposure cannot be excluded) should be started on a boosted PI-containing regimen, as transmitted resistance may lead to failure of NVPcontaining ART. - Children aged < 3 years not exposed to NVP during failed PMTCT may be initiated on either NVP or ritonavir-boosted lopinavir (LPV/r)-containing ART. We recommend that NVP should be given together with three NRTIs (ABC, 3TC and ZDV) in all infants and in children aged 1-3 years with VL > 100 000 copies/ml or signs of CNS involvement as an induction-maintenance strategy, unless any of these drugs are contraindicated (such as ABC in HLA B5701-positive children). - In children aged > 3 years, either NNRTI or boosted PI-based ART is acceptable for initial therapy. Factors such as availability of age-appropriate formulations, palatability, dosing frequency and adherence should be considered when choosing NNRTIs or boosted PIs. - The preferred NNRTI is NVP in children aged < 3 years not exposed to NVP during failed PMTCT, and EFV in children aged > 3 years. The preferred PI in children aged < 6 years is LPV/r, in children aged 6−12 years it is ATV/r, and in children aged > 12 years it is ATV/r or DRV/r. - INSTI-based ART may be an alternative regimen in children over age 12 years. - The preferred first-line NRTIs are ABC/3TC in children aged < 12 years and TDF/FTC or ABC/3TC (if VL < 100 000 copies/ml) in children aged > 12 years. - Age, HLA B5701 genotype, previous drug exposure, resistance profile, coinfections, available formulations and likely adherence should be taken into account when choosing a first-line regimen. - See [fig_ref] Table 4: Recommended first-line antiretroviral therapy [/fig_ref] for details of recommended first-line ART regimens. ## General principles of treatment To achieve long-term virological suppression requires high levels of ART adherence. Children's doses should be checked for age and weight or surface area at each visit, and this should be done frequently during periods of rapid growth, especially infancy. Doses should be rounded up (not down) to convenient syrup volumes or tablet formulations, and parents should be given careful instructions on dosage, timing, administration, repeating doses if there is vomiting within 1 hour after taking medication, and seeking medical attention rather than discontinuing if drugs are refused or side effects are suspected. Supervised initiation of therapy in hospital or at home with visiting nurses may be appropriate for some children and families, particularly newly diagnosed infants. When drugs show comparable toxicity and efficacy profiles, clinicians should be aware of pricing, drug availability and national policies. The standard first-line treatment regimen remains two NRTIs with either an NNRTI or a boosted PI (see [fig_ref] Table 4: Recommended first-line antiretroviral therapy [/fig_ref]. Although transmitted viral resistance remains rare in children, it may lead to suboptimal response to the firstline treatment [bib_ref] Effect of transmitted drug resistance on virological and immunological response to initial..., Wittkop [/bib_ref]. Therefore, pretreatment resistance genotyping should be performed. ## Nnrti or boosted pi for first-line art? Boosted PIs have a higher barrier to viral resistance, but have more potential drug interactions and cause higher rates of dyslipidaemia, while NNRTIs are often more palatable although virological failure frequently results in whole-class resistance. Recent studies have produced discordant results on whether or not NNRTI-and boosted PI-based regimens are equally effective, especially in the youngest children. This discordance has resulted in conflicting recommendations for first-line drug regimens and merits consideration. ## Infants and young children (< 3 years old) Infected infants exposed to NVP during failed PMTCT (or in whom perinatal NVP exposure cannot be excluded) should be started on a boosted PI-containing regimen, as transmitted resistance may lead to failure of NVP-containing ART [bib_ref] Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression:..., Coovadia [/bib_ref] [bib_ref] Antiretroviral treatment for children with peripartum nevirapine exposure, Palumbo [/bib_ref]. LPV/r should not be administered to premature involvement until VL has been suppressed for at least 3 months. ‡ Four-drug induction for infants on NVP-based therapy may be considered until VL has been suppressed for at least 3 months, followed by three-drug maintenance therapy. § Tenofovir (TDF)/emtricitabine (FTC) is preferred in older children with VL > 100 000 copies/ml. Some clinicians would advocate deferring the use of TDF until after puberty. ¶ ZDV should be avoided if possible, apart from the indications described in the above notes. In rare instances (e.g. transmitted resistance or toxicity), raltegravir (RAL) may be used as first-line therapy in children < 12 years of age. neonates or to term neonates below 2 weeks of postnatal age because of the increased risk of toxicities reported in premature and very young babies [bib_ref] Twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir therapy, Mcarthur [/bib_ref] [bib_ref] Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal dysfunction among..., Simon [/bib_ref]. International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1060 suggested better efficacy for LPV/r than for NVP in children aged below 3 years, even without prior NVP exposure. Children randomized to an NVPcontaining regimen were twice as likely as those on an LPV/ r-based regimen to reach a composite endpoint of: virological failure, treatment discontinuation or death at 24 weeks of follow-up (40.8% versus 19.3%, respectively; P < 0.001). Transmitted NVP resistance, emergence of NVP resistance because of high VL in infancy and possible low NVP levels during lead-in dosing [bib_ref] Effectiveness of antiretroviral therapy in HIV-infected children under 2 years of age, Penazzato [/bib_ref] may have played a role. A composite endpoint at only 24 weeks, and the low-income setting, make it difficult to extrapolate the results in terms of longer outcomes and generalizability to higher income settings. In contrast, PENTA 9/ Pediatric AIDS Clinical Trials Group (PACTG) 390 (PENPACT-1), a randomized trial conducted in resource-rich settings, showed no difference between firstline NNRTI -and boosted PI-based regimens in virological outcomes in children aged 0.1-17.8 years (median age 6.5 years) [bib_ref] First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor..., Babiker [/bib_ref]. An underpowered subanalysis by individual drug in children younger than 3 years of age found no difference in virological outcome between children on NVPand LPV/r-containing ART regimens (G. Tudor-Williams, unpublished results). In agreement with PENPACT-1, the Prevention of Malaria and HIV Disease in Tororo, Uganda (PROMOTE) study, a small open-label RCT in Uganda of children aged 0.4-5.9 (median 3.1) years not exposed to NVP, showed comparable results at 48 weeks in terms of virological suppression, CD4 gain and severe adverse events for NNRTI-and LPV/r-containing ART regimens [bib_ref] Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or..., Ruel [/bib_ref]. The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study, of children under 1 year of age commencing ART at a median age of 3.6 months, showed no difference in virological suppression or CD4 response between children receiving NNRTI-based ART (mostly NVP) and those receiving LPV/r-based ART over a median of 5.9 years of follow-up. The power to detect small differences was low as comparatively few infants started boosted PI-based ART. However, in this cohort study, children on an NNRTI-based four-drug regimen (NNRTI + 3 NRTIs) had significantly better virological suppression and CD4 gain at 12 months after ART initiation when compared with either PI-or NNRTI-based three-drug regimens [bib_ref] treatment response and duration of first-line regimens, Judd [/bib_ref]. The initial rapid virological suppression and immune reconstitution on an NVP-based four-drug regimen compared with a threedrug regimen have been confirmed in ARROW, although differences in virological/immunological outcomes were not sustained following a switch to three-drug therapy at 36 weeks from ART initiation [bib_ref] Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in..., Arrow Trial Team [/bib_ref] (see Section 6.5). ## The evaluation of virological outcomes in real-life clinical settings in the national cohort of hiv-infected children in the uk/ireland [collaborative hiv paediatric study (chips)] showed similar rates of VL suppression by 12 months for different first-line regimens in children aged < 3 years (NVP + 2 NRTIs; NVP + 3 NRTIs; LPV/r + 2 NRTIs) [bib_ref] Long-term virological outcome in children on antiretroviral therapy in the UK and..., Duong [/bib_ref]. However, three-drug NVP-based regimens were associated with faster progression to virological failure long term, while four-drug NVP-based regimens had the lowest risk of failure. In practice, the poor palatability of boosted LPV/r liquid formulation precludes its use in many young children, and NVP remains a first-line option in infants and young children not exposed to NVP perinatally. NVP has good palatability, high cerebrospinal fluid (CSF) penetration and a favourable lipid profile. Taking the above into consideration, either NVP-or LPV/r-containing ART may be initiated in children younger than 3 years of age. However, in view of the above-mentioned evidence and the fragility of NVP at high VLs, we recommend that NVP should be accompanied by three NRTIs, as an induction-maintenance strategy, in infants and young children with VL > 100 000 copies/ml or signs of CNS involvement, including neurodevelopmental delay [fig_ref] Table 4: Recommended first-line antiretroviral therapy [/fig_ref]. Earlier viral suppression and greater early CD4 responses with the use of four-drug induction with a triple NRTI backbone [bib_ref] treatment response and duration of first-line regimens, Judd [/bib_ref] [bib_ref] Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or..., Ruel [/bib_ref] may have potential benefits in terms of reduced viral reservoirs and reduced risk of CNS compartmentalization. Early detection of treatment failure should be picked up by regular monitoring of viral response in the first few months following treatment initiation. ## Children > 3 years of age As mentioned above, PENPACT-1 found no difference in clinical, virological or immunological outcomes between NNRTI-and PI-based regimens [bib_ref] First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor..., Babiker [/bib_ref]. The virological outcome analysis in the CHIPS cohort study showed that in children aged > 3 years overall virological suppression by 12 months was high (> 93%) and there was no difference between NNRTI-and PI-based regimens. However, the progression to virological failure was different between regimens: in the first 2 years on therapy, it was slowest for EFV + 2 NRTIs or NNRTI + 3 NRTIs and fastest for NVP + 2 NRTIs. After 2 years on therapy, the risk was similar for EFV and NVP three-drug ART, and remained lowest for NNRTI four-drug ART, although the number of children on the latter regimen was small [bib_ref] Long-term virological outcome in children on antiretroviral therapy in the UK and..., Duong [/bib_ref]. Either NNRTI-or boosted PI-containing regimens are acceptable for initial therapy in children above 3 years of age. Issues to consider when choosing an NNRTI or boosted PI regimen include the availability of age-appropriate formulations, palatability, dosing frequency and adherence. For EFV and NVP, single point mutations in the reverse transcriptase gene rapidly lead to virological failure and whole-class resistance. Families should be counselled carefully about these issues before starting ART. If predicted adherence is questionable, as is often seen in teenagers, a more forgiving PI-based regimen should be initiated with a possibility of subsequent simplification to an NNRTI FDC one-tablet-once-daily regimen when virological suppression is sustained and adherence is established. ## Which nnrti? The choice for the first-line NNRTI-based therapy in children is either EFV or NVP. Until recently, only NVP was licensed for children < 3 years of age because of very poor bioavailability of EFV syrup in this age group. The US Food and Drug Administration (FDA) have recently approved EFV capsule sprinkles for children as young as 3 months of age, based only on the results of a paediatric pharmocokinetic (PK) population model including three open-label paediatric studies and a PK comparison study in adults [bib_ref] Population pharmacokinetics of efavirenz in pediatric patients to inform dosing in children..., Bertz [/bib_ref]. Variable EFV exposure in young children, as shown in a recent study of EFV PK in children under 3 years old, and lack of experience with EFV sprinkle formulation in children may prevent its widespread use. While waiting for the results of further studies, EFV sprinkles should only be considered as an alternative regimen to NVP in this age group and PK monitoring is currently recommended. Pharmacogenetics may be a useful adjunct in the future as testing for cytochrome P450 2B6 (CYP2B6) polymorphisms has been shown to predict adequate dosing. As seen in adult studies [bib_ref] Outcomes for efavirenz versus nevirapine-containing regimens for treatment of HIV-1 infection: a..., Pillay [/bib_ref] , two recent retrospective paediatric cohort studies, in resource-limited and resourcerich settings, comparing EFV and NVP showed that EFV was associated with superior virological outcomes [bib_ref] Association between efavirenz-based compared with nevirapine-based antiretroviral regimens and virological failure in..., Lowenthal [/bib_ref] [73], although in the UK/Ireland CHIPS cohort, the benefit of EFV-based regimens over NVP-based regimens in terms of virological failure was very modest after 2 years of therapy [bib_ref] Long-term virological outcome in children on antiretroviral therapy in the UK and..., Duong [/bib_ref]. In the ARROW trial, a nonrandomized comparison of NNRTI-based regimens showed favourable short-term VL suppression with EFV; however, long-term suppression depended on age, and was better with EFV in children aged < 10 years, and with NVP in those aged > 10 years [bib_ref] Virologic Response To Efavirenz vs Nevirapine-Containing ART in the ARROW Trial, Kekitiinwa [/bib_ref]. A recent systematic review and meta-analysis which included data on nearly 4000 children showed a lower frequency of severe adverse events and treatment discontinuations with EFV than NVP, although EFV use was associated with higher rates of CNS adverse events [bib_ref] Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic..., Shubber [/bib_ref]. Overall, these data support the use of EFV as the preferred NNRTI in children aged > 3 years. However, for children with neurodevelopmental and psychiatric comorbidities, NVP may be a better choice in view of potential CNS side effects associated with EFV. In summary, the preferred NNRTI is NVP in children aged < 3 years, and EFV in children aged > 3 years. ## Which boosted pi? PI use in children should be ritonavir-boosted to optimize efficacy. Consideration of which PI should be used is based on balancing pill burden, toxicity, experience, available paediatric data and available formulations for a given age group. LPV/r [Kaletra (AbbVie, North Chicago, IL, USA)] is the only combined PI/ritonavir liquid or tablet formulation for children and the only PI licensed for children aged < 3 years in Europe. It must be given twice daily [bib_ref] Final results of koncert: a randomized noninferiority trial of QD vs BD..., Lyall [/bib_ref]. ATV/r, a once-daily PI, is licensed for children aged > 6 years in Europe, and is the preferred boosted PI in this age group. DRV/r is licensed for children aged > 3 years in the USA (treatment-naïve and treatment-experienced) and Europe (treatment-experienced aged > 3 years; treatment-naïve > 12 years). Paediatric studies with once-daily administration of DRV/r have not been conducted in children aged 6-12 years. It is therefore recommended that DRV/r be used twice daily in children aged < 12 years while awaiting new data. In view of this, we recommend DRV/r as an alternative first-line PI in children in this age group (6-12 years), especially when there is known transmitted PI resistance or intolerance precluding use of other PIs. Both ATV/r and DRV/r are acceptable first-choice PIs in older children (> 6 years old for ATV/r and > 12 years old for DRV/r) because of their favourable virological outcomes and the availability of once-daily treatment [fig_ref] Table 4: Recommended first-line antiretroviral therapy [/fig_ref]. Fosamprenavir/r (fAPV/r), a twice-daily PI, is licensed for children from age 6 years in Europe. Although fAPV/r is approved by the FDA in children aged > 4 weeks, it is not recommended for children aged < 6 months because of low drug exposure in this age group. In view of limited paediatric experience, the adverse effect on lipids, the twice-daily regimen and meal requirements, it is not recommended for first-line therapy in children. Some PIs (ATV and fAPV) may be used unboosted in special circumstances where ritonavir is not tolerated, but this is not recommended because of reduced efficacy. Where possible, doses of unboosted PIs should be monitored by TDM. In summary, the preferred PI for children less than 6 years old is LPV/r, for children 6-12 years old it is ATV/r, and for children > 12 years old it is ATV/r or DRV/r [fig_ref] Table 4: Recommended first-line antiretroviral therapy [/fig_ref]. ## Choice of nrti backbone Factors to consider when choosing the dual NRTI combination: - the potential for resistance and cross-resistance (and hence future therapy options); - tolerability and toxicity; - dosing frequency; - age-appropriate formulations including FDCs. 3TC and ABC are the preferred first-line NRTIs in children < 12 years of age. Superiority of ABC over ZDV has previously been reported in children [bib_ref] Lamivudine/abacavir maintains virological superiority over zidovudine/ lamivudine and zidovudine/abacavir beyond 5 years..., Green [/bib_ref]. Starting with ABC and 3TC also has the advantage of preserving (and even increasing) susceptibility to ZDV for future options in cases of virological failure, whereas starting on ZDV may lead to accumulation of thymidine analogue-associated mutations (TAMs) affecting subsequent susceptibility to ABC [bib_ref] HIV-1 resistance after randomized virologic switch at 1000 or 30,000 c/ml in..., Harrison [/bib_ref] [bib_ref] Evolution of antiretroviral phenotypic and genotypic drug resistance in antiretroviral-naive HIV-1-infected children..., Gibb [/bib_ref]. Both ABC and 3TC can be given once daily to children over 3 months old, which is supported by PK data in PENTA 13 and PENTA 15, and virological outcomes in ARROW [bib_ref] Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or..., Ruel [/bib_ref] [bib_ref] Pharmacokinetics and acceptability of once-versus twice-daily lamivudine and abacavir in HIV type-1-infected..., Musiime [/bib_ref]. 3TC and ABC both have palatable liquid formulations, and scored breakable tablets have recently become available. Children over 30 kg can be given the adult fixed dose combined pill [Kivexa (ViiV Healthcare, Middlesex, UK)]. As a consequence of inferior 96-week virological efficacy of ABC/3TC compared with TDF/FTC in adults with VL ≥ 100 000 copies/ml [bib_ref] British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral..., Williams [/bib_ref] , an ABC/3TC backbone is recommended as an alternative rather than the preferred backbone in older children with very high VLs [fig_ref] Table 4: Recommended first-line antiretroviral therapy [/fig_ref]. ZDV is recommended as a substitute for ABC in children with the HLA genotype B5701, as they have an increased risk of severe hypersensitivity reactions to ABC. ZDV is also recommended alongside ABC and 3TC in infants and in young children with high VLs receiving NVP (see Section 6.3 above). It should be given twice daily. It is not recommended as first-line treatment in other situations, but remains an important component of neonatal PEP. TDF has been licensed for children aged > 2 years by the FDA and European Medicines Agency (EMA); however, the long-term risk of renal and bone toxicity remains a possible concern (see Section 9 on drug toxicity). As a result of limited long-term safety data in young children and unresolved concerns over the effects on bone and kidneys with prolonged use, TDF is recommended as a preferred first-line NRTI only in older children (aged > 12 years or weight > 35 kg) with no underlying renal insufficiency or other risk factors significantly affecting bone and renal health. Some clinicians prefer to wait until after puberty because of uncertain effects on bone health [fig_ref] Table 4: Recommended first-line antiretroviral therapy [/fig_ref]. TDF is also recommended as a first-line NRTI in all children aged > 2 years with HBV coinfection (see Section 10 on coinfections). It is available in co-formulated tablets with FTC as mentioned above. FTC is chemically very similar to 3TC and they are interchangeable. FTC has been co-formulated with TDF [Truvada (Gilead, Forest City, CA, USA)] and TDF and EFV (Atripla, Bristol-Myers Squibb, New York, NY, USA and Gilead), which may be used in older children (see below). It is also included with TDF in the more recently developed FDCs based on the second-generation NNRTI rilpivirine (RPV) [Eviplera (Gilead and Janssen Therapeutics, Titusville, NJ, USA)] and the INSTI elvitegravir (EVG) [Stribild (Gilead)]. Where possible, once-daily and fixed dose formulations should be used to reduce pill burden and potentially improve adherence. In view of well-documented toxicities, stavudine (d4T) is no longer recommended for treatment of HIV-infected children in Europe. However, its efficacy is acknowledged and it is accepted that, in rare circumstances, it may be the only option available. Didanosine (ddI) is no longer recommended for first-line therapy because of the high risk of toxicities and the availability of safer options (see Section 9 on toxicity). Children arriving in Europe from other regions on d4T or ddI should be changed to another regimen if possible. ## Nrti-only regimens Triple NRTI therapy has been shown to have inferior virological and immunological outcomes and a high risk of selection for resistance mutations in ART-naïve adult patients. The ARROW study showed that children on a three-NRTI maintenance regimen with 3TC, ABC and ZDV had inferior virological outcomes at week 144 and more ZDV-related neutropenia, but no difference in disease progression or immunological outcomes when compared to NNRTI plus 3TC and ABC [bib_ref] Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or..., Ruel [/bib_ref]. Based on these data, triple-NRTI regimens are not recommended except in special circumstances when significant drug interactions or toxicity risks prevent the use of NNRTI-or PI-containing ART (e.g. for concomitant TB treatment; see Section 10 below). ## Integrase inhibitors (instis) RAL, a twice-daily INSTI, in combination with two NRTIs is now a first-line options for adults [bib_ref] British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral..., Williams [/bib_ref] and is licensed for treatment-experienced children from 4 weeks of age. Dolutegravir (DTG), a second-generation INSTI, has recently been licensed for treatment-naïve adults and children > 12 years of age. An international paediatric trial of its use in ART-naïve and -experienced children is planned (the PENTA 20 trial). EVG, a once-daily INSTI, requires boosting with ritonavir or cobicistat. It is a component of the FDC Stribild and is now recommended as another preferred regimen for ART-naïve adult patients in the USA and Europe [bib_ref] British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral..., Williams [/bib_ref]. Given the evidence on the efficacy and safety of RAL and DTG derived from studies of treatment-naïve adults and treatment-experienced children [bib_ref] Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV+ children, Viani [/bib_ref] [bib_ref] Safety and efficacy of dolutegravir in HIV treatment-experienced adolescents: 48-week results, Viani [/bib_ref] , RAL-and DTG-containing regimens can now be recommended as alternative first-line ART in children older than 12 years. In children younger than 12 years, there are no data on the use of either drug in treatment-naïve children. Their firstline use should therefore be restricted to specific circumstances (transmitted resistance and intolerance). ## Adherence and hiv knowledge - Adherence to treatment is paramount and should be discussed at each clinic visit. - Every effort should be made to simplify a regimen to support adherence (e.g. using once-daily regimens, FDCs and 'forgiving' regimens with higher barriers to resistance). Simple adherence aids should be used when appropriate. - Children should know of their HIV diagnosis before adolescence. - Monitoring for psychological, neurocognitive and mental health issues should be routine, allowing early supportive and therapeutic intervention. Optimal adherence to treatment is of paramount importance for long-term efficacy of ART, and younger children rely on caregivers to deliver this. Although there are some data on the barriers to and predictors of adherence [bib_ref] Barriers to medication adherence in behaviorally and perinatally infected youth living with..., Macdonell [/bib_ref] , there are few studies of successful interventions to improve it [bib_ref] Multisystemic therapy for poorly adherent youth with HIV: results from a pilot..., Letourneau [/bib_ref] [bib_ref] Interventions to improve adherence to antiretroviral therapy in children with HIV infection, Bain-Brickley [/bib_ref] , and there is no gold standard for measuring it. Adherence can be influenced by many factors, including those related to the child/young person (e.g. developmental stage, treatment fatigue and knowledge of status), family and caregivers (e.g. relationship to the child, responsibility for adherence and caregiver beliefs), the antiretroviral regimen (e.g. convenience, palatability, formulation and toxicity), culture and society [bib_ref] Adherence to antiretroviral therapy for pediatric HIV infection: a qualitative systematic review..., Simoni [/bib_ref] [bib_ref] Pediatric adherence to HIV antiretroviral therapy, Haberer [/bib_ref]. Some of these factors are outside the control of the treating clinician, but should be acknowledged and addressed. Factors that can be influenced by the medical team include once-daily medication regimens, side effects, choice of formulation and route of administration (e.g. oral versus gastrostomy). A recent meta-analysis of RCTs in adults has highlighted that oncedaily regimens and lower pill burden are associated with better adherence, the latter also being associated with better virological suppression [bib_ref] Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: a..., Nachega [/bib_ref]. Despite the difficulties and a lack of easy solutions, the issue of adherence should always be addressed nonjudgementally, both before and after starting children on ART. It is acknowledged that adherence issues change with age and that adherence may be particularly difficult in adolescence [bib_ref] Adolescents with perinatally acquired HIV: emerging behavioral and health needs for long-term..., Koenig [/bib_ref]. Despite every effort to support adherence, some HIV-infected children and young people may have difficulty with taking medications, leading to detectable VL and associated risk of poor health status, development of drug resistance and risk of onward transmission in sexually active adolescents. In these individuals, careful consideration should be given to options such as a switch to a regimen with a higher barrier to resistance, or even treatment interruption alongside ongoing education regarding HIV transmission. Every effort should be made to simplify adherence to treatment for children and caregivers. Simple aids to adherence should be used where appropriate -including adherence apps, dossette boxes, pill diaries, text messages and phone alarms. The following adherence points should be considered before prescribing a child's antiretroviral regimen. - Is there a once-daily regimen? - What is the most forgiving regimen in terms of: - timing? (Can a dose be missed or late from time to time? Does administration need to be timed with food intake? What timing best suits the family's routine?) - pill count? (Is an FDC available?) - barrier to resistance? (Should a boosted PI backbone be used?) - Are the parents on treatment, and could the same regimen be used for the child? - What are the possible side effects of the regimen -might they reduce adherence (e.g. jaundice with ATV)? - Who is taking responsibility for adherence supportwithin the family and the medical team? - How is adherence going to be measured (VL, drug levels, pill counts etc.)? Before a child or young person goes home from the clinic with their new medication, an adherence support plan should be in place, with contact numbers, a review schedule, peer support plan etc. Families should be encouraged to call the clinic team if there are problems, rather than struggle unsupported. Children's knowledge of their illness should be assessed and an age-appropriate process of gradual knowledgebuilding started. Increasingly, clinicians now address issues of disclosure at an earlier age than previously [bib_ref] Impact of disclosure of HIV infection on health-related quality of life among..., Butler [/bib_ref] , with awareness that early, general discussions focusing on healthy diet and lifestyle and knowledge about the blood and immune system can provide a useful foundation for later, specific discussions about HIV. It will generally be appropriate for most children to know their HIV status (i.e. for the disease to be named) before adolescence (i.e. from age 9-10 years), although the timing of naming HIV will vary according to the young person's pre-existing knowledge, maturity and developmental age, and the process can be initiated earlier if deemed appropriate by the family and the multidisciplinary team (reviewed in [bib_ref] Disclosing HIV status to HIV positive children before adolescence, Saunders [/bib_ref]. This process may be delayed in children with significant cognitive/ learning difficulties. Once disclosure is complete, adolescents should understand the risks of onward sexual transmission, and safe sex and contraception should be regularly addressed. Giving young people an opportunity to speak with clinic staff on their own is an important part of this process. Appropriate services for adolescents with perinatally acquired HIV infection and the management of transition of their care to adult services are discussed in Section 13. ## Monitoring on art - The aim of ART is to achieve an undetectable VL (< 50 copies/ml plasma) and CD4 reconstitution. - Laboratory monitoring for drug toxicity should be performed initially within 2-4 weeks of starting a new drug, then at least every 6-8 months if there are no ongoing toxicity concerns. - After starting ART, VL should be checked early (at around 1 month) to confirm that VL is decreasing (this can coincide with toxicity monitoring). - VL and CD4 count can then be monitored 3−4-monthly once the patient has been established on treatment. - Once CD4 cells are reconstituted and VL has been < 50 copies/ml consistently for over 1 year, CD4 parameters can be monitored less frequently (every 6-8 months, i.e. at alternate clinic visits). - More frequent clinical and laboratory monitoring is required: - in infancy; - if adherence is poor; - soon after starting or changing therapy (e.g. Liver function tests should be performed within 2 weeks); - in the context of ongoing drug toxicity; - when giving medications with significant drug interactions with ART, such as antituberculous therapy. Clinical and laboratory monitoring requirements for children on ART are similar to those of ART-naïve children (see Section 3). In addition to the routine clinical, growth, development, urinalysis, vaccination status/immunity and laboratory monitoring, it is important to check specifically for adherence to therapy, side effects and the need for dose modification with changing age and weight. Other current medications should be regularly reviewed, as there is potential for ART to interact with medication obtained from other sources (e.g. oral contraceptive, inhaled steroids and antacids). Other medical teams who may prescribe such medication (e.g. family doctors) should be informed of the potential for drug interactions when children are started on ART. Monitoring needs to be more frequent in infancy and shortly after initiating or changing therapy, but once children are established on treatment and stable, clinic visits can be 3-4-monthly. In order to minimize disruption to schooling, appointments can be made after school or to coincide with school holidays. Recent modifications to adult guidelines have recommended less frequent laboratory monitoring in those on long-term suppressive ART [bib_ref] British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral..., Williams [/bib_ref]. The results of the ARROW trial in children have also shown clinical monitoring to be a safe and effective alternative to laboratory monitoring, in resource-poor settings [bib_ref] Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or..., Ruel [/bib_ref]. This supports a recommendation that monitoring of CD4 count and laboratory tests for drug toxicity can safely be performed less frequently than every 3 months when a child is clinically well, has had VL < 50 copies/ml for over 1 year and is not severely immunosuppressed. TDM of NNRTIs and PIs is available in several qualitycontrolled laboratories in Europe. There are no studies to inform recommendations for routine use of TDM in children, but it may be particularly useful where there is: (1) suspicion of drug toxicity, poor adherence or drug interactions (e.g. TB treatment); (2) failure to suppress viraemia despite good reported adherence; (3) renal or hepatic dysfunction; (4) use of unlicensed dosing regimens [bib_ref] The role of therapeutic drug monitoring in pediatric HIV/AIDS, Burger [/bib_ref] [bib_ref] Can therapeutic drug monitoring improve pharmacotherapy of HIV infection in adolescents?, Rakhmanina [/bib_ref]. More evidence is required regarding the utility of TDM in monitoring use of drugs with highly variable PK (e.g. EFV). TDM may also be considered in infants and neonates, or with new drugs where PK data are less well established. TDM is generally not indicated for NRTIs as intracellular levels of the active metabolite are difficult to measure/ interpret and large blood volumes are required. One effect of starting ART may be immune reconstitution inflammatory syndrome (IRIS). This occurs within a few weeks or months after starting therapy, is often associated with an exaggerated immune response to an underlying opportunistic infection and is not specific to any drug. The diagnosis is clinical and requires the exclusion of active infection and drug toxicity. Symptoms can be severe and may need treatment with anti-inflammatory drugs (e.g. steroids) and additional therapy for underlying opportunistic infection. In the majority of cases ART should be continued. ## Drug toxicities and interactions - Toxicities depend on the individual drugs and ART combination and should be assessed at each clinic visit. - Drug interactions should be considered when starting new medications in a child on ART. Use http://www.hivdruginteractions.org/ to check drug interactions and toxicities. - See for common ART-associated toxicities. Drug toxicity has been a major limitation of ART to date, and one of the aims of modern ART regimens is to reduce side effects. Side effects can be acute, appearing early (usually within days to a few weeks after initiation), or late, declaring themselves after prolonged use of particular antiretrovirals. Acute toxicities can be caused by any antiretroviral and include nausea, diarrhoea, headache, rash [mild to severe dermatological manifestations, such as Stevens−Johnson syndrome (SJS)], liver dysfunction (from asymptomatic elevation of liver enzymes to drug-induced hepatitis) and allergic reactions . If severe events occur, ART should be discontinued with a subsequent replacement of drugs suspected to have caused the reaction (see Section 11 on switching). Some side effects, such as vomiting and diarrhoea, are transient and tend to resolve with time, but close monitoring and supportive/symptomatic treatment may be required. Early adherence may be affected by common side effects that cause significant disturbance to daily life -for example diarrhoea caused by LPV/r, dysphoria caused by EFV, and nausea or headache caused by ZDV. Patients and their carers should be counselled appropriately prior to the start of ART and necessary support and close liaison should be assured during the first few weeks. In the longer term, specific organ dysfunction, haematological complications and metabolic disturbances including mitochondrial toxicity, bone mineral loss, lipodystrophy, elevated cholesterol and triglycerides, and altered glucose homeostasis may occur. A recent cohort study of European children reported that nearly half had signs of fat redistribution and nearly a quarter had an abnormal lipid profile [bib_ref] Body fat abnormality in HIV-infected children and adolescents living in Europe: prevalence..., Alam [/bib_ref]. Risk factors included advanced HIV disease, and use of d4T, NNRTIs, PIs and triple-class ART. The relationship between lipodystrophy and ART is complex because of multiple exposures to different antiretrovirals and physiological changes in body composition during childhood and adolescence. Late side effects should be monitored for and addressed appropriately at every visit (see . A number of studies have documented increased rates of cardiovascular and cerebrovascular disease in HIV-infected adults, which appear to be multifactorial and relate both to HIV disease itself and ART, with the greater risk associated with PIs and ABC [bib_ref] Risk of cardiovascular disease from antiretroviral therapy for HIV: a systematic review, Bavinger [/bib_ref] [bib_ref] Relative risk of cardiovascular disease among people living with HIV: a systematic..., Islam [/bib_ref]. Several mechanisms have been postulated, including metabolic and lipid derangement (especially related to PI), insulin resistance, direct vascular injury and increased inflammation [bib_ref] Cardiovascular disease and HIV infection: host, virus, or drugs?, Martinez [/bib_ref]. Some studies in children have shown an increase in markers of cardiovascular risk such as immune activation markers, carotid Common side effects of antiretroviral therapy in children* ## Toxicities antiretrovirals Neuropsychiatric symptoms/insomnia/other CNS symptoms Efavirenz, raltegravir and atazanavir Neuropathy Didanosine, stavudine and zidovudine Myopathy Zidovudine Headache All antiretrovirals Nausea and vomiting All antiretrovirals, in particular zidovudine and protease inhibitors Diarrhoea Protease inhibitors (in particular lopinavir) and didanosine Pancreatitis Didanosine, stavudine and raltegravir Hepatitis/liver toxicity/liver dysfunction All antiretrovirals (in particular nevirapine and didanosine). Indinavir and atazanavir cause hyperbilirubinaemia Renal dysfunction Tenofovir and atazanavir Bone demineralization/osteopenia/osteoporosis Combination antiretroviral therapy, especially following initiation, regardless of regimen; in particular, protease inhibitors, tenofovir and stavudine Severe dermatological conditions (SJS/EM major/TEN) All antiretrovirals, in particular, nevirapine, efavirenz, etravirine, fosamprenavir, abacavir, darunavir, zidovudine, didanosine, boosted lopinavir and atazanavir Rash All antiretrovirals, in particular NNRTIs Skin hyperpigmentation Emtricitabine (more prominent in non-Caucasians) Systemic hypersensitivity reaction Abacavir, nevirapine and enfuvirtide Lipodystrophy All protease inhibitors and efavirenz (lipohypertrophy). Didanosine, stavudine and zidovudine (lipoatrophy) Dyslipidaemia All protease inhibitors, NRTIs, especially stavudine, and NNRTIs (efavirenz > nevirapine) Glucose intolerance NRTI thymidine analogues (stavudine, didanosine and zidovudine intima-media thickness (IMT) and carotid-radial pulsewave velocity [bib_ref] Increased arterial stiffness in HIV-infected children: risk factors and antiretroviral therapy, Charakida [/bib_ref] [bib_ref] Inflammation markers correlate with common carotid intima-media thickness in patients perinatally infected..., Biagio [/bib_ref]. Other adverse effects related to specific organ dysfunction, such as CNS disorders, renal abnormalities, hepatitis or bone loss, may also be attributable to either ART or HIV itself. The SMART trial in adults has been important in demonstrating that treatment with ART results in fewer such problems than withholding drugs. ## Common toxicities with antiretrovirals used in children ## Nnrtis The main toxicity of EFV is neuropsychological symptoms (e.g. bad dreams, mood swings, drowsiness, dizziness, impaired learning and depression) which anecdotally may be worse in older children (possibly secondary to a reporting bias). This should be borne in mind when considering which drug to use in children with established psychological/neurological disturbance. Other complications associated with EFV are dyslipidaemia, abnormal fat distribution [bib_ref] Body fat abnormality in HIV-infected children and adolescents living in Europe: prevalence..., Alam [/bib_ref] and gynaecomastia. NVP may be associated with skin rash, hepatitis and SJS, which typically occur within the first few months of exposure. Rash and hepatic dysfunction are less common when a 2-week half-dose lead-in dosage is used. NVP should not be used in children with liver dysfunction or co-administration of other hepatotoxic drugs. Prolongedrelease tablet formulations are available for children > 6 years old and produce a more even drug exposure, but are not suitable for the 14-day lead-in phase when starting NVP. Rash is much less common with EFV than with NVP; however, there are insufficient data to recommend switching from NVP to EFV in cases of dermatological hypersensitivity reactions, as repeat rash after substitution has been reported to occur in more than 12% of adult patients [bib_ref] Is it safe to switch between efavirenz and nevirapine in the event..., Mehta [/bib_ref]. ## Pis PIs are associated with dyslipidaemia and lipodystrophy [bib_ref] Body fat abnormality in HIV-infected children and adolescents living in Europe: prevalence..., Alam [/bib_ref] [bib_ref] Metabolic complications and treatment of perinatally HIV-infected children and adolescents, Barlow-Mosha [/bib_ref] [bib_ref] Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based..., Arpadi [/bib_ref] [bib_ref] PENTA 2015 paediatric HIV-1 treatment guidelines HIV-infected patients in relation to antiretroviral..., Rhoads [/bib_ref]. However, once-daily PIs, such as ATV/r and DRV/r, in adults tend to cause fewer lipid abnormalities [bib_ref] Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in..., Orkin [/bib_ref] [bib_ref] Outcomes of switch to atazanavir-containing combination antiretroviral therapy in HIV-1-infected patients with..., Lu [/bib_ref]. Measures to improve dyslipidemia can include lifestyle modifications (diet and exercise) and change of ART to 'lipid friendly' antiretrovirals (NVP, ATV/r, DRV/r and RAL). In rare cases when no effect is seen from ART substitution, lipid-lowering agents, such as statins, may be used. However, in view of their frequent side effects and drug interactions with antiretrovirals, this ideally should be done in consultation with experts in ART and lipid agents. The common side effect of ATV in children is hyperbilirubinaemia, which was reported in 45% of treated children in clinical studies. It is not associated with elevation of liver enzymes, and often improves with time. In cases when hyperbilirubinaemia is significant and jaundice is noticeable by the patient's peers, consideration should be given to substitution of the drug with an alternative agent. ## Nrtis A rare but clinically important early side effect is ABC hypersensitivity associated with the presence of HLA B5701.This may be fatal if the drug is reintroduced after a reaction. Possible cardiovascular toxicity of ABC in adults remains controversial. A meta-analysis of RCTs did not find an increased cardiovascular risk [bib_ref] Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished..., Cruciani [/bib_ref] and the biological mechanism of possible cardiovascular toxicity of ABC has not been established. To date, no link to cardiovascular toxicity has been found in ABC-exposed children. TDF is associated with bone and renal toxicity, precluding its use as a preferred NRTI in younger children. Studies of TDF-associated bone toxicity in treatment-experienced children yielded conflicting results [bib_ref] Bone health in children and adolescents with perinatal HIV infection, Puthanakit [/bib_ref]. A significant loss of bone mineral density (BMD) was observed in young and pre-pubertal children, and in those who received higher exposures to TDF because of higher doses or concomitant use of PIs [bib_ref] Decreased bone mineral density with off-label use of tenofovir in children and..., Purdy [/bib_ref] [bib_ref] Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as..., Gafni [/bib_ref]. Reassuringly, in most children on TDF-containing ART, BMD z-scores after an initial decrease tend to stabilize [bib_ref] Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as..., Gafni [/bib_ref] [bib_ref] 48-week safety of tenofovir when administered according to weight-band dosing in HIV+..., Sirisanthana [/bib_ref]. Although the clinical significance of delayed bone mineralization has not been established, the concern is that suboptimal bone accrual in childhood and failure to achieve expected peak bone mass could result in increased fractures in adulthood. Paediatric data on TDF renal toxicity are also controversial, showing conflicting results from no renal dysfunction to increased rates of proteinuria and hypophosphataemia. Extrapolating from adult studies showing that renal dysfunction is associated with increased TDF plasma levels and PI use [bib_ref] Tenofovir nephrotoxicity: 2011 update, Fernandez-Fernandez [/bib_ref] , dosing accuracy and meticulous attention to monitoring for renal dysfunction in children, especially in those who are on concomitant PIs, are of particular importance. The use of NRTIs, in particular d4T, ddI and to a lesser extent ZDV, is associated with lipoatrophy, peripheral neuropathy, lactic acidosis and other toxicities linked to mitochondrial damage. Noncirrhotic portal hypertension has been reported as a rare complication of exposure to ddI in adults [bib_ref] Genetic determinants of idiopathic noncirrhotic portal hypertension in HIV-infected patients, Vispo [/bib_ref] [bib_ref] Non-cirrhotic portal hypertension in HIV-infected individuals, Scourfield [/bib_ref] [bib_ref] Association of noncirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with..., Kovari [/bib_ref] and children [bib_ref] Splenomegaly and variceal bleeding in a ten-year-old HIV-infected girl with noncirrhotic portal..., Giacomet [/bib_ref] [bib_ref] Antiretroviral therapy associated liver disease in 4 HIV-1 infected adolescent girls, Scherpbier [/bib_ref] , may be associated with a genetic predisposition [bib_ref] Genetic determinants of idiopathic noncirrhotic portal hypertension in HIV-infected patients, Vispo [/bib_ref] and can become evident after ddI has been discontinued. PENTA does not support the use of d4T or ddI in first-or second-line ART. However, in cases of multiple resistance, if no alternatives are available, ddI may be used to construct a fully active ART regimen. It should be noted that ddI should not be used together with TDF in view of increased toxicity. ZDV, still frequently used in paediatrics, affects bone marrow, causing macrocytic anaemia and neutropenia, and rarely thrombocytopenia or bone marrow suppression with pancytopenia. 3TC and FTC are generally well tolerated; however, they can cause allergic reactions and constitutional symptoms. ## Instis RAL and DTG have a very good safety profile in adults and are well tolerated, although data on long-term exposure are more limited. The most common adverse effects reported in adult patients are constitutional symptoms (fatigue, nausea, dizziness, insomnia and headache), rash, diarrhoea, abnormal liver function tests and raised creatinine kinase. Hypersensitivity reactions have been reported and were characterized by rash and, in some cases, hepatic failure. ## Fusion and entry inhibitors These two classes of drug are not recommended for firstline use and are discussed in more detail in Section 11. The CCR5 receptor antagonist maraviroc (MVC) is not licensed for patients under the age of 18 years. Paediatric studies on safety and efficacy in children are ongoing [bib_ref] Safety and efficacy of maraviroc in CCR5-tropic HIV-1-infected children aged 2 to..., Giaquinto [/bib_ref]. In adults, MVC is generally well tolerated but has been associated with hepatic toxicity, severe skin and hypersensitivity reactions and postural hypotension. The HIV fusion inhibitor enfuvirtide (T20) is almost universally associated with injection site reactions but is otherwise well tolerated apart from mild constitutional symptoms. For detailed side effects of individual medicines, useful resources include the Electronic Medicines Compendium (http://www.medicines.org.uk/emc/), DHHS website (http://aidsinfo.nih.gov/drugs) and EMA website (http:// www.ema.europa.eu/ema/). For all drugs, the effects of prolonged use for decades remain to be seen, and this will be of greater significance as more children start ART at an earlier age. ## Drug interactions It is widely known that drug−drug interactions are important in HIV treatment in adults; this is true for children as well, although the frequency and type of comorbidities and related co-medication may be different. ART can both be affected by drug interactions (i.e. the plasma concentrations of the ART may be changed) and/or be the cause of a drug interaction (i.e. the ART influences the plasma concentration of another drug). Increased toxicity or therapy failure may occur. Many of the drug interactions occur as the result of drug-induced modification of cytochrome P450 (CYP450) enzyme activity, although other systems, such as mem-brane transporters [e.g. P-glycoprotein (P-gp) or UDPglucuronyltransferase (UGT)], may be relevant too. ## Art as the cause of a drug interaction There are a few general rules to remember: PIs are generally inhibitors of CYP450 3A (CYP3A and other isoenzymes) or P-gp and can lead to increased levels of co-administered medication. This is, for instance, the case with inhaled corticosteroids, oral contraceptives, benzodiazepines, statins, antidepressants, etc. Both ritonavir and cobicistat are specifically used together with PIs or EVG for their ability to strongly inhibit liver enzymes and increase blood concentration of their co-administered antiretroviral. The NNRTIs NVP, EFV and etravirine (ETR) are enzyme inducers. They generally reduce the plasma levels of any agents metabolized via the CYP450 pathways with potentially suboptimal therapeutic response. ## Drug interactions affecting art The greatest risk for ART in terms of drug interaction is when antiretroviral drugs are combined with other enzyme inducers such as rifampicin, carbamazepine and phenytoin. Lower plasma concentrations of the ART can lead to the development of resistance and treatment failure. ## Management of drug interactions In the large majority of cases, drug interactions can be managed by selecting the appropriate co-medication or change in ART. TDM of the ART or co-medication might be helpful. We recommend referring to http://www.hiv -druginteractions.org to assess potential drug interactions with ART, and that a pharmacist is included in the multidisciplinary team. ## Coinfections ## Hbv and hcv - Untreated HIV infection increases the progression of liver disease in HBV or HCV coinfection. - HBV and HCV coinfections both increase the risk of hepatotoxicity with ART (especially NVP). - Drugs used to treat HBV may select for resistant HIV and vice versa. - Liver disease in children with HBV or HCV coinfection should be managed jointly with paediatric experts in viral hepatitis. - HCV coinfection is an indication for starting ART. - For HBV coinfection, if treatment of HIV is not indicated and there is no evidence of liver disease, HIV treatment should be considered but may be deferred. ## Screening for viral hepatitis Baseline screening All children with HIV infection should be screened for viral hepatitis when they first present. Screening should include the following: (a) Testing for coinfection, past infection or immunity to HBV. This should include the following markers: HBV surface antigen (HBsAg), HBV core antibody (HBcAb) and HBV surface antibody (HBsAb). Children diagnosed with HBV coinfection should be screened for hepatitis delta virus (HDV) with HDV immunoglobulin M (IgM) and IgG and HDV RNA PCR. (b) Testing for coinfection with HCV. This should include HCV antibody and HCV RNA PCR when available, as rates of 3-13% of HCV-seronegative infection have been reported in HIV-infected adult and paediatric cohorts [bib_ref] Progressive liver disease in patients with vertically acquired HIV/HCV co-infection in Spain, Abad [/bib_ref] [bib_ref] Factors associated with seronegative chronic hepatitis C virus infection in HIV infection, Chamie [/bib_ref] [bib_ref] Hepatitis C virus viremia in HIV-infected individuals with negative HCV antibody tests, George [/bib_ref]. HCV antigen might be used by some laboratories in screening algorithms. As data on the use of this marker in paediatric infection are lacking, HCV RNA is currently preferred. (c) Testing for immunity to hepatitis A virus (HAV) infection (HAV IgG). Vaccination for hepatitis A and B of seronegative children should be recommended if a child is found to be seronegative and levels of HBV antibody should be assessed regularly and booster vaccinations or repeated courses given as required [bib_ref] Guidance on vaccination of HIV-infected children in Europe, Menson [/bib_ref]. Annual screening for HCV is recommended in adolescence and adults in case risk factors exist such as use of recreational drugs and/or sexual exposure. Screening of infants exposed to HBV or HCV When the mother is coinfected with HBV, screening of the exposed infant should include HBsAg, HBsAb and HBcAb at around 14-15 months of age following the last (fourth) vaccination at 1 year of age. Infants born to women coinfected with HCV should be screened for evidence of HCV. In most centres this screening includes a combination of PCR for detection of HCV RNA in infancy as well as HCV antibody at 12-18 months when maternal antibody is expected to wane. HCV RNA-positive results in infancy do not equate to longterm infection, and follow-up is required as a small proportion of HCV-monoinfected children will undergo spontaneous clearance of infection within the first 3-5 years of life [bib_ref] Spontaneous clearance of hepatitis C virus in vertically infected children, Farmand [/bib_ref] [bib_ref] Long-term course of chronic hepatitis C in children: from viral clearance to..., Bortolotti [/bib_ref]. Published data are sparse on the rates of spontaneous HCV clearance in HIV coinfected children. ## Investigation of deranged liver function tests In the case of unexplained deranged liver function tests and/or liver disease, viral hepatitis should be considered, including HAV, HBV, HCV, CMV and Epstein−Barr virus (EBV) infection. Screening should ideally include: HAV IgM and IgG, HBsAg, HBcAb, HBV DNA, HCV RNA, HEV IgM and IgG, HEV RNA, CMV IgM and IgG, and EBV serology. Alternative diagnoses for persistent transaminitis, such as nonalcoholic fatty liver disease, autoimmune hepatitis, Wilson's disease, alpha-1 antitrypsin deficiency, coeliac disease and muscular dystrophy, should be considered. HBV or HCV coinfection is a risk factor for hepatocellular carcinoma (HCC). HCC is rare in childhood and more data are required to evaluate the best approach to monitoring for this complication. Adult guidelines recommend monitoring for HCC with 6-12-monthly serum alphafetoprotein and liver ultrasound in all HBV-coinfected patients and in HCV-coinfected patients with cirrhosis . In the absence of better monitoring methods, this guidance is endorsed for children and adolescents. ## Hbv coinfection In adults, there is a well-documented interaction between HIV and HBV infection, with increased rates of liver disease. Long-term follow-up data for coinfected children are sparse but, in view of the concern about an increased risk of liver disease progression in adult life, ART should be considered in coinfected children regardless of clinical stage or CD4 cell count. 3TC, FTC and TDF have activity against HIV and HBV. They therefore should only be administered as part of fully active ART in order not to select for HIV resistance. In addition, treatment with 3TC or FTC without TDF may quickly select HBV resistance to these drugs and also reduce sensitivity to entecavir, thus compromising future HBV treatment options [bib_ref] Antiviral resistance and hepatitis B therapy, Ghany [/bib_ref]. Combinations of TDF with FTC or 3TC have been shown to increase HBV viral clearance in HBV-coinfected adults . We recommend that two active drugs against HBV (TDF/3TC or TDF/FTC) should be given, unless this is not possible because of prior treatment that has selected for resistant HBV strains. In children > 2 years of age, we recommend starting TDF/3TC or TDF/FTC. In children with HBV infection under 2 years of age, for whom TDF is not yet licensed, if treatment for HBV infection is not required (see treatment algorithm for paediatric patients with chronic hepatitis B infection [bib_ref] Management of chronic hepatitis B in childhood: ESPGHAN clinical practice guidelines: consensus..., Sokal [/bib_ref] , there are two options: either starting (1) 3TC/FTC-sparing ART (unless HLA B5701 positive this would be ABC/ZDV) in order to avoid 3TC/FTC monotherapy and selection for HBV resistance or (2) TDF-containing ART (off-licence TDF in this age group) with careful monitoring of TDF bone and renal toxicity. Children with evidence of past HBV infection (HBsAg negative and HBcAb positive) are at risk of reactivation and ideally ART should include an agent active against HBV. The clinical implications of the rare phenomenon of occult hepatitis B (HBsAg negative, with low replication in the liver and plasma; usually HBV DNA well below 1000 IU/ml) are not clear. These patients should also be treated with ART that contains an agent active against HBV. Some anti-HBV drugs (such as entecavir and telbivudine) have partial activity against HIV, which is insufficient to fully suppress HIV but is sufficient to select for resistance mutations. These drugs should not be used to treat HBV infection in HIV-coinfected patients without an accompanying fully suppressive ART regimen. In an HBV-coinfected child on ART who develops TDF toxicity or intolerance, the options are very limited. Extrapolating from adult guidelines [139], entecavir as an add-on drug to fully suppressive ART can be used in older children with TDF intolerance. Children with HBV coinfection who discontinue anti-HBV antivirals are at risk of HBV reactivation and need to be monitored closely with clinical reviews and liver function tests. Seek expert advice for the appropriate management of HBV-coinfected children. ## Hcv coinfection HCV coinfection also increases the risk of liver disease, but long-term follow-up data for coinfected children are sparse. No anti-HIV ART drugs are effective against HCV. In older children and adults, HCV coinfection is associated with more rapid HCV progression [bib_ref] HIV/HCV co-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies, Operskalski [/bib_ref] [bib_ref] Impact of human immunodeficiency virus coinfection on the progression of mother-to-child transmitted..., Claret-Teruel [/bib_ref] and may also have an adverse effect on HIV progression [bib_ref] HIV/HCV co-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies, Operskalski [/bib_ref] , and therefore early HIV treatment is recommended. Currently in children only combination treatment with pegylated interferon (PEG-IFN) and ribavirin can be used to treat HCV infection. New direct-acting antiviral agents (DAAs) against HCV have been approved for treatment of liver disease in adults, and phase III trials of many other compounds are under way. It is anticipated that PEG-IFNfree regimens will be available for adults and children in the near future, particularly for genotype 1 and 4 infection. In children with HCV coinfection, debate is ongoing as to whether clinicians should treat HCV infection immediately or wait for better treatment options. Some experts prefer starting treatment earlier as there is better treatment response and tolerability of PEG-IFN and ribavirin in children compared with adults [bib_ref] Chronic hepatitis C virus infection in children, Mohan [/bib_ref] [bib_ref] NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants,..., Mack [/bib_ref]. This may be especially relevant for patients with HCV genotypes 2 and 3, for whom sustained virological response with PEG-IFN and ribavirin over 24 weeks is much better than for genotype 1 (sustained virological response in HCV-monoinfected children 89-93% [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children..., Sokal [/bib_ref]. However, PEG-IFN has an adverse effect on growth in children, and the risk−benefit ratio should be carefully considered during growth spurts [bib_ref] Current treatment options and response rates in children with chronic hepatitis C, Wirth [/bib_ref]. Some specific interactions to consider include: - ribavirin enhances intracellular phosphorylation of ddI; fatal lactic acidosis has been described, and therefore ddI should be avoided; - ribavirin and ZDV both may cause anaemia; - ABC may reduce ribavirin efficacy; - d4T may cause mitochondrial (liver) toxicity; - ATV may increase hyperbilirubinaemia, but there is no clear evidence that this is worse in HCV-coinfected children. Seek expert advice for the appropriate management of HCV-coinfected patients. ## Tb coinfection - All HIV-infected children exposed to an individual with infectious TB and all children with evidence of latent TB infection should have preventive TB treatment (once active TB disease has been excluded). - In children with active TB disease, TB treatment should be started at TB diagnosis. ART should be started as soon as practicable, and within 2 and 8 weeks of TB treatment in children with severe and moderate immunosuppression, respectively. ART may be deferred at higher CD4 counts until TB treatment is completed. - There is significant interaction between ART and TB therapy. TDM, where available, should be used in the context of potential significant interactions. - Children with TB coinfection should be managed in consultation with an expert in the treatment of paediatric TB. A specialist in DRTB should be involved in the management of DRTB contacts and cases. - See [fig_ref] Table 6: Antiretroviral therapy [/fig_ref] for ART choices in children with TB. HIV-infected children are at increased risk of acquiring TB infection and progression from latent to active TB compared with HIV-negative children [bib_ref] High incidence of tuberculosis among HIV-infected infants: evidence from a South African..., Hesseling [/bib_ref] [bib_ref] Diagnostic and management challenges for childhood tuberculosis in the era of HIV, Marais [/bib_ref]. In the combination ART era, in both high and low TB prevalence countries, TB incidence is decreasing, but remains substantially higher in HIV-positive children [bib_ref] Reduction in mycobacterial disease among HIV-infected children in the highly active antiretroviral..., Jensen [/bib_ref] [bib_ref] Incident tuberculosis and risk factors among HIV-infected children in Tanzania, Li [/bib_ref] [bib_ref] Anti-retroviral therapy reduces incident tuberculosis in HIV-infected children, Edmonds [/bib_ref] [bib_ref] HAART and risk of tuberculosis in HIV-infected South African children: a multi-site..., Martinson [/bib_ref]. ## Management of children with tb exposure and latent tb infection All HIV-infected children should be screened for TB infection at HIV diagnosis with clinical examination, TST or IGRA and chest X-ray (see Section 3). Preventive TB treatment has been shown to effectively reduce the incidence of TB disease in HIV-positive children exposed to an infectious TB source case [bib_ref] Isoniazid preventive therapy in HIV-infected and -uninfected children (0-14 years), Schaaf [/bib_ref]. We recommend that all HIV-infected children exposed to an individual with infectious TB and all those with evidence of latent TB infection (positive TST or IGRA) and no clinical or radiological signs suggestive of TB disease should have preventive TB treatment. A Cochrane review of preventive regimens in HIVinfected individuals aged over 13 years found no difference in incidence of TB disease between a 6-month regimen with isoniazid monotherapy and 3 months of treatment with co-administered isoniazid and rifampicin. However, the combination regimen was associated with more discontinuations because of adverse effects. A few paediatric studies have shown that a 3-month regimen of isoniazid and rifampicin treatment is safe and effective [bib_ref] The effectiveness of a 9-month regimen of isoniazid alone versus 3-and 4-month..., Spyridis [/bib_ref] [bib_ref] Effectiveness of 3 months of rifampicin and isoniazid chemoprophylaxis for the treatment..., Bright-Thomas [/bib_ref]. Therefore, we recommend that children with HIV infection who have been exposed to TB or have latent TB infection and who are not receiving ART can be treated with either 3 months of isoniazid and rifampicin or 6−9 months of isoniazid (according to local policy in HIVuninfected children); for those on ART, in view of drug interactions, the preferred preventive treatment is 6-9 months of isoniazid. For children exposed to drug-resistant TB, preventive therapy should be decided on an individual basis in consultation with a TB expert. Preventive treatment should only be administered once active TB has been excluded. Children with nonspecific chest X-ray changes, and no improvement after the course of treatment for their suspected underlying respiratory illness (lymphocytic interstitial pneumonia, chest infection), should be treated for possible TB disease (see below). ## Tb disease in hiv-infected children There are particular difficulties relating to TB diagnosis, drug interactions and immune reconstitution disease in HIV-infected children coinfected with TB. Negative results of a TST or IGRA cannot be used to rule out TB disease [bib_ref] Interferon-gamma release assays for the diagnosis of active tuberculosis: a systematic review..., Sester [/bib_ref] [bib_ref] Interferon-gamma release assays for the diagnosis of Mycobacterium tuberculosis infection in children:..., Chiappini [/bib_ref]. Every effort should be made to make a confirmatory microbiological diagnosis but this is often not possible. New technologies such as Genexpert (Cepheid, California, USA) can expedite diagnosis while providing early information on rifampicin sensitivity [bib_ref] Evaluation of GeneXpert MTB/RIF for the detection of Mycobacterium tuberculosis and resistance..., Bunsow [/bib_ref]. Anti-TB treatment should always be started at TB diagnosis. All HIV-infected children diagnosed with TB should also be started on ART; however, the optimal timing of ART initiation depends on the degree of immunocompromise. Adult RCTs showed significant reduction in mortality and progression to AIDS with earlier ART in patients with CD4 counts < 50 cells/μl (Starting ART at 3 Points in TB (SAPIT) [bib_ref] Integration of antiretroviral therapy with tuberculosis treatment, Karim [/bib_ref] , Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA) [bib_ref] Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis, Blanc [/bib_ref] and Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis (STRIDE) [bib_ref] Timing of antiretroviral therapy for HIV-1 infection and tuberculosis, Havlir [/bib_ref]. A retrospective study in South African children, most of whom were severely immunocompromised with median CD4 percentage < 12%, also showed that delay of ART for longer than 2 months was associated with increased mortality and worse virological response [bib_ref] Effect on mortality and virological response of delaying antiretroviral therapy initiation in..., Yotebieng [/bib_ref]. Therefore, children with severe immunosuppression should start ART within 2 weeks of beginning TB treatment, and those with moderate immunosuppression within 8 weeks. Data in adults suggest that delayed ART in patients with no or mild immunocompromise is not associated with worse outcomes. The potential benefits of delayed ART in this group are decreased pill burden and drug interactions, which may lead to better drug tolerance and adherence, as well as reduced occurrence of IRIS. There are insufficient data in children with no or mild immunocompromise but, based on the results of adult studies, delaying ART until TB treatment is well tolerated (or even completed) can be considered. The optimal time for ART initiation in the context of TB meningitis remains to be determined. In the absence of TB drug resistance, standard TB treatment with isoniazid, rifampicin, pyrazinamide and ethambutol is recommended. Rifampicin, a potent CYP3A4 inducer, has significant interactions with other medicines metabolized through CYP450 enzymes, reducing their blood levels. Considerable interaction occurs when rifampicin is co-administered with NVP or PIs, whereas interaction with EFV is less significant and achieving therapeutic levels is possible without dose alteration. If available, rifabutin may be used instead of rifampicin to reduce drug interactions. In settings where TDM is available, dose adjusting of antiretrovirals and rifampicin/ rifabutin is recommended. The choice of ART in children co-treated for TB depends on the child's age, whether the child is receiving ART or starting ART, history of previous ART exposure and availability of TDM [fig_ref] Table 6: Antiretroviral therapy [/fig_ref]. In ART-naïve children less than 3 years of age on TB therapy, it is recommended to start with LPV/r-based ART with added ritonavir to achieve an LPV/ritonavir ratio of 1:1 (superboosting) [bib_ref] Antiretroviral therapy outcomes in HIV-infected children after adjusting protease PENTA 2015 paediatric..., Frohoff [/bib_ref] [bib_ref] Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis, Ren [/bib_ref]. Alternatively, ART-naïve children under 3 years of age can be started on NVP-based ART but without lead-in dose and at the maximum recommended dose (200 mg/m 2 twice daily). A PK study in children aged < 3 years co-treated for TB with rifampicin showed suboptimal exposure to NVP on a 300-400 mg/m 2 daily dose [bib_ref] Pharmacokinetics of nevirapine in HIV-infected children under 3 years on rifampicin-based antituberculosis..., Oudijk [/bib_ref]. In order to obtain better exposure in younger children, the maintenance dose can be further increased by 20-30% 2 weeks after starting treatment (H. Lyall and S. Welch, unpublished data). The doses of both rifampicin and NVP can be further adjusted with the results of TDM. NVP should be decreased back to a regular 300-400 mg/m 2 daily dose 1-2 weeks after stopping rifampicin. In settings where TDM is not available, superboosted LPV/ r-based ART is a preferable option in children under 3 years of age initiating ART. Recently, EFV sprinkles were approved by the FDA for children aged 3 months to 3 years [bib_ref] Population pharmacokinetics of efavirenz in pediatric patients to inform dosing in children..., Bertz [/bib_ref]. Further PK, efficacy and safety studies in children < 3 years old receiving anti-TB treatment are under way. Until the results are available, the use of EFV sprinkles in younger children receiving treatment for TB cannot be widely recommended. In children aged below 3 years who are already on ART, the options for adjusting doses of antiretrovirals discussed above are applicable. A recent RCT [bib_ref] Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or..., Ruel [/bib_ref] showed that a triple-NRTI maintenance regimen (ABC + 3TC + ZDV) is immunologically and clinically similar to NNRTI-based ART and can be valuable in children with controlled HIV infection who develop TB, and is an alternative regimen. For children aged over 3 years initiating ART, the preferred regimen is EFV-based ART. Children aged > 3 years who have been receiving NVP should be switched to EFV. If EFV cannot be used (because of NNRTI resistance, neurocognitive problems or suboptimal predicted adherence), an alternative option is superboosted LPV/r as above or other PI-based ART. For PI-based ART, TDM should be used where available. Children aged over 3 years who have been receiving PI-based ART can continue on their regimen with adjustment of PI doses as above, or they can be switched to EFV. A triple-NRTI regimen is another alternative option. RAL has been shown to be an effective option in the treatment of HIV/TB-coinfected adults [bib_ref] Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS..., Grinsztejn [/bib_ref]. There are no data available for coinfected children. RAL cannot therefore be routinely recommended as a treatment option at present; however, its use can be considered with specialist advice and TDM. Data on the use of DTG in this context are awaited. The duration of TB treatment depends on the response to TB, which in turn depends on the degree of immunocompromise and the extent of TB disease. There are no comparative studies suggesting that the duration of TB treatment should be prolonged in HIV-infected children. In uncomplicated TB, the duration of treatment should be the same as in non-HIV-infected children; however, if at the end of the treatment there is an incomplete response, then TB treatment may be extended. Adherence, drug levels, drug resistance and IRIS should be adequately addressed. Drug-resistant TB should be managed in conjunction with an expert. It should be treated with a TB regimen chosen according to bacterial drug resistance and national TB guidelines. Care needs to be taken to anticipate potential drug interactions and cumulative toxicities between ART and the TB regimen; the choice of ART may be simpler in TB regimens that do not contain rifampicin. TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) is not uncommon in children starting ART [bib_ref] Incidence, spectrum and outcome of immune reconstitution syndrome in HIV-infected children following..., Gkentzi [/bib_ref] [bib_ref] Immune Reconstitution Syndrome in HIV-1 infected children -a study from India, Shah [/bib_ref] [bib_ref] Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children..., Walters [/bib_ref] [bib_ref] Tuberculosis during early antiretroviral-induced immune reconstitution in HIV-infected children, Zampoli [/bib_ref] [bib_ref] Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected..., Puthanakit [/bib_ref]. TB-IRIS usually develops within 3 months of starting ART, with higher risk in those patients with advanced HIV disease, low pre-ART CD4 count and shorter interval to starting ART after initiation of TB treatment [bib_ref] Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected..., Puthanakit [/bib_ref] [bib_ref] Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome after early initiation of antiretroviral therapy..., Laureillard [/bib_ref] [bib_ref] Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings, Meintjes [/bib_ref]. ART should be continued, but steroids may be necessary to manage IRIS. Further details on management of TB in HIV-infected children can be found in the WHO and The International Union Against Tuberculosis and Lung Disease (IUATLD) guidelines. ## Opportunistic infections The management of children presenting with opportunistic infections can be complex, especially when a child presents very unwell. These patients should ideally be managed on a case-by-case basis. Generally it is recommended that ART should be initiated as early as possible, apart from in the context of cryptococcal meningitis, where a single RCT in adults has shown that delaying ART may be associated with reduced mortality [bib_ref] Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and..., Makadzange [/bib_ref]. ## When to switch, resistance testing and second and subsequent art regimens ART regimens may be changed because of treatment failure or toxicity, or during successful treatment for simplification. ## Virological failure -second and subsequent regimens - Switching to second-line therapy following virological failure should occur early (VL > 1000 copies/ml) for those failing on combinations including drugs with a low genetic barrier to resistance (NNRTIs or RAL). - Where there are blips in VL (detectable VL < 400 copies/ ml), blood tests should be repeated within 4 weeks to confirm re-suppression. - Reinforcement of adherence support, as the main reason for treatment failure, should be prioritized. Switching treatment when there are ongoing problems with adherence may lead to loss of efficacy of further classes of ART. - [fig_ref] Table 7: Switching to second-line antiretroviral therapy [/fig_ref] summarizes potential strategies for choosing second-line therapy. If the suggested options are not applicable, seek expert advice. Virological failure is almost always attributable to poor adherence. In adult practice, ART is switched early if there is detectable viraemia, because of the risk of accumulation of further resistance mutations, which may make subsequent regimens less effective. PENPACT-1 randomized ART-naïve children to two NRTIs with either an NNRTI or a boosted PI. Those experiencing virological failure were randomized to switch to second-line therapy at VL > 1000 copies/ml or > 30 000 copies/ml. Delayed switching (VL > 30 000 copies/ml) on NNRTI-based ART was not associated with poorer clinical outcome but was associated with increased rates of NRTI resistance. Rates of NNRTI resistance were similar irrespective of VL at the time of switching, with NNRTI resistance being acquired early in virological failure. Children failing therapy on boosted PIs showed very low rates of PI and NRTI resistance irrespective of the timing of the switch to second-line therapy. PENPACT-1 is the only paediatric RCT addressing the timing of the switch to second-line therapy [bib_ref] First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor..., Babiker [/bib_ref]. Accumulation of NRTI resistance with delayed switching following VL failure on NNRTI-based ART has also been reported in paediatric cohort studies; however, the impact of this resistance on clinical outcome has not been addressed [bib_ref] Early virologic failure and the development of antiretroviral drug resistance mutations in..., Ruel [/bib_ref]. Considering the length of time they are likely to require treatment, it is important that children have not used up all ART options before adulthood. Sequencing of newer classes of antiretroviral drugs should take into account the CCR5 receptor antagonists (e.g. MVC), which are only active against viral populations that use the CCR5 co-receptor for cell entry. The proportion of perinatally infected adolescents with R5 variants, for whom MVC is a potential option, is highly variable within cross-sectional studies [bib_ref] High prevalence of X4/DM-tropic variants in children and adolescents infected with HIV-1..., Briz [/bib_ref] [bib_ref] CCR5 antagonists: a therapeutic option in HIV-1 perinatally infected children experiencing virologic..., Frange [/bib_ref]. Co-receptor tropism should be performed within 3 months of the proposed treatment switch that includes MVC for those with detectable viraemia. Paediatric studies of MVC are ongoing in treatment-experienced children aged 2-18 years (http://clinicaltrials.gov/show/ NCT00791700). Of note, as in adults, single VL blips (single VL values > 50 but < 400 copies/ml that subsequently return to < 50 copies/ml) do not predict subsequent virological failure, but these should always be followed up as soon as Seek expert advice if the patient is aged < 3 years and failing LPV/r with mutations and for any child < 2 years old failing first-line therapy with NRTI mutations. 3TC, lamivudine; ABC, abacavir; ATV/r, ritonavir-boosted atazanavir; DRV/r, ritonavir-boosted darunavir; INSTI, integrase inhibitor; LPV/r, ritonavir-boosted lopinavir; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; NVP, nevirapine; TDF, tenofovir; ZDV, zidovudine. DRV/r is not licensed for < 3 years of age. † TDF is not licensed for < 2 years of age. possible, to make sure that they are not the beginning of significant viral rebound [bib_ref] Transient viral load increases in HIV-infected children in the U.K. and Ireland:..., Lee [/bib_ref]. In children, switching therapy after virological failure should only be considered when adherence has been reviewed. Failure of an NNRTI-based regimen is often a result of viral drug resistance following poor adherence, and switching to a boosted PI is appropriate. In resourcerich settings, those failing NNRTI-based regimens should not continue on NNRTI-based ART, to avoid the accumulation of further NRTI and NNRTI mutations which will impact on future ART options. Two strategies are available; either a direct switch to PI-based therapy or a short period off ART, if clinical status and CD4 count permit, while adherence is further addressed, followed by PI-based ART. Failure of a boosted PI-based regimen is more likely to be caused by poor adherence than resistance. Children failing PI-based regimens, without documented resistance mutations, may continue their current regimen while adherence is addressed. Simplified regimens using FDCs and once-daily PIs should be considered. A switch to NNRTI-based second-line therapy is likely to result in rapid development of resistance to the new drugs and is not recommended if adherence has not been addressed. If resistance is detected then switching to an alternative PI without overlapping resistance is the preferred option, with the addition of an agent from a newer class (INSTI or CCR5 receptor antagonist) dependent on the resistance profile but aiming for three active agents. 3TC and ABC may be switched to ZDV and TDF, the latter now licensed for patients from 2 years of age. For infants with first-line failure, ddI may be substituted for TDF; however, recent case reports of noncirrhotic portal hypertension in HIV-infected adolescents following prolonged exposure to ddI are of concern [bib_ref] Genetic determinants of idiopathic noncirrhotic portal hypertension in HIV-infected patients, Vispo [/bib_ref] [bib_ref] Non-cirrhotic portal hypertension in HIV-infected individuals, Scourfield [/bib_ref] [bib_ref] Association of noncirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with..., Kovari [/bib_ref] [bib_ref] Splenomegaly and variceal bleeding in a ten-year-old HIV-infected girl with noncirrhotic portal..., Giacomet [/bib_ref] [bib_ref] Antiretroviral therapy associated liver disease in 4 HIV-1 infected adolescent girls, Scherpbier [/bib_ref]. Therefore, ddI exposure should be kept to a minimum with substitution of an alternative agent at the earliest opportunity. Third and subsequent regimens are more complicated and need to take into account all previous drug histories and cumulative resistance mutations as well as the current regimen. This will always require expert virologist input. While virological failure with triple class exposure was reported in 12% of children in Europe [bib_ref] Risk of triple-class virological failure in children with HIV: a retrospective cohort..., Castro [/bib_ref] , rates of triple class resistance are variable, ranging from 12 to 32% and increasing with age [bib_ref] High drug resistance prevalence among vertically HIV-infected patients transferred from pediatric care..., De Mulder [/bib_ref]. Construction of effective third-line and subsequent regimens, ideally with at least two and preferably three fully active agents, requires expert advice. Paediatric experience of combinations that include INSTIs [bib_ref] Potent and sustained antiviral response of raltegravir-based highly active antiretroviral therapy in..., Briz [/bib_ref] , T20 [bib_ref] Short communication: evaluation of the effect of enfuvirtide in 11 HIV-1 vertically..., Palladino [/bib_ref] , ETR [bib_ref] Etravirine in treatment-experienced, HIV-1-infected children and adolescents: 48-week safety, efficacy and resistance..., Cahn [/bib_ref] [bib_ref] Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients, Briz [/bib_ref] , MVC [bib_ref] Safety and efficacy of maraviroc in CCR5-tropic HIV-1-infected children aged 2 to..., Giaquinto [/bib_ref] and DRV/r is accumulating. For patients where a suppressive regimen cannot be constructed with currently available ART, newer agents should be obtained (and may be used off-label with expert advice) through named patient and expanded access programmes and clinical trials. Single agents should not be added to nonsuppressive regimens because of the risk of accumulating further mutations impacting on future treatment options. In this situation, nonsuppressive ART, including 3TC or FTC, may be continued to prevent further immunological decline. As discussed above (Section 6), RAL and DTG have recently been licensed for paediatric use. ETR, a secondgeneration, twice-daily NNRTI, is licensed for treatmentexperienced children aged > 6 years. It is not fully crossresistant with NVP and EFV, but once more than two NNRTI mutations are present its efficacy significantly decreases [bib_ref] Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with..., Ruxrungtham [/bib_ref]. RPV, a once-daily NNRTI, is licensed for patients > 18 years old. It is available as once-daily FDC with TDF and FTC (Eviplera). Although it has fewer CNS side effects than EFV, a smaller pill size, and the possibility of co-administration with oral contraceptives, the significant disadvantages of increased virological failure rates in patients with VL > 100 000 copies/ml and CD4 count < 200 cells/μL, higher overall rates of resistance mutations compared with EFVcontaining regimens (phase 3 TMC278-C209 and TMC278-C215 trials; FDA pooled analysis, and administration with a meal requirement preclude its use as a first-line drug in most situations, but it can be considered in specific circumstances (e.g. patient preference or substitution for EFV intolerance). In young people with fully suppressed HIV and a regular meal pattern (absorption requires ingestion with a meal), Eviplera may be considered for simplification, for example where there is intolerance to EFVbased therapy. Ongoing studies in children will provide important information on the place of ETR and RPV in paediatric treatment strategies [IMPAACT P1090 (http:// clinicaltrials.gov/show/NCT01504841); IMPAACT P1111 (http://clinicaltrials.gov/show/NCT01975012)]. ## Simplification Where possible, regimens should be simplified (once-daily, fixed dose combinations), but switching to NNRTI-based regimens or PI monotherapy is not advised if there are adherence issues. Treatment simplification may involve reducing the number of drugs or tablets as a child becomes older, changing from twice-to once-daily therapy, or changing from a boosted PI-based regimen to an NNRTI-based regimen once viral suppression is achieved and adherence is assured. Simplification should not be carried out with detectable viraemia because of the risk of selecting for resistance mutations. Simplification is much easier as children reach 35−40 kg as adult co-formulations are available and oncedaily options include the following. Three-drug FDCs: EFV, TDF and FTC (Atripla); RPV, TDF and FTC (Eviplera); EVG, cobicistat, TDF and FTC (Stribild). Dual NRTI combinations: TDF and FTC (Truvada); ABC and 3TC (Kivexa). Children virologically suppressed on twice-daily boosted LPV-based ART may benefit from simplification to oncedaily boosted PIs (ATV/r or DRV/r) when they are able to swallow larger tablets, typically reducing daily pill burden from five to three pills for those over 40 kg. Switching to once-daily boosted PIs has been associated with improved lipid profiles in adult studies and now this has been demonstrated in a paediatric population [bib_ref] Improved serum cholesterol in paediatric patients switched from suppressive lopinavir-based therapy to..., Xiang [/bib_ref]. Children suppressed on ART may also switch to reduce the likelihood of ART toxicity. The Nevirapine Resistance Study (NEVEREST), a randomized trial of switching NVP-exposed infants from suppressive LPV/r-to NVP-based ART (after at least 3 months of VL < 400 copies/ml), showed that this strategy can be successful in infants without evidence of transmitted NVP resistance on conventional testing [bib_ref] Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression:..., Coovadia [/bib_ref] [bib_ref] Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression..., Kuhn [/bib_ref]. Children switched to NVP had less long-term dyslipidaemia and subcutaneous fat loss [bib_ref] Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based..., Arpadi [/bib_ref]. Furthermore, the recently reported results of the NEVEREST-3 study [bib_ref] Virologic efficacy of efavirenz maintenance therapy in nevirapine prophylaxis-exposed children, Coovadia [/bib_ref] indicate that switching children fully suppressed on LPV/r to EFV-based ART is a safe and effective strategy in the context of prophylactic NVP exposure. High rates of virological failure (without development of resistance limiting future treatment options) were reported in the Protease Inhibitor Versus Ongoing Triple-therapy (PIVOT) trial of PI monotherapy in adults [bib_ref] Randomised controlled trial of a PI monotherapy switch strategy for long-term HIV..., Paton [/bib_ref]. Reducing the number of drugs below a standard three-drug regimen is not currently recommended in children outside clinical trials. The lack of CNS penetration of such regimens is of potential concern for children with HIV encephalopathy [bib_ref] Short communication: evaluation of the effect of enfuvirtide in 11 HIV-1 vertically..., Palladino [/bib_ref] [bib_ref] Simplified human immunodeficiency virus maintenance therapy in virologically suppressed children with Ritonavir-boosted..., Neth [/bib_ref] [bib_ref] Monoboosted lopinavir/ritonavir as simplified second-line maintenance therapy in virologically suppressed children, Bunupuradah [/bib_ref]. ## Stopping treatment and treatment interruptions - Treatment interruptions cannot be routinely recommended and starting ART currently means lifelong therapy. - Judicious use of planned treatment interruptions may be considered in circumstances when ART needs to be stopped such as because of toxicity or adherence difficulties, while the latter is being addressed. - Stopping NNRTIs when HIV is fully suppressed requires a replacement or staggered stop to reduce the risk of developing NNRTI resistance as a result of the longer half-life of NNRTIs. A replacement stop is preferable. It is now clear that immune activation is a key component of HIV immunopathogenesis, and is characterized by polyclonal B-and T-cell activation, increased T-cell turnover, high levels of apoptosis and raised proinflammatory cytokines and chemokines. Immune activation drives CD4 decline, immunosenescence and immune exhaustion. The aetiology of HIV-related immune activation is multifactorial but includes immune responses to HIV and other reactivated chronic viral infections, direct T-cell activation by HIV components, depletion of CD4 regulatory T cells and translocation of microbial products across the gut mucosa [bib_ref] Microbial translocation, immune activation, and HIV disease, Klatt [/bib_ref]. Many studies have shown that levels of immune activation are reduced but not normalized by ART, and it is the ongoing inflammation that may underlie the noninfectious complications of HIV infection such as heart and brain disease. Indeed, the SMART trial, a large randomized CD4 cell count-driven treatment interruption study in adults, was stopped early because of higher rates of non-AIDSrelated complications and deaths (cardiovascular, liver and renal) in the treatment interruption arm as a result of presumed increased levels of immune activation off ART. Largely because of the SMART trial results, treatment interruptions are no longer recommended in adult patients. In view of these studies in adults, studying treatment interruptions in children has been difficult. However, earlier ART initiation in children and commencement of ART in all those diagnosed during infancy increase the importance of addressing the question of whether children can undergo periods off ART safely. There are many reasons why children may have superior responses to intermittent therapy than adults. These include the much lower short-term risk of cardiovascular complications in children, and the benefit of a more active thymus, which facilitates improved capacity for immune reconstitution. In a paediatric feasibility trial, PENTA 11, assessing clinical, immunological and virological data for planned treatment interruption (PTI) in older children with a median age at entry of 9 years, there were no deaths or serious clinical events in the treatment interruption arm. By 2 years after the end of the trial, when the majority of children were back on ART, there was no difference in immunological recovery or viral suppression in the treatment interruption and continuous arms [bib_ref] Outcomes after reinitiating antiretroviral therapy in children randomized to planned treatment interruptions, Bunupuradah [/bib_ref]. Independent predictors of attaining a higher CD4 percentage after re-start of ART were higher baseline CD4 percentage prior to PTI and higher CD4 percentage prior to re-start of ART. Although the PENTA 11 trial showed some evidence of immune reactivation during PTI [bib_ref] The immunological and virological consequences of planned treatment interruptions in children with..., Klein [/bib_ref] , this did not translate into clinical events. Reassuringly, there was no difference in height or weight gain and no difference in developmental test scores between the two arms. In addition, most carers and children reported better quality of life during PTI, and the clinicians were more likely to re-start ART after PTI with simpler regimens and FDCs [bib_ref] Outcomes after reinitiating antiretroviral therapy in children randomized to planned treatment interruptions, Bunupuradah [/bib_ref]. Can treatment be interrupted after starting early ART in infants? The CHER trial in South Africa showed that it is safe to stop ART at 1 or 2 years of age where clinical, virological and immunological parameters do not meet criteria for ART. However, most of the children who stopped ART at 1 or 2 years of age needed to re-start in a median time of 33 weeks or 70 weeks, respectively [bib_ref] Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected..., Cotton [/bib_ref]. Nevertheless, nearly a third of children who stopped ART at 2 years of age were still off ART at the end of the 6-year trial. Unfortunately, the study had no comparator continuous treatment arm to ascertain whether it is more advantageous to stay on continuous ART beyond 2 years of age. A small randomized trial in young Kenyan children, with a median age of 30 months, comparing continuous versus interrupted treatment after 2 years of ART, was stopped early because a high proportion required to re-start ART: 66% by 3 months post interruption and 86% by 18 months. So, at present, ART interruption cannot be routinely recommended even after ART has been started in infancy. Despite the recommendation for continuous therapy, unplanned treatment interruptions in children as a result of adherence difficulties or side effects of ART are common [bib_ref] CD4+ lymphocyte-based immunologic outcomes of perinatally HIV-infected children during antiretroviral therapy interruption, Siberry [/bib_ref]. Interruption of treatment occurred in nearly a quarter of children and young people in the Adolescent Master Protocol study in the USA [bib_ref] CD4+ lymphocyte-based immunologic outcomes of perinatally HIV-infected children during antiretroviral therapy interruption, Siberry [/bib_ref]. In the light of such frequent unplanned treatment interruptions, strategically planned treatment interruptions may be preferable. Where possible, this should be done safely to avoid development of resistance to classes of drugs that could be used again in the future. The options are a 'staggered stop', where the NRTI backbone is continued for at least 7-10 days after stopping the NNRTI to cover the 'tail', or a 'replacement stop', where the NNRTI is replaced by a boosted PI before discontinuing the PI and NRTIs simultaneously. There are no randomized comparisons of these strategies; however, evaluation of emergent resistance mutations in the SMART trial showed higher rates of follow-up resistance mutations in patients undertaking a simultaneous or staggered stop compared with a replacement stop (although this did not reach statistical significance) [bib_ref] Viral resuppression and detection of drug resistance following interruption of a suppressive..., Fox [/bib_ref]. A replacement stop is therefore preferable. The EFV 'tail' may be longer compared with that of NVP because of the longer half-life, and therefore the replacement stop may need to be longer (21 days of the PI and NRTIs) [bib_ref] Plasma drug concentrations and virologic evaluations after stopping treatment with nonnucleoside reverse-transcriptase..., Cressey [/bib_ref]. Further studies of treatment interruptions in adults and children may give better understanding of their place in the management of HIV infection in children and young people. The results of the Botswana/Baylor Antiretroviral Assessment trial as well as a 5-year follow-up on immunological and neurodevelopmental outcomes in PENTA 11 are awaited. Further research is needed to ascertain whether PTI can reduce unplanned interruptions in older children and young adults and be advantageous in terms of reduction of resistance, preservation of future treatment options and improvement of quality of life. Might the case be different following early ART for primary infection? The results of the Short Pulse Anti Retroviral Therapy at HIV Seroconversion (SPARTAC) trial in adults, comparing short-term ART initiated during primary HIV infection (ART for 48 weeks or 12 weeks) versus standard of care (no ART), showed that a 48-week course resulted in delayed decline of CD4 count and lower VL off treatment as compared with standard care. Disappointingly, time off treatment was not significantly longer than the 48-week treatment period and the increase in CD4 count on long-term ART was similar across all three groups. In contrast to the SMART trial, there were no adverse effects on clinical outcomes [bib_ref] Short-course antiretroviral therapy in primary HIV infection, Spartac Trial Investigators [/bib_ref]. Adult case series from prospective observational cohort studies and the results of the Agence Nationale de Recherche sur le SIDA (ANRS) Virological and Immunological Studies in Controllers after Treatment Interruption (VISCONTI) study suggest that some patients with different genetic characteristics and characteristic CD8 cell response to HIV, after prolonged treatment of primary HIV infection, can control HIV replication post treatment interruption for at least several years [bib_ref] Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to..., Lodi [/bib_ref] [bib_ref] Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of..., Saez-Cirion [/bib_ref]. It appears that restricting the pool of HIV-infected cells by very early treatment might decrease long-lived viral reservoirs [bib_ref] Reduced markers of HIV persistence and restricted HIV-specific immune responses after early..., Ananworanich [/bib_ref] , which may be essential for successful control without therapy [bib_ref] Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of..., Saez-Cirion [/bib_ref]. In addition to these adult studies, there is a case report of ART-free 'HIV remission' for over 2 years in a child who was started on ART at 36 hours after birth [bib_ref] Absence of detectable HIV-1 viremia after treatment cessation in an infant, Persaud [/bib_ref] , and a more recent report of an infected infant on continuous ART treatment from 4 hours of age with undetectable proviral DNA by 6 days of life [bib_ref] Very early combination antiretroviral therapy in perinatal HIV infection: two case PENTA..., Persaud [/bib_ref]. Although the first patient has now been reported as having detectable VL and has commenced ART, these reports together provide a proof of concept that in some individuals, after early treatment of primary infection, a prolonged treatment interruption may be possible with preservation of control of HIV replication. The phenomenon of post-treatment HIV controllers is rare and treatment interruption cannot be applied to routine management of children. Extensive research is being undertaken to identify correlates for prolonged remission in post-treatment controllers. In summary, routine treatment interruptions cannot be recommended at present and starting ART currently means lifelong therapy. In circumstances where unplanned treatment interruption is unavoidable, it needs to be done safely, as outlined above. Strategic treatment interruption may be considered in individual circumstances of problematic adherence in order to avoid resistance and preserve future treatment options. ## Adolescence, mental health and transition Improved survival produced by ART, high rates of uptake of antenatal HIV screening and successful interventions reducing mother-to-child transmission have resulted in an aging European paediatric population, with many children born with HIV infection now transitioning to adult care. Transition has been defined as 'the planned purposeful process that addresses the medical, psychosocial and educational/vocational needs of adolescents and young adults with chronic physical and medical conditions as they move from child-centred to adultoriented health care systems'. In chronic diseases of childhood no single model of transition has been shown to be superior, although planned transition programmes improve attendance, disease control, self-management and patient and carer satisfaction. Data are emerging on the transition preferences of HIV-infected adolescents, with lack of confidence in negotiating adult services, stigma associated with HIV and fear of ending lifelong patient−carer relationships identified as barriers to transition [bib_ref] The HIV experience: youth identified barriers for transitioning from pediatric to adult..., Wiener [/bib_ref] [bib_ref] Crossing the divide: transition care services for young people with HIV-their views, Bundock [/bib_ref] [bib_ref] We never thought this would happen: transitioning care of adolescents with perinatally..., Vijayan [/bib_ref]. Integrated paediatric and adult care in an age-specific environment, increasing autonomy, patient-centred timing of transition and comprehensive management explanations facilitate transition to adult care. Data suggest that adolescents have poorer adherence to ART when compared with younger children [bib_ref] Evaluating adherence to medication in children and adolescents with HIV, Khan [/bib_ref]. In adolescents commencing first-line therapy, a boosted PI -based regimen potentially reduces the risk of accumulating resistance mutations in the event of virological failure; however, such regimens have a higher pill burden than the FDCs based on NNRTIs or EVG which have a lower genetic barrier to resistance. Adolescents who suppress on a boosted PI-based regimen can subsequently simplify to an FDC once adherence has been established. It is increasingly acknowledged that HIV-infected young people have relatively high rates of mental health disorder [bib_ref] Adolescents with perinatally acquired HIV: emerging behavioral and health needs for long-term..., Koenig [/bib_ref] [bib_ref] Rates and types of psychiatric disorders in perinatally human immunodeficiency virus-infected youth..., Mellins [/bib_ref] [bib_ref] Facing adolescence and adulthood: the importance of mental health care in the..., Domek [/bib_ref]. Whether these are higher than in other patient groups with chronic medical conditions, HIV-exposed but uninfected siblings or well-matched healthy controls is yet to be fully determined [bib_ref] Rates and types of psychiatric disorders in perinatally human immunodeficiency virus-infected youth..., Mellins [/bib_ref] [bib_ref] Prevalence and change in psychiatric disorders among perinatally HIV-infected and HIV-exposed youth, Mellins [/bib_ref] [bib_ref] Mental health functioning among children and adolescents with perinatal HIV infection and..., Malee [/bib_ref] [bib_ref] Co-occuring psychiatric symptoms in children perinatally infected with HIV and peer comparison..., Gadow [/bib_ref]. Nevertheless, it is essential that the multidisciplinary team at least monitor for symptoms and signs of psychological distress and mental health disorder, as children progress into adolescence and young adult life. Early and ongoing support from clinical psychologists with specialist paediatric knowledge is recommended. The possibility of other interventions including the wider family and peer support should also be considered. Negotiating adolescence with any chronic disease may be difficult, but to do so with one potentially transmissible to future partners and offspring before one has explored one's own sexuality adds a layer of complexity, often compounded by stigma and secrecy associated with HIV. ## Pipeline and upcoming trials There are considerable incentives and/or penalties from regulatory agencies to ensure that any new drug that might be of benefit to children must be studied in this population. This is mandatory with both the EMA, which enforces penalties for companies that do not provide a paediatric investigational plan as part of their application (or request a waiver), and the FDA, which also extends 6-month patent protection to companies that perform requested paediatric studies (voluntary). Companies must include PK data for all age groups of children, efficacy, tolerability, and differences in side effects. They must have stability and palatability data for formulations and demonstrate that they are able to achieve PK targets associated with efficacy in adults. Most paediatric development programmes take a staggered approach, starting with the older cohorts of children and working down in age. The studies are conducted in children as soon as there are sufficient data from studies in adults. The current paediatric antiretroviral pipeline is shown in [fig_ref] Table 8: The paediatric antiretroviral pipeline Phase II/III [/fig_ref] ; greater detail can be found in the annually updated i-Base/TAG Pipeline Report (available at http://www.pipelinereport.org). Planned PENTA studies will look at two new drugs for children in the integrase inhibitor class: DTG and EVG. . ## Supplementary table [fig] 2: Comparison of child and adult data Comparison of the short-term risks of disease progression in pre-ART adult seroconverters in the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) cohort collaboration and in children aged 5 years and older in the paediatric HIV Paediatric Prognostic Markers Collaborative Study (HPPMCS) cohort showed [/fig] [fig] Figure 1: Predicted long-term CD4 count following antiretroviral therapy (ART) initiation at thresholds of 250, 350, 500, 750 and 1000 cells/μL (curves), using models derived from the AntiRetroviral Research for Watoto (ARROW) study. Delaying treatment in children younger than 5 years (to the left of the vertical line) results in relatively small differences in long-term expected CD4 count. In contrast, children aged over 5 years (right of the vertical line) are predicted to experience a steady deterioration in long-term CD4 count as ART is initiated at increasingly older ages (and a constant CD4 threshold). Dashed lines show that a 6-year-old delaying treatment until the age of 13 years, with a CD4 count of 350 cells/μL throughout, may expect the long-term CD4 count to be lowered by 151 cells/μL: from 770 to 619 cells/μL. [/fig] [table] Table 4: Recommended first-line antiretroviral therapy (not in the context of hepatitis B virus or tuberculosis coinfection) 3TC, lamivudine; ABC, abacavir; ATV/r, ritonavir-boosted atazanavir; CNS, central nervous system; DRV/r, ritonavir-boosted darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; LPV, lopinavir; NVP, nevirapine; RAL, raltegravir; TDF, tenofovir; VL, viral load; ZDV, zidovudine. Prior to starting abacavir (ABC), patients should be tested for human leucocyte antigen (HLA) B*5701. If positive, then ABC should not be prescribed. † In children < 3 years, consider adding zidovudine (ZDV) to nevirapine (NVP)-based regimens if there is a very high viral load (VL) or central nervous system (CNS) [/table] [table] Table 6: Antiretroviral therapy (ART) regimens for children treated for tuberculosis (TB) coinfection with rifampicin-containing regimens [/table] [table] Table 7: Switching to second-line antiretroviral therapy (ART) Reinforce adherence support. This is the main reason for treatment failure. 4 Simplify regimens where possible (once-daily and fixed dose combinations). Switching to NNRTI-based regimens or PI monotherapy is not advised if there are serious adherence issues. 5 If resistance results suggest that these second-line options in the table would not be effective, seek expert advice. [/table] [table] Table 8: The paediatric antiretroviral pipeline Phase II/III; EVG/COBI/FTC/TAF; treatment-naïve adolescents aged 12 to < 18 years; enrolling Co-formulation with FTC under discussion Phase II; adolescents aged 12 to < 18 years with weight > 32 kg; enrolling Phase I/II; children aged > 2 to < 12 years; planned Protease inhibitors and combinations Approved for 3 months and above by FDA Phase III/IIIb; ongoing; RTV-boosted ATV for treatment-naïve and -experienced children aged 3 months to < 6 years Other studies in children aged up to 11 years ongoing ATV/COBI Gilead/BMS Co-formulated boosted PIs in development Phase II/III; treatment-experienced children aged 3 months to As booster with ATV and DRV Under development as component of EVG/COBI/FTC/TDF and EVG/COBI/FTC/TAF Integrase inhibitors and combinations RAL Merck Granules for suspension 6 mg/kg (100 mg sachet) FDA approval for use in children 4 weeks of age and older Neonate passive PK study ongoing (neonates born to women who received RAL in pregnancy and during labour) Neonate PK and safety study for prophylaxis; ongoing in high-risk HIV-exposed neonates from birth to 6 weeks EVG Gilead EVG reduced-strength tablets and suspension in development EVG PK; completed; RTV-boosted; adolescents aged 12 to < 18 years RTV-boosted EVG to be studied in all age groups EVG/COBI/FTC/TDF (Stribild) Gilead Reduced-strength tablets in development Studies underway in treatment-naïve adolescents aged 12 to < 18 years 6 to < 12 years planned (waiver < 6 years) EVG/COBI/FTC/TAF Gilead Reduced-strength tablets in development Studies under way in treatment-naïve adolescents aged 12 to Approved for adolescents aged 12 to < 18 years weighing > 40 kg in USA and Europe Phase I/II study; treatment-naïve and -experienced children aged 6 weeks to < 18 years; ongoing Exposures from granules were moderately higher than with tablets and highest with formula milk in HIV-negative adults DTG/ABC/3TC (572-Trii) Dependent on ongoing studies confirming DTG dose in children and ability to establish appropriate dosing ratios for components CCR5 receptor antagonist MVC ViiV Suspension 20 mg/mL Phase IV; treatment-experienced, CCR5 tropic children aged 2 to < 18 years 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; ETR, etravirine; EVG, elvitegravir; FDA, US Food and Drug Administration; FDC, fixed dose combination; FTC, emtricitabine; LPV/r, lopinavir/ritonavir; RAL, raltegravir; TAF, tenofovir alafenamide; MVC, maraviroc; PI, protease inhibitor; PK, pharmocokinetic; RPV, rilpivirine; RTV, ritonavir; ZDV, zidovudine. [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/hiv.12217	The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV‐1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short‐term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long‐term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first‐ and second‐line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART ‘pipeline’ of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.
2f6125154010b933203cae1b15fa432e76efc055	pubmed	Saudi Society of Maternal-Fetal Medicine guidance on pregnancy and coronavirus disease 2019	Saudi Society of Maternal-Fetal Medicine guidance on pregnancy and coronavirus disease 2019 ## Vertical transmission. Owing to the recent emergence of the COVID-19 pandemic, data are limited and vertical transmission of this virus is uncertain. Chen et al 13 reported on 9 pregnant women with COVID-19 in their third trimester. In that study, samples were obtained from amniotic fluid, cord blood, and neonatal throat swabs, and 6 patients tested negative for COVID-19 for these samples. These results indicated that in women who had developed COVID-19 infection in the third trimester and had been tested, no evidence of intrauterine infection due to vertical transmission was found. In March 2020, Schwartz reported an extensive analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2, maternal COVID-19 infections, and pregnancy outcomes.The analysis concluded that there were no confirmed cases of intrauterine transmission of SARS-CoV-2 from mothers with COVID-19 to their fetuses. All neonatal specimens tested using real-time polymerase chain reaction for SARS-CoV-2 were negative. In a recent study involving 6 neonates born to mothers with COVID-19, no evidence of vertical transmission was reported.However, a recent report published on March 2020 by Dong et al 17 described a case of a neonate born to a mother who tested positive for SARS-CoV-2 IgM, which may represent a neonatal immune response to maternal infection. In another report, Zeng et alreported test results concerning 3 neonates who tested positive for SARS-CoV-2 on Disclosure. Authors have no conflict of interests, and the work was not supported or funded by any drug company. SSMFM Guidance on Pregnancy and COVID-19 ... Faden et al nasopharyngeal and anal swabs. More recently, 2 additional cases involving newborns who tested positive for SARS-CoV-2 have been reported.Considering the limited data, newborns of mothers with COVID-19 should be monitored carefully for evidence of transmission. 2. Pregnancy management during the COVID-19 pandemic 2.1. Antenatal care of women not suspected or confirmed to have COVID-19. Social distancing is the most important intervention during a pandemic.The first priority for physicians caring for pregnant women is to prevent disease spread; therefore, the standard antenatal appointment schedule may need to be modified to minimize direct contact while maintaining adequate maternal and fetal care. In low-risk populations, reducing the number of in-person antenatal visits is encouraged to minimize exposure and support social distancing. In the inverted pyramid of antenatal care proposed by Sonek et al,an early visit is recommended between 11 and 13 gestation weeks to determine dates, undertake prenatal blood tests, and perform risk assessment. If a patient is deemed to be low-risk, subsequent antenatal visits can be arranged at the following gestational ages: 20, 37, and 41 weeks. This model might be used as an alternative to the traditional model of care. In-person visits can involve an office visit or a home visit, depending on each healthcare institution's resources and available healthcare personnel. Telehealth use has grown noticeably in the past few years globally and in the past few months in Saudi Arabia. Multiple successful examples have been reported from local healthcare institutions.One university hospital in Saudi Arabia has been communicating with patients through the WhatsApp application to address all non-urgent questions and relevant matters to minimize obstetric triage visits. Refill prescriptions are sent to patients' homes via mail delivery to avoid patients arriving at hospitals to collect their medication. Another hospital has used a simple telehealth method of telephoning the patient prior to her clinic visit. If care can be provided over the phone, the in-person visit is rescheduled to a later date. These are individual and local attempts to adapt to the global COVID-19 pandemic. There is no robust evidence to support any approach over another in implementing social distancing while providing appropriate antenatal care. Hospitals need to understand their patient populations and resources in devising a system that provides antenatal care while enhancing social distancing. A suggested care model that combines both telehealth and in-person visits is summarized in If hydroxychloroquine is not available: consider chloroquine 600 mg (10 mg/kg) at diagnosis and 300 mg (5 mg/kg) 12 hours later, followed by 300 mg (5 mg/ kg) BID for 5-7 days Consider Remdesivir 200 mg loading dose (IV, within 30 minutes), followed by 100 mg once daily for 5-10 days Chloroquine phosphate 1000 mg at diagnosis and 500 mg 12 hours later, followed by 300 mg BID for 5-7 days Consider Interferon beta-1b 8 MIU subcutaneously on alternative days for 3 doses (may also be considered for mildmoderate disease) Precautions Avoid ibuprofen Avoid ibuprofen Laboratory tests and work-up: CBC, urea/electrolytes, creatine, CRP, LFTs, chest x-ray with additional G6PD screening Laboratory tests and work-up: CBC, urea/electrolytes, creatinine, CRP, LFTs, chest x-ray, with additional G6PD screening If chloroquine will be used, perform ECG every 3 days if initial QTc is 400-500 ms, and biochemistry according to underlying disease If >7 days have passed since the patient's symptoms first appeared, do not administer interferon beta-1b BID: twice a day, CBC: complete blood count, CRP: C-reactive protein, ECG: electrocardiogram, G6PD: glucose-6-phosphatedehydrogenase, ICU: intensive care unit, LFT: liver function tests, NST: non-stress test head covers, gowns, N95 masks, goggles, gloves, and shoe covers. ## Covid-19 therapy in pregnancy Currently, there is no medication that has been proven to be safe and effective for treating COVID-19. 3.1. Chloroquine/hydroxychloroquine and azithromycin. Chloroquine and hydroxychloroquine are effective in inhibiting SARS-CoV-2 infection in vitro. Hydroxychloroquine is observed to have a more potent antiviral activity.The use of chloroquine has been included in treatment guidelines from China's National Health Commission and has been claimed to be associated with reduced progression of disease and duration of symptoms.However, there are no published primary data to support these claimed associations. Antenatal care for high-risk pregnancies in women with suspected or confirmed COVID-19 should be individualized. In this population, when maternal or fetal monitoring cannot be delayed, appointments and fetal scans can be arranged preferably at the end of the working day.For hospitalized patients, a portable ultrasound machine for fetal surveillance can be assigned to these cases if hospital resources allow. Staff providing care should apply personal protective equipment (PPE) precautions, as the Saudi Center for Disease Prevention and Control guidelines have indicated.Clinical areas exposed to these patients should be appropriately sanitized and equipment properly disinfected. However, concerning pregnant women with poorly controlled comorbidities who are suspected to have COVID-19, admission can be discussed by a multidisciplinary team and individualized depending on the patient's status and the institution's capacity and policies. Comorbidities include, but are not limited to, hypertension; diabetes mellitus; asthma; human immunodeficiency virus-positive; chronic heart, liver, lung, and kidney diseases; hemoglobinopathies; and patients on immunosuppressive agents. All pregnant women confirmed as having COVID-19 should be admitted and managed as inpatients, in accordance with Saudi MOH guidelines. ## Hospital care for patients with suspected or confirmed covid-19 (appendix 1). Patients with suspected/confirmed COVID-19 who require admission should be isolated in a negative-pressure room, preferably in hospitals with adequate facilities and multidisciplinary expertise to manage critically ill obstetric patients. Based on clinical evaluation, they should be triaged and stratified into mild, moderate, severe, and critical categories .Patients should be managed by a multidisciplinary team comprising specialists in maternal-fetal medicine, infectious diseases, anesthesiology, neonatology, and intensive care. All medical staff caring for patients with COVID-19 should use PPE, including to evaluate the efficacy of remdesivir for moderate or severe COVID-19. Preliminary data have led expert panels to recommend remdesivir for the treatment of COVID-19 in patients with severe disease, but not in those with mild or moderate disease.It is unknown whether remdesivir is safe for use during pregnancy and lactation. ## Statins. Statins are one of the proposed medications to treat patients with COVID-19. Generally, they are contraindicated in pregnancy. A risk-benefit analysis should be conducted before using investigational therapeutic agents in pregnant women outside of clinical trials. ## Convalescent plasma therapy. There is insufficient evidence in support of convalescent plasma, SARS-CoV-2-specific immune globulin, and non-SARS-CoV-2-specific intravenous immunoglobulin (IVIG), and these are currently not recommended for use except in the context of a clinical trial.3.4. Antibacterial treatment. Empiric antimicrobial treatment for bacterial pneumonia may be considered for patients with suspected or confirmed COVID-19. SARS-CoV-2 may also cause extensive lung damage, which increases the risk of secondary bacterial pneumonia. Prompt initiation of antibiotics is indicated if there is evidence of secondary bacterial infection or if bacterial sepsis is suspected. 3.5. Glucocorticoids. Glucocorticoids have been associated with an increased mortality risk in patients with influenza and delayed viral clearance in patients with MERS-CoV infection. There is no clear evidence of benefit in the management of SARS, while there is convincing evidence of adverse short-and long-term harm.The RECOVERY trial has recently showed reduced 28-day mortality in hospitalized patients with COVID-19 on respiratory support.The Saudi Ministry of Health recently updated their protocol for managing patients with suspected/confirmed COVID-19. Pregnant and breastfeeding patients with severe or critical disease are recommended to receive prednisolone 40 mg orally once daily or intravenous hydrocortisone 80 mg twice daily instead of dexamethasone.3.6. Supportive therapy. Adequate rest, hydration, nutritional support, antipyretics, and water and electrolyte balance are essential supportive measures for patients with COVID-19. Vital signs and oxygen saturation are needed to be closely monitored. Depending on disease severity and extent of hypoxemia, supplemental oxygen inhalation (60%-100% concentration at a rate of 40 L/min) should be given There are limited clinical data on either of these medications. In an open-label study of 36 patients with confirmed COVID-19, hydroxychloroquine administration (200 mg twice daily for 10 days) was associated with a 70% negative result of a nasopharyngeal PCR swab at day 6 compared with a 12.5% negative result in patients with no specific treatment.In this study, azithromycin was used in combination with hydroxychloroquine. Despite the limited clinical data and given the relative safety of short-term use of hydroxychloroquine, the lack of known effective interventions and antiviral activity, some evidence (based on expert opinion) has shown that it is reasonable to use this agent in hospitalized patients with severe or risk for severe infection, particularly if they are not eligible for other clinical trials.Optimal dosing is uncertain; various regimens are being used, including 400 mg twice daily on day one then once daily for 5 days, 400 mg twice daily on day one then 200 mg twice daily for 4 days, and 600 mg twice daily on day one then 400 mg daily for 4 days.Considering the safety of hydroxychloroquine/ chloroquine use in pregnancy, it is reasonable to apply the same regimen as that of non-pregnant patients. Regarding concerns about the risk of death due to arrythmia from single or combined use of these medications, the absolute magnitude is smaller than the potential benefit from treatment of COVID-19. The use of high-dose chloroquine (600 mg twice daily for 10 days) and the combination of hydroxychloroquine and azithromycin is not recommended because of the potential for toxicities. 32,3.2. Antiviral treatment. Antiviral treatment has been routinely used to treat patients with COVID-19 infection in China and is also recommended for pregnant patients. Combination therapy with antiproteases, namely, lopinavir/ritonavir, is currently not recommended, as it has unfavorable pharmacodynamics, and there is lack of evidence on its effectiveness from clinical trials.A recent systematic review of 2 randomized trials and 21 observational studies concluded that it is uncertain whether lopinavir/ ritonavir and other antiretroviral medication improve clinical outcomes in patients with severe symptomatic disease.A more recent randomized controlled trial, RECOVERY, showed no beneficial effect of lopinavir/ ritonavir in patients hospitalized with COVID-19.Remdesivir is a novel nucleotide analog active against SARS-CoV-2 in vitro and related coronaviruses (including SARS and MERS-CoV) both in vitro and in animal studies.Several randomized trials are ongoing through a high-flow nasal cannula. Intubation and mechanical ventilation, or even extra-corporeal membrane oxygenation (ECMO), may be required to maintain oxygenation. Complications may include septic shock, acute kidney injury, and virus-induced cardiac injury. Consequently, it is important to check arterial blood gases, lactate levels, renal function, liver function, and cardiac enzymes, as indicated according to the clinical situation. The use of non-steroidal anti-inflammatory drugs (NSAIDs) early in the course of the disease has been observed to have a negative effect on disease outcome. These findings are based on case reports of 4 young patients who received NSAIDs early in the course of infection and who experienced severe disease. Conversely, there are no clinical or population-based data to confirm the risks of using NSAIDs. The European Medicines Agency and the WHO do not recommend that NSAIDs be avoided when clinically indicated.The Saudi Centers for Disease Control and Prevention has recommended the avoidance of ibuprofen.In light of these concerns, the SSMFM encourages the use of acetaminophen in place of NSAIDs for reduction of fever. ## Obstetric medication concerning patients with covid-19 4.1. Tocolytics. Given the uncertainty regarding the effect of NSAIDs on COVID-19, indomethacin should be avoided currently. Therefore, nifedipine may be used as an alternative in patients presenting with preterm labor and requiring tocolysis. Other tocolytic agents may be contemplated with caution, and interaction with other medications should be considered. ## Betamethasone/dexamethasone. Steroids for fetal lung maturity should be used cautiously in pregnant women with severe COVID-19 disease who are at <34 weeks of gestation. Worsening morbidity of viral pneumonia has been associated with the administration of steroids.However, steroids for fetal lung maturity may be considered for patients with mild to moderate disease who are at <34 gestation weeks. ## Progesterone. Given the lack of evidence on the effects of progesterone on COVID-19 and adverse pregnancy outcomes associated with early progesterone cessation, progesterone use may be continued in cases of mild disease.The use of progesterone in severe cases should be individualized. ## Magnesium sulfate (mgso4). Magnesium sulfate is usually indicated in the obstetric setting for maternal eclampsia prophylaxis or fetal neuroprotection. There is a lack of evidence concerning the effects of MgSO4 on pregnant patients with COVID-19. This medication, excreted by the kidneys, may affect the respiratory status of the patient. Magnesium sulfate may be given to patients with mild disease. In patients with severe disease, administration needs to be individualized depending on the medical condition. Possible drug interactions also need to be considered. ## Thromboprophylaxis. There is increasing evidence that patients with COVID-19 infection are at high risk of developing venous thromboembolism (VTE). In a study conducted in China, COVID-19 patients who received unfractionated heparin (UFH)/ low-molecular-weight heparin (LMWH) had significantly better survival than those who did not. Pregnancy is also a well-known risk factor for VTE. Less mobilization of pregnant women due to the COVID-19 pandemic and hospitalization are likely to further increase the risk. The recommended doses of UFH/LMWH were based on body weight and D-dimer measurements.D-dimer levels in pregnancy differ from those in a non-pregnant state. This should be considered when calculating the risk score assessment for VTE and prescribing LMWH for pregnant women. The SSMFM recommends that a thrombosis expert be included in the care of patients with suspected/ confirmed COVID-19. The SSMFM also recommends commencement of LMWH thromboprophylaxis for all pregnant women with confirmed COVID-19 who are admitted to hospital and who are not expected to deliver within 12 hours. It is recommended to continue postpartum LMWH thromboprophylaxis for at least 10 days postpartum; however, this may be extended to 6 weeks, depending on the patient's clinical status upon discharge and on the presence of other comorbidities. ## Low-dose aspirin. Low-dose aspirin is widely used in obstetrics for pregnant women (example, prevention of pre-eclampsia, fetal growth restriction, and recurrent fetal loss). There is lack of evidence regarding risks associated with aspirin use in pregnant women with suspected/confirmed COVID-19. The SSMFM advises continuation of low-dose aspirin for pregnant women without COVID-19 infection. Low-dose aspirin use in pregnant women with suspected/confirmed COVID-19 infection should be individualized based on the clinical indication, gestational age, and maternal condition.The SSMFM advises to withhold low-dose aspirin in patients with severe-critical COVID-19 infection. ## Managing chronic medications Patients receiving immunomodulatory agents. Immunocompromised patients with COVID-19 are at an increased risk for severe disease and the decision to discontinue prednisone, biologics, or other immunosuppressive drugs in the setting of SARS-CoV-2 infection must be determined on a case-by-case basis. For individuals with underlying conditions who require treatment with these agents and are without COVID-19, there is no evidence that routinely discontinuing treatment is of any benefit. Furthermore, discontinuing these medications may result in a loss of response when the agent is reintroduced. This approach is supported in guidance from various dermatology, rheumatology, and gastroenterology societies.6. Critically ill patients Critically ill patients with severe organ damage, in particular, respiratory and renal failure, will require a multidisciplinary approach in an inpatient setting and in a critical care unit. These patients are managed case-by-case, depending on their condition, as they may require hemodialysis with correction of electrolyte imbalance, respiratory ventilatory support, and wide spectrum antibiotic coverage. Priority is given to stabilizing the maternal condition. Extracorporeal life support during pregnancy is considered effective and safe for the mother and the fetus. Survival rate for the mother is 77.8% and 65.1% for the fetus.Obstetric care is undertaken by a general obstetrician, or a maternal-fetal medicine specialist, based on availability. This care involves fetal monitoring if the pregnancy can be continued, and pregnancy termination if fetal or maternal conditions indicate otherwise. ## Obstetrical factors determining timing of delivery: A. Gestational age. A previable gestational age (<23-24 weeks) pregnancy may need to be terminated to improve the maternal condition if agreed upon by a panel of experts (obstetrician and intensivist/ pulmonologist) who consider continuation of pregnancy life-threatening. For early preterm fetuses (23-24 weeks to 33+6 weeks), although pregnancy can be terminated for maternal indications, counseling should include discussing the risks and benefits of administering steroids as well as MgSO4 for neuroprotection if the maternal condition allows. Planning of delivery for a reasonably mature fetus (≥34 weeks) should be individualized according to the patient's condition. B. Maternal condition. The maternal medical condition should be evaluated by internal medicine and intensive care specialists, and should include an assessment of the medical and social risks of contracting SARS-CoV-2 and the presence of comorbidities. For diagnosis and evaluation of the disease progress, the use of computed tomography scanning and plain chest radiographs are permitted, if indicated, regardless of the fetal gestational age, with the use of abdominal shield protection. Based on a comprehensive evaluation, a decision should be made to determine whether expeditious delivery is needed to improve the maternal condition. If the maternal medical condition necessitates an urgent delivery, a cesarean section can be performed with epidural, spinal, or general anesthesia. Pediatricians should be involved if preterm delivery is decided. C. Fetal assessment parameters. If the maternal medical condition allows trial of vaginal delivery, then continuous fetal monitoring is advised during labor. A cesarean section is only recommended for the standard obstetrical indications. ## D. risk of vertical transmission. If a decision is taken to expedite delivery, then delivery needs to be performed regardless of the risk of vertical transmission for patients in this category. ## Labor considerations for suspected/ confirmed patients with covid-19 (appendix 2) There is no strong evidence that termination of pregnancy or early delivery will improve the overall maternal outcome or decrease the mortality rate. However, previous experience with H1N1 and SARS-CoV showed some improvement in terms of ventilation and oxygenation for those with severe respiratory failure on mechanical ventilation.A multidisciplinary team review with the family should be conducted to make the decision, considering the risk of prematurity and perinatal morbidity and mortality when a patient is <37 weeks' pregnant. The mode of delivery should not be affected owing to COVID-19. Cesarean birth should be performed in line with standard obstetric indications unless the patient's respiratory condition requires urgent delivery. Instrumental delivery may be considered to expedite delivery and shorten the second stage of delivery. Patients in active labor should be admitted to an isolation room, followed with an assessment of the severity status of COVID-19, and then a multidisciplinary approach to patient care implemented. The distance between a healthcare professional (HCP) involved in a delivery and the patient is less than the standard distance advised; therefore, full PPE is recommended. Care should be taken to minimize the number of unnecessary healthcare personnel present in the labor room. The presence of a support person intrapartum is not encouraged. If they are permitted to be present, they should wear full PPE and sign a risk-ofexposure consent form. Given the risk of asymptomatic carrier transmission, it is recommended that all patients and their providers in every delivery unit wear surgical masks during each encounter.This recommendation may be difficult to implement because of supply shortage. Full droplet precautions should be applied, including wearing gloves, a gown, and a surgical mask with a face shield when attending to a patient with respiratory symptoms. An N95 mask should be worn alongside PPE droplet precautions for any patient with suspected or confirmed COVID-19; and for any patient, irrespective of respiratory symptoms, during indispensable aerosolizing procedures.These precautions are also recommended for the second stage of labor.Continuous external electronic fetal monitoring should be undertaken and, if possible, the use of fetal scalp electrodes should be avoided. A cesarean section should not be delayed if fetal well-being is questionable, as fetal blood sampling is discouraged. COVID-19 is not an indication for cesarean delivery. The use of surgical N95 respirators is reserved for HCPs exposed to airborne and fluid hazards (examples, splashes and sprays). A face shield over a standard N95 respirator should be used in case of surgical N95 respirator shortage. There is no contraindication to provide regional analgesia including epidural or spinal anesthesia. However, general anesthesia should be avoided as much as possible as intubation is associated with aerosol generation. Intubation is known as an aerosol-generating procedure, for which the surgical team should wear full PPE and wear N95 respirators for cesarean delivery,even in cases of spinal-epidural anesthesia, as noted in Saudi Anesthesia Society Guidelines,as there is always the possibility of converting from regional to general anesthesia. Delayed cord clamping and early cleaning of the neonate should still be encouraged.Other good practice points include postponing elective cesarean deliveries until the patient is cleared as negative and is, therefore, no longer contagious. Moreover, it is advisable to consider scheduling cesarean delivery for suspected/confirmed patients with COVID-19 at the end of the operating room (OR) list. Appropriate precautions should be made during the transfer of the patient from the labor and delivery room to the OR and from the OR to the post-anesthesia care unit to minimize exposure. Simulation-based training (example, obstetric drills) is strongly recommended in labor and delivery units as part of their preparedness plan. Such activities have been associated with improvement in staff skills, patient safety, and quality of care. Improvement of clinical performance is attributed to identification of system errors during training, followed by timely correction.During the pandemic period, the SSMFM discourages home births for all patients to ensure application of protective measures and availability of required resources and equipment in the event of urgent interventions. condition and stability of the patient. Suspected/ confirmed stable patients with mild symptoms can be nursed in the postpartum ward with appropriate isolation until the infection is cleared. Patients who require respiratory support are likely to be treated and managed in an intensive care unit (ICU). A venous thromboprophylaxis risk assessment should be followed as per the patient's medical condition and local institution policies. Pain control should follow standard guidelines. It has recently been hypothesized that NSAIDs such as ibuprofen could aggravate COVID-19 symptoms;however, the United States FDA does not discourage the use of ibuprofen based on currently available information.Severe illness during pregnancy can increase the risk of mental health illnesses. Women who have experienced severe maternal morbidity have significantly greater odds of being treated for a psychiatric disorder.Maternal-neonatal separation in COVID-19 cases may cause anxiety to parents and lead to maternal depression.Emotional, psychological support, and counseling should be provided. Vigilant monitoring for postpartum depression is recommended. Women who have been critically ill may need post-traumatic stress syndrome support. Standard contraceptive counseling should be provided as appropriate while the patient remains in hospital. No COVID-19-specific data are available concerning the choice of contraception regimen. ## Neonatal care. Maternal health status is relevant in deciding the extent of mother/neonate contact. The issue of segregation should be discussed thoroughly with the patient and family, and individualized care is recommended. Neonates delivered by mothers with confirmed COVID-19 should be categorized as suspected cases and isolated, in line with Saudi MOH guidelines.There is a lack of consensus regarding mother/neonate contact. The RCOG has advised that neonates not otherwise requiring special care be kept together with their mothers in the immediate postpartum period.Qia 64 and Liang et al 65 recommended temporary separation of the mother and her neonate to prevent close contact, to avoid virus transmission. This separation period is recommended to continue for a minimum of 2 weeks.The American College of Obstetricians and Gynecologists Clinical Advisory Board adopted a United States Centers for Disease Control and Prevention recommendation that facilities should consider temporary separation of confirmed or suspected patients with COVID-19 until the mother has been confirmed as being no longer infectious.The SSMFM prefers to err on the side of caution in considering segregation, as the spread method and transmission from the mother to the neonate have not yet been well established. Temporary separation is likely to facilitate care for both a mother and a neonate, and minimize healthcare workers' contact and exposure risks, especially given the current universal shortage of PPE. Chen et al 8 found no evidence that this virus was excreted in breast milk in a limited number of tested samples. However, direct breastfeeding is not recommended, as it requires long and close contact.There is conflicting limited evidence in the literature regarding breastfeeding. The SSMFM recommends a detailed discussion with the mother concerning risks and benefits of breastfeeding in patients with COVID-19, covering the limited available data concerning excretion of the virus in the breastmilk, the potential presence of antibodies, the risks of infection from the neonatal care provider, and the care needed while handling the neonate to avoid infection as well as alternative feeding options, such as expressed breast milk and formula. Ultimately, the family will have to make an informed choice between expressed breast milk and formula, regardless of which strict infection control criteria are applied. Natural or medical methods for milk suppression may be considered if a patient chooses not to express breast milk or if medically indicated. Neonates born to mothers with suspected or confirmed COVID-19 are considered to be high risk and should have clear discharge criteria. The family should be educated appropriately and provided with information, as mentioned in.	None	https://smj.org.sa/content/smj/41/8/779.full.pdf	[No Abstract Available] Saudi Med J 2020; Vol. 41 (8): 779-790doi: 10.15537/smj.2020.8.25222 How to cite this article:Yaser A. Faden, Nadia A. Alghilan, Samiha H. Alawami, Eman S. Alsulmi, Hythem A. Alsum, Yasir A. Katib, Yasser S. Sabr, Fadwah H. Tahir, Nabeel S. Bondagji. Saudi Society of Maternal-Fetal Medicine guidance on pregnancy and coronavirus disease 2019. Saudi Med J 2020; Vol. 41 (8): 779-790. doi: 10.15537/smj.2020.8.25222.
001d12bfa1eb26fb59b35be9aa56e2fcbd1ae86b	pubmed	Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club	Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club Osteoporosis is a major health issue. It is a disease characterised by low bone mass and altered bone architecture leading to an increased susceptibility to fractures (1).Osteoporosis is defined by a value of bone mineral density (BMD), measured by dualenergy X-ray absorptiometry (DXA) on the spine or hip, more than 2.5 SD below the normal peak values for young adults (T-score < )2.5) (WHO criteria) or by the occurrence of a low trauma fracture.So, BMD measurement is the pivotal mainstay in the decision to initiate an anti-resorptive treatment. BMD is used also to monitor treatment efficacy. However, BMD alone presents some shortcomings, both for the diagnosis of osteoporosis and for the treatment monitoring. With regard to diagnosis, many fractures occur in patients who do not have a T-score < )2.5. As far as monitoring is concerned, BMD changes in response to anti-resorptive treatment are slow (2-5% per year, or a maximum of < 3% in 3-6 months). So, at least 1 year of treatment is necessary before a significant change in BMD can be observed and, furthermore, absence of BMD increase does not imply absence of therapeutic response. The changes in bone turnover rate are much faster and several analytes, which can be measured easily in serum or urine, reflect the rate of bone formation or bone resorption. These bone turnover markers (BTM) will be presented here. WeS U M M A R YObjectives: To review the clinical value of bone turnover markers (BTM), to initiate and ⁄ or monitor anti-resorptive treatment for osteoporosis compared with bone mineral density (BMD) and to evaluate suitable BTM and changes in BTM levels for significance of treatment efficiency. Methodology: Consensus meeting generating guidelines for clinical practice after review and discussion of the randomised controlled trials or meta-analyses on the management of osteoporosis in postmenopausal women. Results: Although the correlation between BMD and BTM is statistically significant, BTM cannot be used as predictive markers of BMD in an individual patient. Both are independent predictors of fracture risk, but BTM can only be used as an additional risk factor in the decision to treat. Current data do not support the use of BTM to select the optimal treatment. However, they can be used to monitor treatment efficiency before BMD changes can be evaluated. Early changes in BTM can be used to measure the clinical efficacy of an anti-resorptive treatment and to reinforce patient compliance. Discussion: Determining a threshold of BTM reflecting an optimal long-term effect is not obvious. The objective should be the return to the premenopausal range and ⁄ or a decrease at least equal to the least significant change (30%). Preanalytical and analytical variability of BTM is an important limitation to their use. Serum C-terminal cross-linked telopeptide of type I collagen (CTX), procollagen 1 N terminal extension peptide and bone specific alkaline phosphatase (BSALP) appear to be the most suitable. Conclusion: Consensus regarding the use of BTM resulted in guidelines for clinical practice. BMD determines the indication to treat osteoporosis. BTM reflect treatment efficiency and can be used to motivate patients to persist with their medication.Review CriteriaAn extensive Pubmed search was used to identify the relevant literature, which included randomised controlled trials and meta-analyses, considering the use of biochemical markers of bone turnover in osteoporosis. A critical appraisal of the data was obtained through consensus expert meetings. The guidelines for the clinical practice are the conclusions of these analyses and discussions.Message for the ClinicStandardised guidelines defined in the consensus 'how to use bone turnover markers' will help clinicians in a better management of osteoporosis. As bone turnover markers decrease rapidly after initiation of anti-resorptive treatment, they represent useful surrogate markers not only to reflect therapeutic success but also to monitor patient's compliance. ## S u m m a r y Objectives: To review the clinical value of bone turnover markers (BTM), to initiate and ⁄ or monitor anti-resorptive treatment for osteoporosis compared with bone mineral density (BMD) and to evaluate suitable BTM and changes in BTM levels for significance of treatment efficiency. Methodology: Consensus meeting generating guidelines for clinical practice after review and discussion of the randomised controlled trials or meta-analyses on the management of osteoporosis in postmenopausal women. Results: Although the correlation between BMD and BTM is statistically significant, BTM cannot be used as predictive markers of BMD in an individual patient. Both are independent predictors of fracture risk, but BTM can only be used as an additional risk factor in the decision to treat. Current data do not support the use of BTM to select the optimal treatment. However, they can be used to monitor treatment efficiency before BMD changes can be evaluated. Early changes in BTM can be used to measure the clinical efficacy of an anti-resorptive treatment and to reinforce patient compliance. Discussion: Determining a threshold of BTM reflecting an optimal long-term effect is not obvious. The objective should be the return to the premenopausal range and ⁄ or a decrease at least equal to the least significant change (30%). Preanalytical and analytical variability of BTM is an important limitation to their use. Serum C-terminal cross-linked telopeptide of type I collagen (CTX), procollagen 1 N terminal extension peptide and bone specific alkaline phosphatase (BSALP) appear to be the most suitable. Conclusion: Consensus regarding the use of BTM resulted in guidelines for clinical practice. BMD determines the indication to treat osteoporosis. BTM reflect treatment efficiency and can be used to motivate patients to persist with their medication. ## Review criteria An extensive Pubmed search was used to identify the relevant literature, which included randomised controlled trials and meta-analyses, considering the use of biochemical markers of bone turnover in osteoporosis. A critical appraisal of the data was obtained through consensus expert meetings. The guidelines for the clinical practice are the conclusions of these analyses and discussions. ## Message for the clinic Standardised guidelines defined in the consensus 'how to use bone turnover markers' will help clinicians in a better management of osteoporosis. As bone turnover markers decrease rapidly after initiation of anti-resorptive treatment, they represent useful surrogate markers not only to reflect therapeutic success but also to monitor patient's compliance. shall review their suitability and potential added value in the selection of patients to be treated and in the follow-up of patients undergoing treatment for osteoporosis. # Methodology We included randomised controlled trials and metaanalyses in postmenopausal women, comparing interventions currently registered in Belgium for the management of osteoporosis with placebo. The results had to be reported with a follow-up of at least 1 year. The relevant articles of the literature review were discussed and a critical appraisal of the data was obtained through a consensus experts meeting. The guidelines for clinical practice, phrased as 'Consensus of the Belgian Bone Club' [fig_ref] Table 1: Consensus of the Belgian Bone Club regarding the use of bone turnover... [/fig_ref] , are the conversion of the conclusions of the consensus expert meeting into daily practice, reviewed by the members of the Advisory Board on Bone Markers. ## Biomarkers of bone turnover To predict bone loss, we should measure at one time-point the rate of bone turnover and the balance between formation and resorption. But, by measuring the concentration of BTM (corresponding to the ratio of their production and degradation), we cannot assess quantitatively the amount of matrix deposited and mineralised or destroyed per unit of time, even though some BTM are more linked to bone resorption and others to bone formation. ## Bone formation ## Bone-specific alkaline phosphatase There are several isoforms of alkaline phosphatase originating from many tissues, mainly liver and bone, with bone contributing for 40-50% in normal adults. The bone enzyme can be separated from the other forms by chemical separative methods such as lectin precipitation, heat resistance or electrophoresis [bib_ref] Age and sex distribution of alkaline phosphatase isoenzymes by agarose electrophoresis, Van Hoof [/bib_ref]. Automation of the specific immunoassays for bonespecific alkaline phosphatase (BSALP) has improved the analytical reproducibility to < 5%. Unfortunately, there is a significant cross-reactivity (± 15%) with the liver form (3), which can be clinically relevant when the patient suffers from liver disease. The half-life of BSALP is 1-2 days, making it less sensitive to circadian variation than other markers with a shorter halflife. The long-term intra-individual variability of BSALP is 10%, and this biological variability represents the major component of variability since the improvement of analytical methods. ## Osteocalcin Osteocalcin is a small protein synthesised exclusively by osteoblasts (and odontoblasts). It is deposited into the bone matrix to form the major non-collagenic part and can be released in part into the circulation. The flux of osteocalcin towards the serum also results from matrix resorption, thus it is not a pure osteoblast function marker. Osteocalcin has a circadian rhythm and is higher in the early morning (4). It is excreted by glomerular filtration and its concentration is increased when glomerular filtration decreases [bib_ref] Effect of renal function on plasma levels of bone Gla-protein, Delmas [/bib_ref]. Osteocalcin can be measured by several immunoassays, but its measurement is complicated by the presence in variable amount of several fragments, by a lack of uniform standardisation (6) and by its degradation in the serum even in the absence of haemolysis causing an important preanalytical problem. The conservation problem can be improved, but only in part, by using an immunoassay, which recognises a large N-terminal fragment [bib_ref] Apparent instability of osteocalcin in serum as measured with different commercially available..., Blumsohn [/bib_ref]. ## Procollagen i extension peptides Type I collagen is synthesised as a precursor flanked at its C-and N-termini with extension peptides, which are cleaved when the collagen is deposited to form the bone matrix. The catabolism of both extension peptides, procollagen 1 C terminal extension peptide and procollagen 1 N terminal extension peptide (P1NP) is under hormonal control, but their concentration is not dependent of renal function. As bone is remodelled faster than other conjunctive tissues, its contribution to serum extension peptides is dominant, at least in the absence of any conjunctive disease. Both peptides can be measured by immunoassay [bib_ref] Immunoassay for intact amino-terminal propeptide of human type 1 procollagen, Melkko [/bib_ref] and have been shown to follow the expected variations in bone turnover in different physiological and pathological conditions. P1NP circulates as a trimer, which is rapidly degraded at 37°; recognition of the monomer varies between assays (10). They follow a circadian rhythm and are higher in early morning. The intra-individual coefficient of variation (CV) is 12.4% for P1NP; combining analytical and biological variability revealed a critical difference between two successive serial measurements of 38% [bib_ref] Critical differences in the serial measurement of three biochemical markers of bone..., Scariano [/bib_ref]. ## Bone resorption ## Acid phosphatase Osteoclasts produce an acid phosphatase isoenzyme, which is not inhibited by tartrate [type 5 tartrate resistant acid phosphatase (TRAP)]. Total TRAP, measured by chemical methods, has long been considered as a marker of bone resorption. However, total TRAP is influenced by enzymes originating from the erythrocytes and platelets, and its measurement can be hampered by circulating inhibitors. Now it can be measured in serum by immunoassays using an immunometric format with a precision of 5% (mass measurement) or 15% (enzyme activity of the captured protein). A kinetic assay to measure specifically type 5b TRAP, a desialylated isoenzyme present only in osteoclasts and alveolar macrophages, has also been described, with a CV of 5-10%. Increased type 5 TRAP levels have been described in diseases characterised by increased bone resorption, such as primary or secondary hyperparathyroidism, Paget's bone disease or metastatic bone disease. There are few studies on type 5b TRAP in osteoporosis studies. ## Pyridinoline and deoxypyridinoline crosslinks These crosslinks (aldehyde links between lysine or hydroxylysine residues) are formed between collagen molecules and they stabilise the conjunctive tissue. They are released into the circulation and excreted into the urine when collagen is catabolised. They reflect only collagen degradation. Deoxypyridinoline (DPD) is found only in skeletal tissue, but both crosslinks mainly originate from bone resorption. When bone metabolism is normal, 50% of the crosslinks are free and 50% bound to peptides [bib_ref] Effect of menopause and hormone replacement therapy on the urinary excretion of..., Uebelhart [/bib_ref]. The measurement most representative of true bone resorption is probably that of the total crosslinks. It was shown indeed that when high turnover bone diseases were treated with anti-resorptive drugs, there was only a minimal decrease in the free crosslinks, while the peptidic forms decreased dramatically with total crosslinks in between [bib_ref] Different effects of bisphosphonate and estrogen therapy on free and peptide-bound bone..., Garnero [/bib_ref]. Today most studies are based on immunoassay measurements, mainly of the peptidic forms. They follow a circadian rhythm and are higher in the early morning. ## Telopeptides of type i collagen These peptides are the non-helical region of type 1 collagen where the crosslinks attach. The measured molecules are either a trimeric carboxyterminal telopeptide (ICTP), which is measured in serum by radioimmunoassay (14) ICTP or a synthetic peptide sequence containing the crosslink site which can be measured in serum or urine [C-terminal crosslinked telopeptide of type I collagen (CTX)] [bib_ref] Measurement of bone degradation products in serum using antibodies reactive with an..., Bonde [/bib_ref]. There are four isomers of CTX, according to the isomerisation of the aspartate (native aand transformed b-CTX) and to its racemisation (l or d). Both racemisation and isomerisation increase with tissue age; thus measurement of the different forms could give an insight into the mean age of bone tissue (with a ⁄ b higher if bone turnover is increased). Practically, there are competition assays, which measure the two isomers in the urine and b-CTX can be measured in the serum with a sandwich immunoassay. Serum and urine CTX values are highly correlated. Another assay called NTX recognises an epitope of the N-terminal telopeptide of the a-2 chain of collagen I [bib_ref] A specific immunoassay for monitoring human bone resorption: Quantitation of type I..., Hanson [/bib_ref]. They follow a circadian rhythm and are higher in the early morning. ## Prediction of postmenopausal bone loss using btm Postmenopausal oestrogen deficiency causes an acceleration of bone remodelling. As osteoclasts, responsible for bone resorption, are triggered by oestrogen deficiency, there is an imbalance in bone formation and bone resorption leading to bone loss. The loss resulting from this imbalance is faster in the trabecular than in the cortical compartment of bone [bib_ref] Endocrinological status of postmenopausal osteoporosis, Nagant De Deuxchaisnes [/bib_ref] [bib_ref] How do you know who needs prevention or treatment?, Devogelaer [/bib_ref]. The increase in the parameters of bone resorption varies from 0% to 150%, with a subsequent increase of 0% to 100% in markers of bone formation [bib_ref] Effect of menopause and hormone replacement therapy on the urinary excretion of..., Uebelhart [/bib_ref] [bib_ref] Increased bone turnover in late postmenopausal women is a major determinant of..., Garnero [/bib_ref]. The increased remodelling can persist until late in life [bib_ref] Increased bone turnover in late postmenopausal women is a major determinant of..., Garnero [/bib_ref] [bib_ref] Biochemical markers of bone turnover reflect femoral bone loss in elderly women, Dresner-Pollak [/bib_ref] [bib_ref] Bone remodeling increases substantially in the years after menopause and remains increased..., Recker [/bib_ref] , more than 30 years postmenopause. Various longitudinal studies strongly support the fact that high bone turnover leads to faster bone loss than normal or low bone turnover [bib_ref] Biochemical markers of bone turnover reflect femoral bone loss in elderly women, Dresner-Pollak [/bib_ref] [bib_ref] Rapid bone loss is associated with increased levels of biochemical markers, Ross [/bib_ref] [bib_ref] Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12..., Hansen [/bib_ref] [bib_ref] Markers of bone turnover predict postmenopausal forearm bone loss over 4 years:..., Garnero [/bib_ref] [bib_ref] Evidence-based guidelines for the treatment of postmenopausal osteoporosis: a consensus document of..., Boonen [/bib_ref]. In one study, using markers such as total serum alkaline phosphatase, fasting urinary calcium and hydroxyproline, women diagnosed as fast losers, based on markers, had lost 26.6% of bone mass after 12 years compared with 16.6% in those classified as slow losers [bib_ref] Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12..., Hansen [/bib_ref]. In elderly patients, aged 75 years, significant associations were found between serum osteocalcin, serum CTX, TRAP and urinary DPD and the areal BMD of the leg region, derived from the whole body measurement (26). No correlation was found with the areal BMD of the spine. It is well known that degenerative osteoarthritic changes at the spine can be a confounding factor for BMD measurements by DXA. The progressive availability of BTM with a better specificity and precision should increase their capability to predict the rate of bone loss. Although the correlation between BMD and the levels of BTM is statistically significant [bib_ref] Relationship of bone turnover to bone density and fractures, Melton [/bib_ref] [bib_ref] Bone resorption in post-menopausal women with normal and low BMD assessed with..., Reginster [/bib_ref] , it is not strong enough to use BTM as predictive markers of BMD in an individual patient. ## Fracture risk assessment: btm is an independent risk factor The major complication of osteoporosis is the occurrence of fractures for minimal trauma with their inherent increase in morbidity and mortality. A decrease in one T-score in BMD, measured by DXA, is associated with a doubling of the relative risk of fracture at the spine, hip and forearm [bib_ref] Meta-analysis of how well measures of bone mineral density predict occurrence of..., Marshall [/bib_ref]. Several studies have shown that some markers of bone resorption are independent predictors of fractures, especially spine and hip [bib_ref] Case-control analysis of bone resorption markers, disability, and hip fracture risk: the..., Van Daele [/bib_ref] [bib_ref] Markers of bone resorption predict hip fracture in elderly women: the EPIDOS..., Garnero [/bib_ref] [bib_ref] Biochemical markers of bone turnover, endogenous hormones and the risk of fractures..., Garnero [/bib_ref] [bib_ref] Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective..., Ross [/bib_ref] [bib_ref] Identification of osteopenic women at high risk of fracture: the OFELY study, Sornay-Rendu [/bib_ref] [bib_ref] Serum type 1 collagen breakdown products (serum CTX) predicts hip fracture in..., Chapurlat [/bib_ref]. In osteopenic women, the 10-year probability of fracture amounted to 26% if at least one risk factor was present (amongst age, elevated BSALP and prior fracture) vs. 6% only in women without any of the three risk factors [bib_ref] Identification of osteopenic women at high risk of fracture: the OFELY study, Sornay-Rendu [/bib_ref]. Elevated serum CTX levels were associated with a significantly increased risk of osteoporotic fractures [bib_ref] Biochemical markers of bone turnover, endogenous hormones and the risk of fractures..., Garnero [/bib_ref] [bib_ref] Serum type 1 collagen breakdown products (serum CTX) predicts hip fracture in..., Chapurlat [/bib_ref] , but only above a certain threshold, suggesting that an increased resorption together with an increased activation frequency (=the appearance rate of the basic multi-cellular unit -BMU -in a histology slide) could lead to a more pronounced fragility of bone superimposed to the fragility already induced by a low BMD [bib_ref] Bone remodeling increases substantially in the years after menopause and remains increased..., Recker [/bib_ref]. There was also an association between the elevation of markers of bone formation and the risk of fracture [bib_ref] Biochemical markers of bone turnover, endogenous hormones and the risk of fractures..., Garnero [/bib_ref] [bib_ref] Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective..., Ross [/bib_ref] [bib_ref] Identification of osteopenic women at high risk of fracture: the OFELY study, Sornay-Rendu [/bib_ref]. An increased risk of hip fracture was observed in ambulatory and institutionalised elderly women with low levels of undercarboxylated osteocalcin, an index for a low vitamin K status [bib_ref] Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture:..., Szulc [/bib_ref] [bib_ref] Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly..., Vergnaud [/bib_ref]. Bone turnover markers and BMD predict fracture risk independently. When both factors are altered, the fracture risk is more increased than for each of them considered separately. In the OFELY study, women suffering from osteodensitometric osteoporosis of the hip combined with an elevated serum CTX had a relative risk of fractures within 5 years amounting to 55%. This is significantly higher than the relative risk linked to an isolated low BMD (39%) or an isolated elevated CTX (25%) [bib_ref] Biochemical markers of bone turnover, endogenous hormones and the risk of fractures..., Garnero [/bib_ref]. It must be mentioned, however, that the markers can only be used as an additional risk factor, not as a surrogate for BMD measurement in the decision to treat. ## Selection of a specific treatment Theoretically, a better response to anti-resorptive treatment should be expected in patients with a high bone turnover rate. However, current data do not support the use of BTM to select the optimal treatment, as the relationship between BTM concentration and response to anti-resorptive treatment is, at best, weak [bib_ref] Potential for bone turnover markers to cost-effectively identify and select post-menopausal osteopenic..., Schousboe [/bib_ref] [bib_ref] Pretreatment levels of bone turnover and antifracture efficacy of alendronate: the fracture..., Bauer [/bib_ref] [bib_ref] Relationship between pretreatment bone resorption and vertebral fracture incidence in postmenopausal osteoporotic..., Seibel [/bib_ref] [bib_ref] Biochemical markers of bone turnover part II: Clinical applications in the management..., Seibel [/bib_ref]. In a post hoc analysis of the Fracture Intervention Trial (FIT), there was no relationship between pretreatment P1NP, BSALP or serum C-terminal crosslinked telopeptide of type I collagen (sCTX) and alendronate efficacy for incident spine fractures among osteoporotic women [bib_ref] Pretreatment levels of bone turnover and antifracture efficacy of alendronate: the fracture..., Bauer [/bib_ref]. Nevertheless, a recent pharmacoeconomic study (Markov model) concluded that measurement of BTM has the potential to identify a subset of postmenopausal women (top BTM quartile), without osteoporosis by BMD criteria, for whom alendronate therapy to prevent fracture is cost-effective [costs per quality adjusted life years (QALY) gained at 34,000 and 50,000 USD for women aged 70 years with high bone turnover and femoral neck BMD T-score of )2.0 and )1.5 respectively] [bib_ref] Potential for bone turnover markers to cost-effectively identify and select post-menopausal osteopenic..., Schousboe [/bib_ref]. A similar analysis of the risedronate phase III clinical programme showed that the reduction in the incidence of vertebral fractures was independent of baseline urinary DPD. However, the number neededto-treat (NNT) to avoid one vertebral fracture at 12 months was 15 in the group of patients with high DPD and 25 in patients with low DPD, an observation which is not unexpected, based on the influence of the prevalent absolute risk on NNT calculation [bib_ref] Relationship between pretreatment bone resorption and vertebral fracture incidence in postmenopausal osteoporotic..., Seibel [/bib_ref]. The authors concluded that although the reduction in overall fracture risk seems to occur independent of baseline bone turnover, patients' stratification by pretreatment bone resorption rate seems to make some sense from a pharmacoeconomic point of view [bib_ref] Relationship between pretreatment bone resorption and vertebral fracture incidence in postmenopausal osteoporotic..., Seibel [/bib_ref] [bib_ref] Biochemical markers of bone turnover part II: Clinical applications in the management..., Seibel [/bib_ref]. ## Early changes of btm, changes of bmd and fracture risk In the Early Postmenopausal Intervention Cohort study, early postmenopausal women, receiving alendronate for the prevention of osteoporosis, with a decrease of 40% for urinary N-terminal telopeptide of type 1 collagen (uNTX) or 20% for osteocalcin at month 6 had a 92% probability of a 2-year positive response in spine BMD. In contrast, the poor specificity and negative predictive value of these percentual cut-offs of BTM changes implied that a change in uNTX or osteocalcin above the cut-point was a poor predictor of bone loss during alendronate treatment [bib_ref] Monitoring of alendronate treatment and prediction of effect on bone mass by..., Ravn [/bib_ref]. In a smaller cohort of French osteoporotic women, the authors claimed that after 4 months of alendronate, sCTX and to a lesser extend uNTX, were the best predictors of a significant gain in spine BMD after 1 year of therapy [bib_ref] Differences in the capacity of several biochemical bone markers to assess high..., Fink [/bib_ref].The authors from the FIT concluded that the correlation between early reduction in bone turnover and long-term fracture reduction during alendronate treatment was at least as strong as that observed with 1-year changes in BMD. For patients with a decrease of 30% in bone turnover, compared with those with a decrease of < 30%, the risk of experiencing a fracture at the end of the trial was significantly lower for spine and hip [bib_ref] Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated..., Bauer [/bib_ref]. In the risedronate vertebral fracture trial, the relationship between vertebral fracture risk and changes from baseline in sCTX and uNTX were not linear (p < 0.05). There was little further improvement in fracture benefit below a decrease of 55-60% for sCTX and 35-40% for uNTX. The authors concluded that the decrease in bone resorption in patients taking risedronate accounts for a large proportion of the reduction in fracture risk but that there may be a level of bone resorption reduction below which there is no further fracture benefit [bib_ref] Relationship of early changes in bone resorption to the reduction in fracture..., Eastell [/bib_ref]. With continuous (2.5 mg daily) or intermittent (20 mg every other day for 12 doses every 3 months) oral doses ibandronate which were linked to a significant reduction in spinal fractures, similar to that seen with alendronate or risedronate, the rate of bone turnover was reduced by 50-60%, a magnitude also within the range observed with the efficacious oral bisphosphonates [bib_ref] Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction..., Delmas [/bib_ref]. For further clinical development of ibandronate, even the role of BTM as a predictor of efficacy was emphasised. Actually, a pharmacokinetic-pharmacodynamic model, accurately describing the urinary excretion of CTX was used to select the appropriate once-monthly dose of ibandronate [bib_ref] Clinical utility of a pharmacostatistical model for ibandronate in postmenopausal osteoporosis, Reginster [/bib_ref].Clinical studies showing the noninferiority and ⁄ or superiority of the 150 mg monthly oral regimen on BMD, over the daily 2.5 mg dose, the dose which previously demonstrated anti-fracture efficacy [bib_ref] Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2-year results..., Reginster [/bib_ref] , confirmed a posteriori the interest of a pharmacostatistical model based on BTM changes to predict the effect of a particular dosage of ibandronate on hard end-points [bib_ref] A new concept for bisphosphonate therapy: a rationale for the development of..., Reginster [/bib_ref]. Data from randomised clinical studies of ibandronate, given orally or intravenously, in different doses and for variable time intervals to women with osteo-porosis, were examined to explore the relationship between intermittent bisphosphonate therapy, changes in bone resorption and fracture risk. The magnitude of the reduction in the rate of bone resorption at the end of the drug-free interval, rather than its fluctuation pattern after bisphosphonate administration, determines anti-fracture efficacy, provided that these fluctuations occur within the premenopausal range [bib_ref] Changes in bone remodelling and antifracture efficacy of intermittent bisphosphonate therapy:implications from..., Papapoulos [/bib_ref]. ## Monitoring bisphosphonate treatment Bisphosphonate therapy inhibits bone resorption and decreases the rate of bone remodelling. So, BTM can be used to measure the effect of an anti-resorptive treatment. However, determining a threshold of BTM to attain an optimal long-term effect is not obvious. ## Setting objectives As opposed to the WHO definition of osteoporosis on basis of a low BMD, currently unanimously accepted criteria to categorise low or high bone turnover, compared with premenopausal state, are not available. Furthermore, as for BMD, there is some overlap between healthy pre-and postmenopausal women, as well as between osteopenic and osteoporotic populations in the values of bone remodelling parameters [bib_ref] Biochemical markers of bone metabolism in the assessment of osteoporosis: useful or..., Seibel [/bib_ref]. The objective should be the return of BTM levels to the premenopausal range. However, half of the women with osteoporosis have BTM levels within the premenopausal range. In these patients, the goal should be a decrease at least equal to the least significant change (LSC). It is interesting to underline that changes in BMD do not explain alone the anti-fracture efficiency of treatment: some patients with unchanged or even decreased BMD may be protected against fracture. Thus, as for determining fracture risk, BTM could be complementary to BMD to predict the anti-fracture efficacy. ## Adherence and persistence In a study testing the impact of monitoring on adherence and persistence with anti-resorptive treatment, physician's reinforcement on adherence to bisphosphonate treatment, using BTM resulted in a lower incidence of new radiologically determined vertebral fractures (odds ratio 0.4; 95% CI: 0.2-1.0). The positive impact of a positive feedback to the patient (by telling him his BTM levels were decreased) was only seen when the decrease in BTM levels was marked (> 30% decrease) [bib_ref] The impact of monitoring on adherence and persistence with antiresorptive treatment for..., Clowes [/bib_ref]. In a randomised controlled trial, monitoring on adherence to and persistence with anti-resorptive treatment were performed by nursing staff. The use of BTM and the supplying of complementary information on the importance of compliance for treatment response were compared with no monitoring. In the monitored group, cumulative adherence to therapy was increased by 57% (p = 0.04), with a trend to persist with therapy for 25% longer (p = 0.07), both compared with no monitoring. However, feedback on BTM alone or nurse-monitoring alone did not show any difference in adherence or persistence rates. Nevertheless, adherence at 1 year was correlated with BMD increase (hip; r = 0.28; p = 0.01) and percentage change in uNTX (r = )0.36; p = 0.002) as response to treatment efficacy [bib_ref] Effect of monitoring bone turnover markers on persistence with risedronate treatment of..., Delmas [/bib_ref]. We should also be aware that a negative feedback (by telling there is no reduction in BTM) could stimulate the patient in his noncompliance. ## Limitations of btm use: variability The production of BTM depends not only on the rate of bone turnover, but also on the skeletal size, reflecting mainly trabecular bone turnover, which is 4 to 5 times more active than cortical bone. A localised bone disease, bed rest and fracture healing can interfere with values. For urine markers, the expression as a ratio to creatinine introduces another factor of variability. The relationship between the measured concentration and what happens in the bone differs intra-and inter-individually. Inter-individual variability is largely determined by differences in age, gender and menopausal status. ## Analytical variability With the improvement in analytical methods, particularly with the introduction of automated immunoassays, the analytical CV remains around 5%. The absence of uniform standardisation still is a concern and makes it difficult to compare values obtained by different methods in different laboratories [bib_ref] Interlaboratory variation of biochemical markers of bone turnover, Seibel [/bib_ref]. That is the reason why all measurements for one individual should be done in the same laboratory. So, the main source of variability is preanalytical, mostly sample conservation and biological variability. ## Conservation variability Concerning sample conservation, osteocalcin and acid phosphatase are the most difficult to handle. Collagen peptides and alkaline phosphatase are much more resistant to degradation. Pyridinoline crosslinks are light sensitive and degraded under the influence of intense UV irradiation. ## Biological variability In adults, the main source of undesirable but controllable biological variability is the circadian rhythm, with higher values in the early morning hours, then a steep decrease in the morning, to attain a nadir at the end of the afternoon [bib_ref] Biochemical markers of bone turnover. Part I: Biochemistry and variability, Seibel [/bib_ref] [bib_ref] Preanalytical variability of biochemical markers of bone turnover, Hannon [/bib_ref]. Most markers follow the same pattern, with the exception of alkaline phosphatase because of its longer half-life. The steepest decline during the morning has been described for serum CTX, but it is attenuated if the patients remain in the fasting state. Practically, it implies that the sampling time for measuring bone markers has to be strictly controlled. There is also a seasonal variation in bone turnover, due in part to fluctuations of vitamin D repletion. ## Serum vs. urine markers Many studies have shown that the intra-individual variability is around 10% for serum markers and between 15% and 25% for urine markers. So, the signal to noise ratio is better for serum markers. This has important consequences for follow up. Indeed, if a marker is measured once, the confidence interval of the result is ±1.96 · SD. The LSC, defined as a difference reflecting a real change with a 5% chance of type 1 error (false-positive), is a change surpassing 2.8 · CV. Thus, for a CV of 10%, a change of at least 25-30% must be observed for serum markers to consider that there is a significant evolution, while a change of 40-70% is required for urine markers. Fortunately, decreases in this order of magnitude are observed in individual patients with anti-resorptive therapy. However, one must be aware of the risk of type 2 error (false-negative), and it must be avoided to change treatment on the basis of an insufficient evolution, at least on two sequential measurements only. ## Consensus of the belgian bone club Choice of markers - Serum markers do not need correction for glomerular filtration rate; automated technology for measurement available for serum CTX and serum P1NP. - Osteocalcin not optimal in routine clinical practice because of its fragility. - Serum BSAP can be added in patients without liver problems (less sensitive to circadian rhythm). - Measurements for one individual must be performed in the same lab using standard procedures; samples should be taken while fasting and always at the same time of day. - There are no data to determine the optimal postintake period to take a blood sample for follow-up of the markers, but at least 7 days after the intake seems to have some support, understanding that it is always the same period in one individual patient. ## Use of markers (pretreatment) - Baseline BTM levels cannot be the base of antiresorptive drug choice, nor do they predict treatment effect. - Bone turnover markers are an independent risk factor of fracture. ## Use of markers (follow-up) - This use relies on the definition of LSC (around 30% for serum markers and 50-60% for urine markers). - Only a decrease higher than the LSC can be interpreted as showing a biological effect. - Early changes in BTM (baseline vs. posttreatment) show a biological effect of the medication, proving patient compliance and persistence. - The early decrease in BTM level is probably predictive of bone gain and anti-fracture efficacy. However, it is not known to which level BTM should be decreased to optimise anti-fracture efficacy. - As we cannot link BTM decrease to a threshold, using premenopausal range seems a rational objective to achieve. 1 The levels of osteoporotic patients whose BTM levels are still in premenopausal range must still decrease by 30%. 2 Premenopausal ranges have been well defined. 3 Analytical differences must be resolved by using the same lab for one individual patient. # Funding Payment by Roche and GSK of honoraries for expert meetings and preparatory work. [table] Table 1: Consensus of the Belgian Bone Club regarding the use of bone turnover markers: in practice [/table]	None	https://europepmc.org/articles/pmc2705815?pdf=render	Objectives: To review the clinical value of bone turnover markers (BTM), to initiate and/or monitor anti‐resorptive treatment for osteoporosis compared with bone mineral density (BMD) and to evaluate suitable BTM and changes in BTM levels for significance of treatment efficiency.
65791a6de747c45811e85496e471c89960633250	pubmed	British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults	British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss. Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel. IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease-with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.EXECUTIVE SUMMARY OF RECOMMENDATIONS AND PRACTICE STATEMENTS Background1. Iron deficiency anaemia (IDA) is common, and a major cause of morbidity worldwide (evidence quality-high, consensus-100%, statement strength-strong). 2. IDA can be caused by a range of GI pathologies including cancer, and so GI investigation on an urgent basis should be considered in adults with a new diagnosis of IDA without obvious explanation (evidence quality-high, consensus-85%, statement strength-strong).Definitions3. We recommend that anaemia is defined as a haemoglobin (Hb) concentration below the lower limit of normal for the relevant population and laboratory performing the test (evidence quality-medium, consensus-100%, statement strength-strong). 4. We recommend that iron deficiency should be confirmed by iron studies prior to investigation. Serum ferritin is the single most useful marker of IDA, but other blood tests (eg, transferrin saturation) can be helpful if a false-normal ferritin is suspected (evidence quality-medium, consensus-92%, statement strength-strong). 5. We recommend that a good response to iron therapy (Hb rise ≥10 g/L within a 2-week timeframe) in anaemic patients is highly suggestive of absolute iron deficiency, even if the results of iron studies are equivocal (evidence quality-medium, consensus-100%, statement strength-strong).Initial clinical assessment 6. We recommend taking a detailed history, as it may provide important clues as to the cause(s) of IDA in the individual case (evidence quality-low, consensus-100%, statement strength-strong). 7. We recommend that initial investigation of confirmed IDA should include urinalysis or urine microscopy, screening for coeliac disease (CD) and in appropriate cases, endoscopic examination of the upper and lower GI tract (evidence quality-moderate, consensus-85%, statement strength-strong). 8. CD is found in 3%-5% of cases of IDA, and we recommend that it should be routinely screened for serologically, or on small bowel biopsy at the time of gastroscopy (evidence quality-high, consensus-84%, statement strength-strong). 9. Age, sex, Hb concentration and mean cell volume are all independent predictors of risk of GI cancer in IDA, and need to be considered as part of a holistic risk assessment. It follows that the cancer risk in iron deficiency without anaemia is low (evidence quality-high, consensus-92%, statement strength-strong).Guidelines10. There are insufficient grounds at present to recommend faecal immunochemical testing for risk stratification in patients with IDA. The evidence base is evolving rapidly, however, and on that basis, this guidance may therefore change (evidence quality-low, consensus-100%, statement strength-weak). 11. We recommend that in men and postmenopausal women with newly diagnosed IDA, gastroscopy and colonoscopy should generally be the first-line GI investigations.In those not suitable for colonoscopy, CT colonography is a reasonable alternative (evidence quality-moderate, consensus-100%, statement strength-strong).Follow-up and recurrent IDA12. Hb levels normalise with iron replacement therapy (IRT) in most cases of IDA, but IDA recurs in a minority of these on long-term follow-up (evidence quality-low, consensus-92%, statement strength-strong).Further evaluation of the small bowel13. In those with negative bidirectional endoscopy of acceptable quality and either an inadequate response to IRT or recurrent IDA, we recommend further investigation of the small bowel and renal tract to exclude other causes (evidence quality-moderate, consensus-85%, statement strength-strong). 14. We recommend capsule endoscopy as the preferred test for examining the small bowel in IDA because it is highly sensitive for mucosal lesions. CT/MR enterography may be considered in those not suitable, and these are complementary investigations in the assessment of inflammatory and neoplastic disease of the small bowel (evidence qualityhigh, consensus-100%, statement strength-strong). 15. After a negative capsule endoscopy of acceptable quality, we recommend that further GI investigation needs to be considered only if there is ongoing IDA after IRT (evidence qualityhigh, consensus-100%, recommendation-strong). 16. We recommend that long-term IRT may be an appropriate strategy when the cause of recurrent IDA is unknown or irreversible (evidence quality-low, consensus-100%, statement strength-strong).Treatment of IDA17. We recommend that IRT should not be deferred while awaiting investigations for IDA unless colonoscopy is imminent (evidence quality-high, consensus-100%, statement strength-strong). 18. We recommend that the initial treatment of IDA should be with one tablet per day of ferrous sulphate, fumarate or gluconate. If not tolerated, a reduced dose of one tablet every other day, alternative oral preparations or parenteral iron should be considered (evidence quality-medium, consensus-92%, statement strength-strong).Limited transfusion of packed red cells may on occasionbe required to treat symptomatic IDA, in which case IRT is still necessary post-transfusion (evidence quality-high, consensus-100%, statement strength-strong). 20. We recommend that patients should be monitored in the first 4 weeks for an Hb response to oral iron, and treatment should be continued for a period of around 3 months after normalisation of the Hb level, to ensure adequate repletion of the marrow iron stores (evidence quality-medium, consensus-92%, statement strength-strong).21.We recommend that parenteral iron should be considered when oral iron is contraindicated, ineffective or not tolerated. This consideration should be at any early stage if oral IRT is judged unlikely to be effective (see the Treatment section), and/or the correction of IDA is particularly urgent (evidence quality-high, consensus-92%, statement strength-strong). 22. There is insufficient evidence to support invasive investigation in non-anaemic iron deficiency unless there are additional indications (see the Definitions section), but periodic blood count monitoring is suggested (evidence quality-low, consensus-92%, statement strength-weak). 23. After the restoration of Hb and iron stores with IRT, we recommend that the blood count should be monitored periodically (perhaps every 6 months initially) to detect recurrent IDA (evidence quality-very low, consensus-85%, statement strength-strong).Special situations-young women24. IDA is common in young women, and major contributory factors include menstrual losses, pregnancy and poor dietary intake (evidence quality-high, consensus-100%, statement strength-strong). 25. Underlying GI pathology is uncommon in young women with IDA, and so after screening for CD, we recommend that further investigation is warranted only if there are additional clinical features of concern-as detailed in the text (evidence quality-moderate, consensus-92%, statement strength-strong). 26. If GI investigation in a pregnant woman is deemed necessary prior to delivery, gastroscopy and (after the first trimester) MR enterography are considered safe in pregnancy (evidence quality-low, consensus-91%, statement strength-strong).Special situations-young men27. Confirmed IDA is uncommon in young men, but when found we recommend that it warrants the same investigational algorithm as for older people (evidence quality-moderate, consensus-100%, statement strength-strong).Special situations-the elderly28. Iron deficiency is common in the elderly, and is often multifactorial in aetiology (evidence quality-high, consensus-100%, statement strength-strong). 29. We recommend that the risks and benefits of invasive endoscopic and alternative investigation(s) are carefully considered in those with major comorbidities and/or limited performance status (evidence quality-medium, consensus-92%, statement strength-strong).Special situations-specific comorbidities30. Functional iron deficiency (FID) is a common contributory factor to the anaemia associated with advanced chronic kidney disease (CKD) (evidence quality-high, consensus-92%, statement strength-strong). 31. Iron deficiency is common in chronic heart failure (CHF), and is often multifactorial (evidence quality-high, consensus-92%, statement strength-strong). 32. Parenteral IRT may improve symptoms and quality of life in CHF with FID (evidence quality-moderate, consensus-100%, statement strength-strong).Guidelines 33. In the management of iron deficiency associated with CKD or CHF, reference to the appropriate specialist published guidelines is recommended (evidence quality-moderate, consensus-92%, statement strength-strong). 34. IDA is a common manifestation of IBD, particularly when the disease is active (evidence quality-high, consensus-100%, statement strength-strong). 35. Intolerance and malabsorption of oral IRT can be particular problems in the treatment of IBD-associated IDA, and parenteral IRT may be required (evidence quality-medium, consensus-100%, statement strength-strong).Special situations-GI surgery36. IDA is common following resection or bypass surgery involving the stomach and/or small bowel, including bariatric surgery (evidence quality-high, consensus-92%, statement strength-strong). 37. In new presentations of IDA, we recommend that a history of GI or bariatric surgery should not preclude a search for other causes of IDA (evidence quality-low, consensus-85%, statement strength-strong).Service considerations38. We recommend that all service providers should have clear points of referral and management pathways for patients with IDA (evidence quality-low, consensus-100%, statement strength-strong). 39. To ensure efficient use of resources, we recommend that IDA pathways should be delivered by a designated team led by a senior clinician (evidence quality-low, consensus-100%, statement strength-strong). 40. We recommend that service providers should aim to have an ambulatory care base for the administration of parenteral iron (evidence quality-low, consensus-100%, statement strength-strong). # Abstract Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss. Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel. IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease-with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments. ## Executive summary of recommendations and practice statements background 1. Iron deficiency anaemia (IDA) is common, and a major cause of morbidity worldwide (evidence quality-high, consensus-100%, statement strength-strong). 2. IDA can be caused by a range of GI pathologies including cancer, and so GI investigation on an urgent basis should be considered in adults with a new diagnosis of IDA without obvious explanation (evidence quality-high, consensus-85%, statement strength-strong). ## Definitions 3. We recommend that anaemia is defined as a haemoglobin (Hb) concentration below the lower limit of normal for the relevant population and laboratory performing the test (evidence quality-medium, consensus-100%, statement strength-strong).. We recommend that iron deficiency should be confirmed by iron studies prior to investigation. Serum ferritin is the single most useful marker of IDA, but other blood tests (eg, transferrin saturation) can be helpful if a false-normal ferritin is suspected (evidence quality-medium, consensus-92%, statement strength-strong). 5. We recommend that a good response to iron therapy (Hb rise ≥10 g/L within a 2-week timeframe) in anaemic patients is highly suggestive of absolute iron deficiency, even if the results of iron studies are equivocal (evidence quality-medium, consensus-100%, statement strength-strong). Initial clinical assessment. We recommend taking a detailed history, as it may provide important clues as to the cause(s) of IDA in the individual case (evidence quality-low, consensus-100%, statement strength-strong). 7. We recommend that initial investigation of confirmed IDA should include urinalysis or urine microscopy, screening for coeliac disease (CD) and in appropriate cases, endoscopic examination of the upper and lower GI tract (evidence quality-moderate, consensus-85%, statement strength-strong). 8. CD is found in 3%-5% of cases of IDA, and we recommend that it should be routinely screened for serologically, or on small bowel biopsy at the time of gastroscopy (evidence quality-high, consensus-84%, statement strength-strong). 9. Age, sex, Hb concentration and mean cell volume are all independent predictors of risk of GI cancer in IDA, and need to be considered as part of a holistic risk assessment. It follows that the cancer risk in iron deficiency without anaemia is low (evidence quality-high, consensus-92%, statement strength-strong). 10. There are insufficient grounds at present to recommend faecal immunochemical testing for risk stratification in patients with IDA. The evidence base is evolving rapidly, however, and on that basis, this guidance may therefore change (evidence quality-low, consensus-100%, statement strength-weak).. We recommend that in men and postmenopausal women with newly diagnosed IDA, gastroscopy and colonoscopy should generally be the first-line GI investigations. In those not suitable for colonoscopy, CT colonography is a reasonable alternative (evidence quality-moderate, consensus-100%, statement strength-strong). ## Follow-up and recurrent ida 12. Hb levels normalise with iron replacement therapy (IRT) in most cases of IDA, but IDA recurs in a minority of these on long-term follow-up (evidence quality-low, consensus-92%, statement strength-strong). Further evaluation of the small bowel. In those with negative bidirectional endoscopy of acceptable quality and either an inadequate response to IRT or recurrent IDA, we recommend further investigation of the small bowel and renal tract to exclude other causes (evidence quality-moderate, consensus-85%, statement strength-strong). 14. We recommend capsule endoscopy as the preferred test for examining the small bowel in IDA because it is highly sensitive for mucosal lesions. CT/MR enterography may be considered in those not suitable, and these are complementary investigations in the assessment of inflammatory and neoplastic disease of the small bowel (evidence qualityhigh, consensus-100%, statement strength-strong).. After a negative capsule endoscopy of acceptable quality, we recommend that further GI investigation needs to be considered only if there is ongoing IDA after IRT (evidence qualityhigh, consensus-100%, recommendation-strong).. We recommend that long-term IRT may be an appropriate strategy when the cause of recurrent IDA is unknown or irreversible (evidence quality-low, consensus-100%, statement strength-strong). Treatment of IDA. We recommend that IRT should not be deferred while awaiting investigations for IDA unless colonoscopy is imminent (evidence quality-high, consensus-100%, statement strength-strong).. We recommend that the initial treatment of IDA should be with one tablet per day of ferrous sulphate, fumarate or gluconate. If not tolerated, a reduced dose of one tablet every other day, alternative oral preparations or parenteral iron should be considered (evidence quality-medium, consensus-92%, statement strength-strong).. Limited transfusion of packed red cells may on occasion be required to treat symptomatic IDA, in which case IRT is still necessary post-transfusion (evidence quality-high, consensus-100%, statement strength-strong).. We recommend that patients should be monitored in the first 4 weeks for an Hb response to oral iron, and treatment should be continued for a period of around 3 months after normalisation of the Hb level, to ensure adequate repletion of the marrow iron stores (evidence quality-medium, consensus-92%, statement strength-strong).. We recommend that parenteral iron should be considered when oral iron is contraindicated, ineffective or not tolerated. This consideration should be at any early stage if oral IRT is judged unlikely to be effective (see the Treatment section), and/or the correction of IDA is particularly urgent (evidence quality-high, consensus-92%, statement strength-strong).. There is insufficient evidence to support invasive investigation in non-anaemic iron deficiency unless there are additional indications (see the Definitions section), but periodic blood count monitoring is suggested (evidence quality-low, consensus-92%, statement strength-weak). 23. After the restoration of Hb and iron stores with IRT, we recommend that the blood count should be monitored periodically (perhaps every 6 months initially) to detect recurrent IDA (evidence quality-very low, consensus-85%, statement strength-strong). ## Special situations-young women 24. IDA is common in young women, and major contributory factors include menstrual losses, pregnancy and poor dietary intake (evidence quality-high, consensus-100%, statement strength-strong). 25. Underlying GI pathology is uncommon in young women with IDA, and so after screening for CD, we recommend that further investigation is warranted only if there are additional clinical features of concern-as detailed in the text (evidence quality-moderate, consensus-92%, statement strength-strong). 26. If GI investigation in a pregnant woman is deemed necessary prior to delivery, gastroscopy and (after the first trimester) MR enterography are considered safe in pregnancy (evidence quality-low, consensus-91%, statement strength-strong). ## Special situations-young men 27. Confirmed IDA is uncommon in young men, but when found we recommend that it warrants the same investigational algorithm as for older people (evidence quality-moderate, consensus-100%, statement strength-strong). Special situations-the elderly. Iron deficiency is common in the elderly, and is often multifactorial in aetiology (evidence quality-high, consensus-100%, statement strength-strong).Anaemia affects about a third of the global population and is a major cause of morbidity worldwide. Iron deficiency is one of the dominant causes, and the resulting anaemia (iron deficiency anaemia (IDA)) has a point prevalence of 2%-5% among adult men and postmenopausal women in the developed world.IDA is the most common form of anaemia seen in primary care in the UK. It is estimated to account for more than 57 000 emergency admissions to UK hospitals each year, costing the National Health Service (NHS) more than £55 million per annum.While menstrual loss is commonly the cause of IDA in premenopausal women, IDA in adult men and postmenopausal women is often due to chronic blood loss from the GI tract. IDA may be the first presenting manifestation of colonic or oesophago-gastric carcinoma, highlighting the importance of swift and complete investigation. There are however many other recognised causes of IDAincluding malabsorption (most commonly from coeliac disease (CD) in the UK), poor dietary intake, blood donation, gastrectomy and use of non-steroidal anti-inflammatory drugs (NSAIDs). IDA is often multifactorial, and dual pathology (ie, significant disease in both upper and lower GI tract) is found in 1%-10% of cases-this should be particularly considered in the older patient. IDA may present in primary care, or across a range of specialties in secondary care, and historically the management of IDA was often suboptimal-with investigation being slow, inadequate or incomplete.Over recent years, however, the recognition that IDA may reflect serious underlying GI pathology has resulted in increasing involvement of gastroenterology services. IDA may now account for 10% or more of all gastroenterology referrals, and a typical district hospital unit in the UK with a catchment of 250 000 may have in excess of 400 IDA referrals per annum. ## Scope The objective of these guidelines is to summarise contemporary evidence on the diagnosis and management of IDA in adults, and to provide recommendations based on this in the light of developments since the original publication in 2000, last updated in 2011.The guidelines are primarily intended for health professionals in primary and secondary care in the UK, though many aspects are relevant to health services elsewhere in the world. # Method These guidelines were commissioned by the British Society of Gastroenterology (BSG) in 2018, following a proposal approved by the Clinical Standards and Services Committee. They were developed in accordance with the BSG guideline process (revised version 2018) and the Agree II instrument. A committee of 13 members was convened from interested individuals representing a range of disciplines including gastroenterology, haematology, specialist nursing and patient groups, under the co-chairmanship of AFG and NB. Two lay members on the Guideline Committee represented patients and the general public. Following discussion of the scope and purpose of the guidelines and the key issues, a formal literature search was undertaken by the National Guidelines Centre using all subcategories of the term "iron deficiency anaemia". Leads were identified to oversee the writing of section drafts based on a review of the relevant literature, and to produce draft sets of recommendations relevant to each section: Definitions-WT; Initial assessment-JS; Coeliac disease and further evaluation-RS; Treatment-ILPB; Special situations-MP, NB, AFG; Service considerations-RL. JS led on collating the consensus statements and editing the section drafts into a unified guideline document. These recommendations were subject to three rounds of anonymised consensus voting by the full committee in an eDelphi exercise during 2020 using an online platform (ECD Solutions, Columbus, USA). Recommendations were modified in the light of feedback from previous rounds, and those reaching a consensus of over 80% were incorporated into the final document. For each statement, section leads provided a grading of the quality of the supporting evidence, and the strength of the recommendation-these assessments were all ratified by the co-chairs. The quality of the supporting evidence was semiquantified using the GRADE system (high, moderate, low, very low).The recommendation strength (strong, weak) was based on the evidence quality, but as in many cases this was low or very low, a range of other factors were considered including (as appropriate) the degree of consensus, the perceived risk/benefit balance, patient views, resource costs and expert opinion. Information regarding evidence quality, eDelphi consensus and recommendation strength is summarised for each statement in the executive summary. The final document was read and approved by all members of the guideline committee, and formally assessed and approved by the Clinical Services and Standards Committee of the BSG. ## Definitions 3. We recommend that anaemia is defined as a haemoglobin (Hb) concentration below the lower limit of normal for the relevant population and laboratory performing the test (evidence quality-medium, consensus-100%, statement strength-strong). 4. We recommend that iron deficiency should be confirmed by iron studies prior to investigation. Serum ferritin is the single most useful marker of IDA, but other blood tests (eg, transferrin saturation) can be helpful if a false-normal ferritin is suspected (evidence quality-medium, consensus-92%, statement strength-strong). 5. We recommend that a good response to iron therapy (Hb rise ≥10 g/L within a 2-week timeframe) in anaemic patients is highly suggestive of absolute iron deficiency, even if the results of iron studies are equivocal (evidence quality-medium, consensus-100%, statement strength-strong). ## Anaemia The WHO defines anaemia as a haemoglobin (Hb) concentration below 130 g/L in men over 15 years of age, below 120 g/L in non-pregnant women over 15 years of age and below 110 g/L in pregnant women in the second and third trimester. The diagnostic criteria for anaemia in IDA vary between published studies.The normal range for Hb also varies between different populations in the UK. It is reasonable to use the lower limit of the normal range for the laboratory performing the test to define anaemia, but these should be aligned with the WHO defined lower limits.There is little consensus as to the level of anaemia that requires investigation. The National Institute for Health and Care Excellence (NICE) referral guidelines in the UK for suspected lower GI cancer suggest that IDA with an Hb concentration <110 g/L in men or <100 g/L in non-menstruating women warrants fast-track referral.These cut-off values will however miss some cases of colorectal cancer, especially in men. It is therefore advised that investigation should be considered at any level of anaemia in the presence of iron deficiency, though the case is stronger in those with more severe degrees of anaemia, as they are more likely to have serious underlying GI pathology. Iron deficiency Automated cell counters provide measurements of the changes in red cells that accompany iron deficiency including reduced mean cell Hb (MCH)-hypochromia; and reduced mean cell volume (MCV)-microcytosis.MCH is probably a more reliable marker of iron deficiency as it is less dependent on storage and the counting machine used, and a reduction is seen in both absolute and functional iron deficiency (FID). MCH may also be more sensitive for iron deficiency than MCV.Both microcytosis and hypochromia lose sensitivity for iron deficiency in the presence of chronic disease, thalassaemia or vitamin B12/folate deficiency.The specificity of MCV and MCH for iron deficiency is limited, as microcytosis and hypochromia also occur in many haemoglobinopathies (such as thalassaemia, when the MCV is typically reduced out of proportion to the level of anaemia), in sideroblastic anaemia and in some cases of anaemia of chronic disease. To prevent unnecessary GI investigation, Hb electrophoresis is recommended in those with microcytosis and normal iron studies, particularly if there is an appropriate ethnic background. The serum markers of iron deficiency include low ferritin, low transferrin saturation, low iron, raised total iron-binding capacity, raised red cell zinc protoporphyrin, increased serum transferrin receptor (sTfR), low reticulocyte Hb (Retic-Hb) and raised percentage hypochromic red cells. Serum ferritin (SF) is the most specific test for iron deficiency in the absence of inflammation. An SF level of <15 µg/L is indicative of absent iron stores, while SF levels of less than 30 µg/L are generally indicative of low body iron stores. The lower limit of normal for most laboratories, therefore, lies in the range 15-30 µg/L.As SF is an acute phase protein, however, apparently normal levels may occur with iron deficiency in the context of an inflammatory disease process.An SF cut-off of 45 µg/L has been suggested as providing the optimal trade-off between sensitivity and specificity for iron deficiency in practice.An SF value above 150 µg/L is unlikely to occur with absolute iron deficiency, even in the presence of inflammation.In summary, an SF <15 µg/L is highly specific for iron deficiency (specificity 0.99). A cut-off of 45 µg/L provides a respectable specificity of 0.92, and figures below this may warrant consideration of GI investigation, especially in the context of a chronic inflammatory process with anaemia. ## Guidelines The sTfR concentration is a good marker of iron deficiency in otherwise healthy subjects,but it can also be raised where there is increased erythropoietic drive such as with haemolytic anaemias, thalassaemias and Hb E 29 -and most UK hospitals do not provide this test. The [sTfR/log 10 ferritin] ratio may provide superior discrimination to either test on its own, particularly in chronic disease.A therapeutic trial of oral iron replacement therapy (IRT) for 2-4 weeks may aid with the diagnosis of IDA, but is dependent on compliance. A ≥10 g/L rise in Hb over a 2-week period is highly sensitive for absolute iron deficiency.While further tests to confirm iron deficiency are occasionally necessary, estimation of iron concentration in bone marrow is invasive, often subjective and difficult to justify in most cases. After excluding thalassaemia carriage, low Retic-Hb provides evidence of iron restriction, and should be considered in the laboratory work-up of anaemia particularly where there is chronic renal impairment.Retic-Hb is reported to be a more reliable marker of iron restriction than sTfR in healthy blood donors.An early indicator of response to iron therapy in IDA is provided by a rising Retic-Hb on day 4, 39 similar to the observation of a falling percentage of hypochromic red cells in response to therapy.An algorithm for the diagnostic approach to IDA is suggested in . ## Functional iron deficiency Absolute iron deficiency describes a situation where body iron stores are inadequate to meet demands, while in FID the supply of iron for erythropoiesis is inadequate despite apparently normal iron stores in cells of the monocyte-macrophage system. This restrictive effect is modulated by hepcidin, which also limits iron absorption through the gut mucosa. A common clinical setting for FID is CKD, where parenteral iron therapy facilitates the response to administered erythropoietin to correct anaemia. FID is also one element of the anaemia of chronic disease, occurring in many chronic inflammatory conditions such as rheumatoid arthritis and IBD. A detailed discussion of the complex pathogenesis of the anaemia of chronic disease is beyond the scope of these guidelines. An area of difficulty is establishing whether patients with presumed FID (with raised inflammatory markers and an SF in the normal range) have reduced iron stores indicative of absolute deficiency. When attributing anaemia to FID, it is important to consider whether there is sufficient evidence of a chronic illness. Evidence from studies in CKD suggests that in the absence of thalassaemia, the percentage of hypochromic red cells and Retic-Hb are superior to transferrin saturation in predicting the response to intravenous iron therapy.A transferrin saturation of <20% is indicative of iron restriction, particularly in thalassaemia carriers.Similar evidence that low Retic-Hb is an independent marker of iron restriction in the non-CKD setting,and for example provides a reliable marker of iron stores in patients with IBD.A very low hepcidin level is more commonly seen in absolute than FID, and may therefore indicate the probability of a response to oral IRT,but few UK laboratories offer this test. A good haematological response to a trial of oral iron suggests absolute iron deficiency rather than FID. Given that chronic inflammatory conditions are common and that SF values may therefore be difficult to interpret, it is important to use additional clinical and laboratory information when considering whether further GI investigations are warranted. Clinical features (eg, bowel-related symptoms), inflammatory markers (eg C-reactive protein (CRP)), transferrin saturation, red cell hypochromia and response to oral IRT can all be helpful in this complex clinical setting. ## Non-anaemic iron deficiency The development of anaemia from iron deficiency goes through an initial phase where body iron stores are depleted resulting in hypoferritinaemia, but the Hb concentration is still within the normal range (non-anaemic iron deficiency (NAID)). For example, in a study of young women with menorrhagia, over half had reduced iron stores but only 25% were actually anaemic.The overall prevalence of significant underlying GI pathology, and in particular of GI malignancy, is low in NAID.In the absence of other pointers, GI investigation generally is not warranted in premenopausal women since the cause is likely to be menstrual blood loss and/or recent pregnancy (see the Special situations section). The threshold for investigation of NAID should however be low in men, postmenopausal women, and those with GI symptoms or a family history of GI pathology. ## Initial clinical assessment ## We recommend taking a detailed history, as it may provide important clues as to the cause(s) of ida in the individual case (evidence quality-low, consensus-100%, statement strength-strong). ## We recommend that initial investigation of confirmed ida should include urinalysis or urine microscopy, screening for coeliac disease (cd) and in appropriate cases, endoscopic examination of the upper and lower gi tract (evidence quality-moderate, consensus-85%, statement strength-strong). 8. CD is found in 3%-5% of cases of IDA, and we recommend that it should be routinely screened for serologically, or on small bowel biopsy at the time of gastroscopy (evidence quality-high, consensus-84%, statement strength-strong). 9. Age, sex, Hb concentration and mean cell volume are all independent predictors of risk of GI cancer in IDA, and need to be considered as part of a holistic risk assessment. It follows that the cancer risk in iron deficiency without anaemia is low (evidence quality-high, consensus-92%, statement strength-strong). 10. There are insufficient grounds at present to recommend faecal immunochemical testing for risk stratification in patients with IDA. The evidence base is evolving rapidly, however, and on that basis, this guidance may therefore change. (evidence quality-low, consensus-100%, statement strength-weak). ## We recommend that in men and postmenopausal women with newly diagnosed ida, gastroscopy and colonoscopy should generally be the first-line gi investigations. in those not suitable for colonoscopy, ct colonography is a reasonable alternative (evidence quality-moderate, consensus-100%, statement strength-strong). ## Service provision IDA is a common clinical problem with fairly clear diagnostic criteria, a degree of case homogeneity, and straightforward algorithms for treatment and investigation.These features make the condition eminently suitable for streamlined management in dedicated nurse-led IDA clinics, as have been developed in a number of units around the UK.An algorithm for the management approach to IDA is suggested in figure 2. ## History and examination Clinical assessment of a subject with IDA may reveal manifestations of anaemia (eg, breathlessness, fatigue, heart failure) Guidelines Algorithm for the diagnosis of iron deficiency anaemia. ACD, anaemia of chronic disease; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Hb, haemoglobin; IRT, iron replacement therapy. Algorithm for the management of IDA. Section reference key: 1-diagnosis, 2-treatment, 3-clinical assessment, 4-coeliac disease, 5-further evaluation. IDA, iron deficiency anaemia; IRT, iron replacement therapy; OGD, oesophago-gastroduodenoscopy. and on occasion more specifically of iron deficiency (such as angular stomatitis, glossitis, koilonychia, restless legs syndrome, pagophagia (a craving for ice), blue sclerae). A personal or family background of GI disease may provide a clue as to the cause of IDA. A family history of true iron-refractory IDA is rare, but if given may suggest a genetic disturbance of the pathway controlling iron absorption.Even if present, abdominal symptoms are not a reliable guide to the presence, nature or location of underlying GI pathology.Physical examination is generally unremarkable, but may on occasion provide the diagnosis, for example, in hereditary haemorrhagic telangiectasia. ## Guidelines There are many potential contributors to a negative iron balance, leading to IDA (see. Particular risk factors that should be sought include chronic overt blood loss (eg, nosebleeds, menstruation), blood donation, inadequate dietary intake, longterm NSAID usage and previous resectional or bypass surgery of the GI tract. More recently it has been recognised that long-term proton pump inhibitor(PPI) therapy may contribute to the risk of iron deficiency,presumably as a result of impaired absorption secondary to hypochlorhydria, and that IDA is common in endurance athletes-the mechanism is uncertain, but high hepcidin levels may contribute.Iron deficiency is however often multifactorial, and so the presence of one or more of these risk factors should not necessarily be a deterrent to further GI investigation, particularly in older age groups. ## Preliminary investigations CD is a relatively common cause of IDA and should be routinely excluded in all age groups (see the later section). Renal tract pathology, in particular renal cell carcinoma, 57 is a wellrecognised though uncommon cause of IDA due to chronic blood loss, and so all subjects presenting with unexplained IDA should at least be checked for microscopic haematuria. Urine dipstick testing and mid-stream urine (MSU) analysis have limited sensitivity and specificity for renal tract pathology, but nevertheless, after exclusion of infection, a persisting positive result is an indication for urological investigation. ## Imaging of the gi tract how to investigate Standard practice is to examine the upper and lower GI tracts at gastroscopy and colonoscopy respectively, and many units undertake both procedures at the same session. This approach is more efficient than separate procedures and, given the patient is already prepared, simplifies the decision to proceed to colonoscopy if there are abnormalities of uncertain relevance to IDA in the upper GI tract. Given that most series have revealed some cases with dual unrelated pathology, the recommendation is to defer colonoscopy only if an upper GI cancer is found. Overall, investigation of the GI tract in IDA reveals potentially significant pathology in about a third of cases -there is a myriad of recognised GI causes, as outlined in table 1. CT colonography is an acceptable alternative to colonoscopy, and may be preferable in certain clinical situations, such as in the presence of major comorbidities. The advantage of CT colonography is that it is less invasive, does not require sedation and provides limited imaging of the other viscera. The disadvantage is that it does not identify more subtle mucosal pathology such as vascular malformations, and there may be some circumstances where a colonoscopy is subsequently required to obtain histology, remove a polyp, or insert a tattoo prior to laparoscopic resection. There is a limited place for contrast CT without bowel preparation in those with IDA and major comorbidities including frailty, accepting that this will only identify relatively gross pathology, and will miss some cancers. The value of investigating those where the outcome is unlikely to affect management does however need to be carefully considered (see the Special situations section). There is no longer a role for contrast fluoroscopy in the investigation of the upper and lower GI tract in IDA. Atrophic gastritis is a recognised contributor to the development of IDA, probably because of the impairment of iron absorption that accompanies all causes of achlorhydria.In support of this, subgroup analysis of a small study has suggested that atrophic gastritis may be commoner in those without a definite alternative explanation for IDA than in those with.Helicobacter infection has also been weakly associated with the risk of developing IDA,though it is unclear whether this reflects the effect of related pathologies such as peptic ulceration or atrophic gastritis. The same meta-analysis suggested that Helicobacter eradication does not improve the Hb response to IRT.It, therefore, remains to be established whether the cost of routine gastric biopsies in IDA is justified, given that the results are unlikely to directly alter management. 32 ## Who to investigate The investigation of IDA potentially involves a considerable workload with a relatively low yield, and so there is a strong case for targeting valuable investigational resources. Cancer is by far the most serious pathology underlying IDA, but even following previous guidelines advising investigation of males and postmenopausal women, cancer is only found in 8%-10% of cases -and the majority of investigations reveal no other significant abnormalities either. It is also important to bear in mind that premenopausal women do on occasion develop cancer in the GI tract, and that cancer is not the only GI pathology underlying IDA. There is therefore sometimes justification for investigating younger women-particularly if the IDA is severe or recurrent, and disproportionate to perceived menstrual losses (see the Special situations section). There is now evidence that individuals with IDA can be stratified for the risk of underlying GI cancer based on a set of simple and objective clinical variables-specifically age, sex, MCV and Hb concentration. The IDIOM App 63 has been developed to provide a swift estimate of GI cancer risk in IDA, which may help inform the patient discussion as to the potential benefit of investigation. Further refinement of the risk stratification process with the incorporation of additional clinical variables may allow the identification of sizeable subgroups who can safely avoid invasive procedures altogether. ## Role of faecal immunochemical testing The introduction of faecal immunochemical testing (FIT) for trace quantities of blood in the stool has provided a major step forward in risk stratification for those presenting with clinical features that are potentially due to colorectal cancer (CRC), and the value of it has been demonstrated in a series of large observational studies.FIT is currently recommended by NICE for determining whether IDA in the under-60 age group warrants fast-track referral-while this suggestion is logical, the evidence base is limited. The place of FIT in risk stratification for the IDA population as a whole-either as a stand-alone or in conjunction with established tools-remains to be established. There are reasons Guidelines for caution about a FIT-based triage system for IDA. First, CRC accounts for only a minority of the pathology found on the investigation of IDA, particularly in those under 60. Second, data from six recently published studies of real-world experience confirm that even at the low detection threshold of 10 µg/g, the sensitivity of FIT for CRC ranges from 83% to 91%.Furthermore, although numbers are small, there is the suspicion that IDA may be over-represented in the FIT negative CRC subgroup, accounting for 32 (40%) of the 81 pooled cases. The data are summarised in table 2. This conclusion is supported by a meta-analysis of the few IDA-specific studies in the published literature, which yielded a sensitivity of 83% of FIT for CRC, with concerns that this may be an over-estimate due to publication bias.Currently therefore we are unable to advocate the use of FIT for risk stratification or colorectal cancer exclusion in IDA, though this view may change with the appearance of a stronger evidence base. While it seems logical to consider the result of FIT in the overall assessment of the risk serious organic disease, safety netting is still required to ensure that serious pathology is not missed. BSG guidance will be updated as further evidence for the role of FIT in IDA is evaluated, and a BSG Association of Coloproctology of Great Britain and Ireland (ACPGBI) guidelines group has recently been commissioned to assess this. ## Coeliac disease and ida CD is found in 3%-5% of subjects investigated for unexplained IDA as demonstrated by studies from the UK, Europe, USA and Middle East. Duodenal biopsy histology remains the gold standard for exclusion or confirmation of the diagnosis. Coeliac serology-anti-tissue transglutaminase (tTG) or antiendomysial antibody-is however a useful screening test. A prospective study of 2000 referrals for gastroscopy (all indications including anaemia, mean age 56 years) with parallel serology and histology yielded both a sensitivity and a specificity of tTG IgA antibody for CD of 90.9%, with a negative predictive value of 99.6%.With emerging evidence on the reliability of serology with an anti-tTG IgA titre of greater than 10× the upper limit of normal,the BSG has issued interim guidance on a 'no biopsy' protocol in patients under the age of 50 years during the COVID-19 pandemic, provided they have no alarm symptoms. An updated guideline on the diagnosis of CD in adults is expected in 2022. Retrospective studies suggest that antibody-negative CD accounts for about 2% of the total coeliac population, though this may be an under-estimate due to ascertainment bias (seronegative subjects are less likely to get a biopsy), and the true figure may be nearer 10%. As standard serological screening tests are IgA-based, apparently seronegative CD can result from IgA deficiency. This only accounts for a minority of antibodynegative cases however, and screening for it may not be costeffective as the result only marginally changes the probability of CD. As the relative prevalence of seronegative CD is highest in the elderly, the sensitivity of coeliac serology for CD falls with age. This has importance in the investigation of IDA, where the incidence is highest in the elderly, and the median age at presentation is over 70.As the sensitivity of serology for CD can be as low as 74% in coeliacs presenting with IDA,it may be that an age-related approach to investigation is most appropriate. In a younger patient with IDA, where the sensitivity of serology for CD is high and the risk of other serious pathology low, a check on coeliac serology may be all that is required, with gastroscopy and biopsy only if the result is positive. Other factors of course may influence the need for further investigation-colonoscopy, for example, should be considered in those with a strong family history of colorectal cancer. In an older subject with IDA, the sensitivity of serology for CD is rather lower, while the probability of other pathology and in particular GI malignancy, is much higher, and dual pathology is more common.So a more appropriate approach in this situation might be bidirectional endoscopy (BDE) with duodenal biopsy to exclude CD. Presentation of CD in later life is well recognised, and indeed the seroprevalence of undiagnosed CD is similar to that in younger age-groups.CD in the elderly may however be more likely to present with manifestations of malabsorption, including IDA. There is conflicting evidence as to whether a diagnosis of CD over the age of 50 confers an increased cancer risk relative to the general population of the same age, but the possibility of a concurrent GI neoplasm should always be considered. Older patients with CD and IDA and any patient with alarm features should be considered for BDE, but no specific age or Hb cut-off can be recommended due to lack of published evidence. ## Follow-up and recurrent ida 12. Hb levels normalise with iron replacement therapy (IRT) in most cases of IDA, but IDA recurs in a minority of these on long-term follow-up (evidence quality-low, consensus-92%, statement strength-strong).. We recommend that long-term IRT may be an appropriate strategy when the cause of recurrent IDA is unknown or irreversible (evidence quality-low, consensus-100%, statement strength-strong). 23. After the restoration of Hb and iron stores with IRT, we recommend that the blood count should be monitored periodically (perhaps every 6 months initially) to detect recurrent IDA (evidence . IDA should be treated with IRT as detailed in the Treatment section, and if the initial investigation reveals the cause, it should obviously be addressed as appropriate. However, the majority of individuals presenting with unexplained IDA will have negative BDE, no evidence of CD, no other symptoms, and a complete and sustained haematological response to IRT. In this situation, the outlook is generally favourable, and there is no need for further investigation other than a periodic blood count after completion of IRT to check for recurrent IDA. In an era of Data for an arbitrary detection threshold of 10 µg/g is shown for direct comparison. FIT, faecal immunochemical testing; IDA, iron deficiency anaemia. limited resources, we would suggest checks at perhaps 3, 6, 12 and 24 months. Further investigation is however warranted if there is any evidence of active undiagnosed pathology. Pointers to this possibility include symptoms such as ongoing weight loss or chronic unexplained diarrhoea, persistently elevated inflammatory markers and the persistence or recurrence of IDA. Persistent IDA describes the situation where there is haematological evidence of ongoing iron deficiency despite adequate IRT, while in recurrent IDA the haematological abnormalities resulting from iron deficiency resolve with IRT, only to reappear at a later date. Depending on the circumstances, further investigation may involve repeat BDE, particularly if the original procedures were felt to have provided inadequate views or to be outdated. Detailed imaging of the small bowel is an important element of further assessment (see the Small bowel section). Finally, formal imaging of the renal tract should be considered regardless of the result of testing for microscopic haematuria, in view of the recognised association of renal cell carcinoma with IDA.Depending on the definition employed, IDA proves to be recurrent in the medium term in 12%-25% of cases following previous negative BDE and a complete response to IRT. Recurrent IDA will respond in most cases respond to further IRT. There are no established algorithms for the investigation of recurrent IDA, but our recommendation is to follow the principles outlined earlier. In particular, repeat BDE is advised if the previous investigations are outdated. There is no validated definition of this, but a threshold of 2 years has been suggested on the basis of limited evidence.The diagnostic yield of small bowel examination by capsule endoscopy (CE) is high in recurrent IDA unexplained by adequate imaging of the upper and lower GI tract (see the Small bowel section). The most common findings are vascular malformations (sometimes single but more commonly multiple) and Crohn's disease, though tumours account for a small percentage of cases. The prevalence depends on definitions, but in a significant minority of cases of recurrent IDA, no convincing cause is found despite comprehensive investigation of the GI and renal tracts. Long-term IRT is an appropriate management strategy when the cause of recurrent IDA is unknown or where it is irreversible, for example, secondary to atrophic gastritis or previous GI surgery. ## Further evaluation of the small bowel 13. In those with negative bidirectional endoscopy of acceptable quality and either an inadequate response to IRT or recurrent IDA, we recommend further investigation of the small bowel and renal tract to exclude other causes (evidence quality-moderate, consensus-85%, statement strength-strong). 14. We recommend capsule endoscopy as the preferred test for examining the small bowel in IDA because it is highly sensitive for mucosal lesions. CT/MR enterography may be considered in those not suitable, and these are complementary investigations in the assessment of inflammatory and neoplastic disease of the small bowel . ## After a negative capsule endoscopy of acceptable quality, we recommend that further gi investigation needs to be considered only if there is ongoing ida after irt (evidence quality-high, consensus-100%, statement strength-strong). CE is now the first-line test for assessment of the small bowel in the setting of covert bleeding/IDA, as it has a higher diagnostic yield than radiology. 90-92 A pooled diagnostic yield of 66.6% (95% CI 61% to 72%) has been reported in a systematic review of CE in IDA.Angioectasia, Crohn's disease and NSAID enteropathy are common findings, and factors such as transfusion dependence, increasing age and comorbidity all positively influence the diagnostic yield.A longer small bowel transit time on CE is also associated with a higher yield, so the possibility of missed pathology should be considered when transit is unduly rapid. The pathology found on CE is actually within reach of standard gastroscopy in up to 28% of cases. Such lesions include in particular Cameron's ulcers, gastric antral vascular ectasia and vascular anomalies high on the lesser curve. Repeating gastroscopy prior to CE in all patients is not cost-effective, but should be considered on an individual case basis, particularly if views were previously poor or there has been a major time lapse since the last gastroscopy. Similarly, lesions may be missed in the right colon, particularly in the elderly and when preparation has been suboptimal. While the pick-up rate for small bowel pathology is significantly higher in the elderly, there is emerging evidence of the value of CE in younger age groups with IDA, though with differences in aetiology. A retrospective European cooperative study of 220 cases under the age of 50 revealed significant pathology in 32%, neoplastic in 5%.On multivariate analysis, a low MCV and weight loss were independent predictors of significant pathology.The rebleeding potential is low following a negative CE, and a conservative approach can in general be followed.CE does however have a miss rate, importantly for small bowel tumours.Indications warranting additional investigation after a negative CE may include a further Hb drop of >40 g/L, and a change in presentation from occult to overt bleeding.In the context of suspected small bowel bleeding including IDA, there is limited evidence to support repeating CE after an initial negative study in cases where there remains a strong suspicion of undiagnosed pathology, with a yield of up to 45%. Device-assisted enteroscopy (DAE), an endoscopic technique that allows deep intubation of the small bowel, provides the option for endoscopic biopsy and/or therapy, but this is an invasive procedure, and the need for it should be directed by the findings on CE. Predictably, the diagnostic yield of doubleballoon enteroscopy is significantly higher if preceded by a positive CE than a negative one.Vascular lesions (angioectasia) are a common finding on CE, particularly in the elderly, and cohort studies have demonstrated that endoscopic ablation may reduce rebleeding rates and transfusion requirements. There are however no randomised controlled trials, and a systematic review has suggested that the rebleeding rate after ablation of small bowel angioectasia is not dissimilar to that of historical (untreated) controls.As angioectasia is a benign condition, conservative management with longterm IRT is therefore a reasonable alternative-particularly in the context of non-intrusive IDA and/or significant comorbidity. The majority of small bowel lesions underlying IDA are subtle vascular or inflammatory abnormalities, undetectable by conventional radiology. CT enterography (CTE) does however have a role in delineating small bowel tumours seen on CE, and the combination of arterial venous and phases is helpful in characterising vascular small bowel tumours and detecting metastases. In addition of course, CTE may reveal evidence of other neoplasia underlying IDA, such as lymphoma or tumours of the renal tract. Most series in the published literature on studies comparing CTE and small bowel endoscopy have combined cases of IDA Guidelines and overt small bowel bleeding. Meta-analyses have concluded that CTE and CE/DAE are best considered complementary investigations. CTE may have a higher yield for tumours, although this is a tentative conclusion due to small numbers. ..We recommend that the initial treatment of IDA should be with one tablet per day of ferrous sulphate, fumarate or gluconate. If not tolerated, a reduced dose of one tablet every other day, alternative oral preparations or parenteral iron should be considered (evidence quality-medium, consensus-92%, statement strength-strong). ## Treatment of ida ## We recommend that irt should not be deferred while awaiting investigations for ida unless colonoscopy is imminent (evidence ## Limited transfusion of packed red cells may on occasion be required to treat symptomatic ida, in which case irt is still necessary post-transfusion (evidence quality-high, consensus-100%, statement strength-strong). ## We recommend that patients should be monitored in the first 4 weeks for an hb response to oral iron, and treatment should be continued for a period of around 3 months after normalisation of the hb level, to ensure adequate repletion of the marrow iron stores (evidence quality-medium, consensus-92%, statement strength-strong). ## We recommend that parenteral iron should be considered when oral iron is contraindicated, ineffective or not tolerated. this consideration should be at any early stage if oral irt is judged unlikely to be effective (see text), and/or the correction of ida is particularly urgent (evidence quality-high, consensus-92%, statement strength-strong). ## There is insufficient evidence to support invasive investigation in non-anaemic iron deficiency unless there are additional indications (see text), but periodic blood count monitoring is suggested (evidence quality-low, consensus-92%, statement strength-weak). ## After the restoration of hb and iron stores with irt, we recommend that the blood count should be monitored periodically (perhaps every 6 months initially) to detect recurrent ida (evidence quality-very low, consensus-85%, statement strength-strong). The treatment of iron deficiency aims to (i) restore normal circulating Hb levels, (ii) replenish body iron stores, (iii) improve quality of life and (iv) improve physiological function. Successful IRT should achieve all of these outcomes. An algorithm providing an overview of the treatment of IDA is shown in , and the elements of this are discussed in more detail below. ## Oral irt It is usual to start treatment for IDA as soon as the diagnosis has been confirmed by laboratory investigation, so that the treatment and investigation of IDA proceed in parallel. There is usually a beneficial rise in Hb within 2 weeks of commencing oral IRT.Oral iron preparations often stain the stools and may cause constipation, so it is usual practice to pause these prior to bowel preparation for colonoscopy. Therefore, if a patient is to be investigated for IDA within 2 weeks, it would be appropriate to delay treatment until after the colonoscopy has been completed. There is no need to withhold oral iron before gastroscopy or CT colonography. Traditionally oral iron salts were taken as split dose, two or three times a day. More recent data suggest that lower doses and more infrequent administration may be just as effective, while probably associated with lower rates of adverse effects. In addition, it may be inconvenient for some people to find three periods during the day to take iron on an empty stomach. Various oral iron preparations are available in the UK. Traditional oral iron salts (ferrous sulfate, ferrous gluconate and ferrous fumarate) are inexpensive, effective, safe and readily available-and they remain the standard therapies for IDA. Their use is supported by considerable clinical experience and observational data. In a pooled analysis of trial data, 72.8% of patients with IDA demonstrated a satisfactory response to an oral iron formulation, defined as an Hb rise of >10 g/L within 2 weeks, though rates of normalisation of Hb were lower with continued bleeding or clinically evident GI disease.A Cochrane analysis in 2014 highlighted that the reviewed trials were of poor quality, but concluded that in comparison to placebo oral IRT significantly improves Hb levels in IDA, and probably reduces blood transfusion requirements.When given in standard doses there do not appear to be important differences in efficacy or adverse events,although side effects may be lower with less than daily dosing.Modified release preparations (table 3) release iron in the more distal small bowel beyond the areas of most active assimilation-they do not enhance iron absorption or reduce side effects,and their use is not recommended. The absorption of oral iron salts is significantly impaired if taken with food. Taking iron with meals can reduce bioavailability by up to 75%.This necessitates iron being taken either in the fasting state first thing in the morning or in periods between meals during the day. It is not clear how soon after oral iron food can be taken, but the inhibitory effect of tea on iron absorption dissipates within 60 min.Despite previous suggestions of benefit,coadministration of vitamin C with oral IRT is not recommended-a recent large randomised controlled trial has confirmed that it neither enhances the haematological response or rate of iron loading, nor diminishes side effects.Iron absorption from oral preparations is determined by a complex interplay involving total body iron stores, erythropoietic activity of the bone marrow, recent exposure of the small intestine to iron and systemic inflammation. Hepcidin is the most important inhibitor of iron absorption. Hepcidin levels follow a diurnal pattern and increase after oral iron intake, impairing fractional absorption of subsequent doses. Short-term studies of iron-depleted but otherwise healthy women have shown that oral doses of 60 mg elemental iron stimulate increased hepcidin levels for the next 24 hours, thus reducing subsequent iron absorption by 35%-45%.As a consequence, the overall absorption of iron from 60 mg of elemental iron taken once a day was similar to that from 60 mg two times a day. Therapy with low dose oral iron has been reported to be successful and safe in elderly patients with IDA-a daily dose of 15 mg of elemental iron was as effective as 50 mg or 150 mg in terms of the Hb response, with a lower incidence of adverse effects.There are limited data on outcomes at lower dosage frequencies. Alternate day dosing leads to a significantly increased fractional iron and total iron absorption in iron-depleted healthy women. Fractional iron absorption was significantly higher with alternate day administration of 100 mg or 200 mg elemental iron compared with daily dosing.Importantly, the overall iron absorption from 200 mg on alternate days was almost twice that from the equivalent dosage of 100 mg on consecutive days.In Overview of treatment algorithm for IDA. IDA, iron deficiency anaemia; IRT, iron replacement therapy. Guidelines a randomised trial comparing treatment regimes in subjects with IDA, 60 mg elemental iron two times a day produced a faster rate of Hb rise than 120 mg on alternate days (ie, half the equivalent daily dose), though similar Hb increments were seen with alternate day dosing after the same total dose had been given, with a significantly lower prevalence of nausea.Intermittent oral iron (defined as less frequently than daily) has been reported to be at least as effective as daily dosing in raising Hb levels in young women and during pregnancy, although less effective in boosting iron stores in the short-term. Intermittent oral iron is associated with a lower incidence of GI adverse events in pregnant women (relative risk 0.56; 95% CI 0.37 to 0.84).The optimal drug, dosage and timing of oral IRT for adults with IDA are not clearly defined, and the effect of alternate day therapy on compliance and ultimate haematological response are unclear. Based on the available literature, a once daily dose of 50-100 mg of elemental iron (eg, one ferrous sulfate 200 mg tablet a day) taken in the fasting state may be the best compromise option for initial treatment. Whatever agent and regimen are chosen, it is essential to monitor the initial haematological response, and modify as appropriate with apparent therapeutic failure. The best option for patients with significant intolerance to oral IRT (usually GI disturbance) is also unclear. Depending on the individual, oral ferric maltol, alternate day oral iron and parenteral iron are all options. The standard practice of switching to a different traditional iron salt is not supported by evidence. Ferric maltol is a relatively new preparation, which is licenced for the treatment of IDA of any cause. In patients with inactive IBD, previous intolerance to or failure of traditional iron salts and moderate IDA (Hb >95 g/L), 12 weeks of treatment with ferric maltol normalised the Hb in 63%-66% of cases. GI side effects and overall rates of treatment cessation were comparable to placebo.Due to a relatively low iron content, the rate of iron loading is comparatively slow with ferric maltol, but iron loading and tolerance were maintained during a year of active treatment, with normalisation of Hb in 89% of cases.Although more expensive than traditional iron salts, ferric maltol is considerably less expensive than parenteral irons. Blood transfusion is rarely required to treat IDA, first because most patients with slowly developing anaemia adapt to the resulting physiological stress. Second, as parenteral iron reliably produces a clinically meaningful Hb response with a week, it should always be considered as an alternative. Transfusion should therefore be reserved for those with severe symptomatic and/ or circulatory compromise. If used, packed red cells should be transfused in accordance with established good practice guidelines,and a target Hb of 70-90 g/L (80-100 g/L in those with unstable coronary artery disease) would be reasonable. Since a unit of packed red cells contains about 200 mg of elemental iron, it will not replenish the iron store deficit in severe IDA, and so restrictive transfusion should be followed by adequate iron replacement. There should be a prompt and measurable haematological response to the initiation of IRT, and early monitoring should detect those patients not responding to or intolerant to oral iron. Failure to respond to oral iron has many causes including non-compliance, malabsorption, systemic disease, bone marrow pathology, haemolysis, continued bleeding and concurrent deficiency of vitamin B12 or folic acid. The absence of an Hb rise of at least 10 g/L after 2 weeks of daily oral IRT is strongly predictive of subsequent failure to achieve a sustained haematological response (sensitivity 90.1%, specificity 79.3% for adequate subsequent response).In this situation, parenteral iron is more effective than continuing traditional oral therapy.Logistically it may be difficult to arrange monitoring 2 weeks after starting oral IRT in all cases. Indeed because of the lower doses of iron used in alternate day regimens, a 28-day review may be more appropriate.At this point, a rise in Hb of 20 g/L or into the normal range would be accepted as an adequate response.Whichever monitoring regimen is used, intolerance and/or ineffectiveness should be managed promptly and appropriately. For patients with intolerance or failure of Hb response at the 2-4 weeks point, alternate day traditional iron salts (if not already used) or ferric maltol may be alternatives to parenteral iron on those with mild-moderate anaemia (Hb >95 g/L). The tolerability and response should be assessed, and failure of the Hb to rise by 10 g/L at 4 weeks for alternate day iron, or 6 weeks for ferric maltol, indicates the need for parenteral IRT. Regular Hb monitoring is recommended to ensure an ultimately satisfactory response. The optimal interval is not clear, but every 4 weeks until the Hb is in the normal range seems reasonable. After normalisation of the Hb, oral iron needs to be continued to replenish the iron stores. Traditionally it has been recommended that oral iron is continued for 2-3 months to do this. However, the duration required and indeed the appropriate measure of true iron repletion are both unclear. In healthy, almost iron-replete subjects, 2 months of continued iron was considered sufficient.However, in patients with chronic disease, continuing blood loss, impaired absorption or GI inflammatory disease (where iron is lost from the GI mucosa), it is likely that a longer period would be required. ## Parenteral irt Parenteral IRT replenishes body iron stores more quickly than oral IRT. However, for the majority of patients with IDA, this is not translated into a clinical benefit in terms of rise in Hb.The Hb response to parenteral and oral iron is typically similar, 148 or marginally faster with parenteral iron-for example, 0.7 g/L higher after 23 days treatment in postoperative cases.A course of oral 200 mg ferrous sulfate once a day was as effective as a single ferric carboxymaltose infusion in restoring Hb after a GI haemorrhage.Therefore, the oral route is generally preferred on the grounds of cost and convenience with comparable efficacy. The intravenous route for IRT may however be preferable from the outset in those with ongoing significant bleeding, malabsorption due to GI disease, the combination of iron deficiency and anaemia of inflammation, or issues with administration (eg, severe dysphagia) or compliance. Parenteral iron may also be indicated in those failing to respond to oral IRT due to intolerance, pharmacodynamic failure or continued bleeding. Intravenous IRT has been shown to be superior to continuing oral therapy in cases with IDA that failed to show a significant Hb rise with oral IRT (defined as an increase of 10 g/L or more after 2 weeks),or had ongoing menorrhagia.A variety of parenteral iron preparations are available in the UK, and these all have the advantage of providing a much greater iron load per dose than oral iron. They all are more expensive than traditional oral iron preparations, and there are additional associated costs relating to the facilities, staffing and equipment required for administering infusions. Some preparations (ferric carboxymaltose), iron derisomaltose (previously iron isomaltoside 1000) and (low molecular weight) iron-dextran can effectively replenish total body iron stores in one or two infusions. Iron sucrose requires multiple infusions because the maximum dose per administration is 200 mg. Irondextran is rarely used, as the much longer time required for infusion (4-6 hours) means this is much less convenient than the other total dose preparations, which can be given over 15-40 min. The dose of parenteral iron may be calculated using the original Ganzoni formula.Modifications using a lower target Hb level (130 g/L) have also been used.Overall the different intravenous iron formulations appear equivalent in terms of the ultimate haematological response and safety, 152 but the total dose preparations provide more rapid replenishment of body iron stores, usually in just one or two infusions. Monitoring for a satisfactory Hb response after 2-4 weeks should be undertaken, and then as outlined below. ## Treatment of naid The efficacy of IRT for NAID (also termed isolated hypoferritinaemia) is unclear. There are limited studies in adults, with a variety of inclusion criteria and outcomes. A meta-analysis of these concluded that NAID was not significantly associated with physiological impairment assessed objectively by VO2 max or respiratory exchange ratio max (RERmax), and that IRT did not significantly improve either these parameters or maximal heart rate.There is however evidence that IRT may provide subjective improvement of fatigue, mental quality of life and subjective cognitive function in premenopausal women.Therefore, given the safety of the available iron preparations, it would be reasonable to offer treatment for NAID if symptomatic. ## Monitoring after irt The optimal follow-up protocol after IRT remains to be established, but given the possibility of recurrent IDA indicating underlying disease, and the prevalence of persistent anaemia after IRT seen in some real-world studies,periodic monitoring is advised. Once the Hb has reached the normal range, a check blood count 3-monthly for 12 months and then 6-monthly for 2-3 years would be reasonable. Although SF is a reliable measure of total body iron stores, there are insufficient data to recommend routine ferritin monitoring. ## Safety of irt GI adverse effects (such as nausea, diarrhoea, constipation) are much commoner with oral preparations, and there is no convincing evidence for the superiority of any of the readily available traditional iron salts. GI side effects are significantly commoner with oral ferrous sulfate than placebo (OR 2.32 (95% CI 1.74 to 3.08)) or parenteral iron (OR 3.05 (95% CI 2.07 to 4.48)), and there is no dose-effect relationship over the range 50-400 mg of elemental iron per day.Despite the high prevalence of mild side-effects, the rates of discontinuation in clinical trials due to adverse events are relatively low (0%-24%), though higher than rates of discontinuation of parenteral iron (0%-18%). Discontinuation of oral IRT seems to be commoner in observational and population studies, with reported rates of up to 40%. Infusion-related reactions are uncommon with modern intravenous iron preparations, but hypersensitivity-type and infusion reactions (approximate incidence-0.5%) are commoner than with oral iron or placebo.Serious adverse reaction rates are low, however, and similar for oral and parenteral iron preparations.Caution is advised regarding the use of parenteral iron in the context of acute and chronic infection, although studies have consistently shown no significant increase in clinically important infective episodes associated with the use of parenteral IRT. Infection should not be regarded as a contraindication to parenteral IRT if the risk/benefit assessment favours treatment of the anaemia, though it should be withheld in those with ongoing bacteraemia. Hypophosphataemia has been reported with all parenteral iron preparations. This seems to relate to the molecules complexed to the iron, rather than the iron itself. Rates of hypophosphataemia are higher with ferric carboxymaltose (58%) than with iron derisomaltose (4%) or iron sucrose (1%), but Guidelines the clinical importance of this has not been established. Most of the episodes are biochemically moderate (serum phosphate in the range 0.32-0.64 mmol/L) and asymptomatic, and resolve without the need for intervention. However, because of the rare association with hypophosphataemic osteomalacia, the Medicines and Healthcare products Regulatory Agency issued a recommendation in 2020 advising that serum phosphate levels should be monitored in those with risk factors for hypophosphataemia, and in those receiving long-term or multiple high-dose infusions of ferric carboxymaltose. 172 ## Special situations young women 24. IDA is common in young women, and major contributory factors include menstrual losses, pregnancy and poor dietary intake (evidence quality-high, consensus-100%, statement strength-strong). 25. Underlying GI pathology is uncommon in young women with IDA, and so after screening for CD, we recommend that further investigation is warranted only if there are additional clinical features of concern-as detailed in the text (evidence quality-moderate, consensus-92%, statement strength-strong). ## If gi investigation in a pregnant woman is deemed necessary prior to delivery, gastroscopy and (after the first trimester) mr enterography are considered safe in pregnancy (evidence quality-low, consensus-91%, statement strength-strong). The prevalence of IDA in otherwise healthy premenopausal women is 5%-12%. It usually reflects some combination of dietary insufficiency, menstrual losses, and increased demand for iron in pregnancy and breastfeeding.Multiple studies have analysed the yield of GI investigation in young women with IDA.As CD is found in up to 4% of cases, all premenopausal women with IDA should be considered for serological screening. Malignant tumours can occur in otherwise asymptomatic premenopausal women, but they are extremely uncommon-two studies suggesting a higher prevalence have been criticised on the grounds of selection bias. In general, therefore IDA in young women is not an indication for endoscopic investigation. There are however various situations where direct endoscopic investigation of premenopausal women with IDA may be appropriate. These include : ► Age over 50-as age is a strong predictor of the risk of malignancy in IDA. ► Non-menstruating women-for example, following hysterectomy. ► Associated red flag symptoms, as outlined in NICE referral guidelines.184 ► Indications of a major genetic risk of GI pathology-for example, colorectal cancer affecting two first-degree relatives, or one first-degree relative affected before the age of 50 years. ► Recurrent or persistent IDA which appears disproportionate to other potential causes of iron deficiency such as menstrual losses-accepting that this is usually a rather subjective judgement. Mild IDA is common in pregnancy. IRT should be encouraged, but there is no need for endoscopic investigation unless there are pointers to the presence of underlying GI pathology in the history or on coeliac serology. If further investigation prior to delivery is felt to be warranted, gastroscopy, duodenal biopsy and MR enterography are considered safe for mother and fetus in pregnancy, though the National Radiological Protection Board considers it prudent to avoid MRIs in the first trimester. There are insufficient data on the safety of colonoscopy in pregnancy, and because of the potential to cause serious adverse events, it should be only be considered for the most pressing of indications. 185 ## Young men ## Confirmed ida is uncommon in young men, but when found we recommend that it warrants the same investigational algorithm as for older people (evidence quality-moderate, consensus-100%, statement strength-strong). IDA is relatively uncommon in young men, but the yield of pathology on examination of the GI tract is considerably higher than in women of the same age. IDA in young men therefore generally warrants the same investigational algorithm as described for older people, unless a convincing explanation for it is evident. ## The elderly 28. Iron deficiency is common in the elderly, and is often multifactorial in aetiology (evidence quality-high, consensus-100%, statement strength-strong). ## We recommend that the risks and benefits of invasive endoscopic and alternative investigation(s) are carefully considered in those with major comorbidities and/or limited performance status (evidence quality-medium, consensus-92%, statement strength-strong). Anaemia is common in older people, affecting more than 20% of those over the age of 85 years, and more than 50% of residential/nursing home residents. The aetiologies responsible for anaemia in this age group are complex, and often multiple. Iron deficiency is however a contributory factor in about half of cases, sometimes associated with deficiencies of vitamin B12 and/or folate. Anaemia in older patients has been shown to contribute to worsening of physical performance, cognitive function and frailty.Iron deficiency in the elderly has many potential contributory causes including poor diet, reduced iron absorption, occult blood loss, medication (eg, aspirin) and chronic disease (eg, CKD, CHF). Blood loss from mucosal lesions may be compounded by concurrent antiplatelet/anticoagulant therapy. Older patients are more likely than younger ones to have more than one contributing cause. The diagnosis can be confirmed by measurement of ferritin and transferrin saturation, though the former may be difficult to interpret in the presence of coexisting inflammatory conditions. Evaluation of the upper and lower GI tract should be considered if IDA has been confirmed, though CT colonography may be a more attractive alternative to colonoscopy for some older individuals. The prevalence of malignancy and of dual unrelated pathology in this age group strengthens the case for imaging both the upper and lower GI tract.However, the potential risks and benefits of invasive investigation should be carefully weighed up in older adults, particularly those who are frail, have significant comorbidities or reduced life expectancy. Furthermore, these considerations should be discussed with each patient and his/her family, taking their views into account. As in other age groups, the cause of IDA cannot always be established despite thorough investigation. Oral iron administration remains the standard first-line treatment in most patients, but parenteral iron is a convenient and relatively safe alternative if oral iron is not tolerated. ## Specific comorbidities 30. Functional iron deficiency (FID) is a common contributory factor to the anaemia associated with advanced chronic kidney disease (CKD) (evidence quality-high, consensus-92%, statement strength-strong). ## Iron deficiency is common in chronic heart failure (chf), and is often multifactorial (evidence quality-high, consensus-92%, statement strength-strong). ## Parenteral irt may improve symptoms and quality of life in chf with fid (evidence quality-moderate, consensus-100%, statement strength-strong). 33. In the management of iron deficiency associated with CKD or CHF, reference to the appropriate specialist published guidelines is recommended (evidence quality-moderate, consensus-92%, statement strength-strong). 34. IDA is a common manifestation of IBD, particularly when the disease is active .. Intolerance and malabsorption of oral IRT can be particular problems in the treatment of IBD-associated IDA, and parenteral IRT may be required . Several chronic disorders such as CKD, CHF and IBD are associated with iron deficiency. While the cause of iron deficiency in these conditions is often multifactorial, altered production of hepcidin and ferroportin is thought to be a major contributory factor. Nevertheless, the presence of iron deficiency should be actively sought because IRT may improve patient outcomes.The assessment and management of iron deficiency in these conditions do have certain nuances, and consultation with detailed published guidelines is therefore recommended. Similar clinical considerations apply to other inflammatory disorders such as rheumatoid arthritis. ## Chronic kidney disease Anaemia is a frequent complication of CKD. CKD is a potential cause for anaemia in anyone with a glomerular filtration rate (GFR) of less than 60 mL/min/1.73m 2 . As the prevalence of anaemia increases with deteriorating renal function, CKD is especially likely to be the cause of anaemia when the GFR is less than 30 mL/min/1.73m 2 . The investigation and management of anaemia in CKD is a complex area, and readers are advised to consult specific guidelines relevant to UK practice published by NICE and the Renal association for more detailed recommendations. The causes are anaemia in CKD are multifactorial. Iron deficiency is a major element, but multiple other mechanisms (eg, haemolysis, plasma cell dyscrasias) may also contribute towards the development of anaemia, hence the requirement for detailed haematological investigation. The causes of iron deficiency in CKD are also multifactorial. Renal failure itself contributes, but this may also be compounded by reduced iron intake, reduced iron absorption and blood loss via either the GI tract or other routes such as dialysis and phlebotomy.Assessment of iron deficiency in CKD can be difficult. Measurement of ferritin and transferrin saturation may be helpful, but the interpretation of results is not the same as in patients who do not have CKD. Specifically, absolute iron deficiency in CKD has been defined as transferrin saturation ≤20%, with SF ≤100 µg/L (in predialysis and peritoneal dialysis patients) or ≤200 µg/L (in haemodialysis patients).Patients with CKD may of course also have GI pathology underlying their confirmed iron deficiency. The decision about the need for endoscopic evaluation of the upper and lower GI tract in CKD can be difficult, and should ideally be made in conjunction with a nephrologist. However, the majority of CKD patients with confirmed IDA warrant GI investigation as long as they are fit enough to undergo these procedures. The management of iron deficiency in the context of CKD is beyond the scope of these guidelines and is discussed in detail elsewhere. Treatment is usually initiated and monitored by the nephrology team. In brief, oral iron replacement may be tried in patients who are predialysis. However, intravenous IRT is required if this is not tolerated or ineffective, or if dialysis has been commenced. Other treatments for anaemia such as erythropoietin may also be needed, but these should be managed by the nephrology team. ## Chronic heart failure Evidence of some degree of iron deficiency, as defined by an SF <100 µg/L and/or a transferrin saturation of <20%, is found in 40%-70% of cases with CHF.The causes are again multifactorial with malabsorption, malnutrition and GI blood loss (potentially exacerbated by anticoagulants or antiplatelet agents) all potentially contributing. In addition, the chronic inflammatory state present in many patients with CHF can lead to increased hepcidin release by the liver, resulting in reduced iron absorption/mobilisation. Patients with CHF should be screened for iron deficiency by measurement of ferritin and transferrin saturation.Endoscopic evaluation of the upper and lower GI tract should be considered if they have evidence of absolute iron deficiency (see the Definitions section) to exclude treatable GI causes. Decisions about the need for and safety of endoscopic evaluation should ideally be made in conjunction with the cardiology team. The majority however have FID rather than absolute iron deficiency. Nevertheless, both forms of ID are associated with reduced functional capacity, impaired quality of life and poorer prognosis in CHF.Patients who meet the above criteria for iron deficiency in this condition should therefore be considered for intravenous IRT,as this has been shown to have prognostic benefit in meta-analyses. No prognostic benefit has been demonstrated for oral iron, and this is best avoided as in CHF it may be poorly absorbed due to gut oedema, and is frequently associated with side-effects.Specific guidelines should be consulted for detailed recommendations about the investigation and management of iron deficiency in this patient group. ## Inflammatory bowel disease A third of patients with active IBD are estimated to have iron deficiency, though other mechanisms including vitamin B12 and folate deficiency, marrow suppression due to the anaemia of chronic disease, and overt blood loss may all contribute to the anaemic state.SF levels of up to 100 µg/L in the presence of inflammation may still reflect iron deficiency,and so an estimate of transferrin saturation may be helpful. The absorption of oral iron may be impaired by the systemic inflammatory process, as well as by small bowel involvement and/or previous surgery, and this may favour intravenous IRT in some cases.Current European guidelines suggest that oral IRT in patients with IBD should contain no more than 100 mg elemental iron a day.Intravenous iron is indicated for those who are intolerant of oral iron and have moderate to severe IDA (Hb <100 g/L). Optimising nutritional and pharmacological management to bring active IBD into remission would be expected to help improve IDA metrics and response to iron therapy. Guidelines It has been suggested that patients with IBD and IDA should be monitored for recurrent iron deficiency every 3 months for at least a year after correction, and periodically thereafter.Recurrent IDA may indicate persistent intestinal inflammatory activity even in the face of clinical remission and normal inflammatory biomarkers. ## Gi surgery 36. IDA is common following resection or bypass surgery involving the stomach and/or small bowel, including bariatric surgery .. In new presentations of IDA, we recommend that a history of GI or bariatric surgery should not preclude a search for other causes of IDA (evidence quality-low, consensus-85%, statement strength-strong). Resection or bypass surgery involving the stomach and/ or small bowel generally predisposes to IDA.This includes the expanding population with a history of bariatric surgery, including sleeve gastrectomy. Reduced nutritional intake and malabsorption are probably the major underlying mechanisms,and therefore IDA in this situation may occur in the context of other nutritional deficiencies-in particular of vitamin B12. The prevalence of IDA depends on the specific diagnostic criteria employed, but it is found in approximately a quarter of subjects 2 years following Roux-en-Y gastric bypass, and is markedly commoner in women,and in those with preoperative evidence of low iron stores.The figure for sleeve gastrectomy is probably lower. Predictably, the yield of other causative lesions on BDE is lower in individuals with IDA and a history of GI surgery than in those without.Nevertheless, it is unsafe to automatically attribute IDA to previous surgery without excluding other possibilities, particularly in those at risk of underlying GI malignancy-bearing in mind that partial gastrectomy may predispose to the later development of cancer in the gastric remnant.Without supplementation, the percentage prevalence of IDA tends to increase over the first 10 postoperative years.Long-term oral IRT is often effective, though because of underlying malabsorption this is not always the case, and intravenous therapy may be required. ## Service considerations ## We recommend that all service providers should have clear points of referral and management pathways for patients with ida (evidence quality-low, consensus-100%, statement strength-strong). 39. To ensure efficient use of resources, we recommend that IDA pathways should be delivered by a designated team led by a senior clinician (evidence quality-low, consensus-100%, statement strength-strong).. We recommend that service providers should aim to have an ambulatory care base for the administration of parenteral iron (evidence quality-low, consensus-100%, statement strength-strong). ## Organisation IDA has a considerable impact on referrals for urgent investigation for suspected cancer and non-elective services. This is due to the prevalence of IDA in the population, difficulty in distinguishing IDA from other causes of anaemia, and in some areas the absence of a dedicated referral pathway for the management of anaemia. In many hospitals IDA is no longer the prime interest of haematology, so becoming an 'orphan' condition without clinical leadership. This can lead to duplication of services, prolonged referral pathways and inappropriate investigation.Anaemia is common in elderly patients and those with multiple comorbidities. The anaemia of chronic disease can mimic IDA, and in a study of fast-track referrals with suspected IDA, the diagnosis was confirmed in only 11% of cases.Therefore it is important to establish at an early stage that anaemia is due to iron deficiency. Fortunately, artificial intelligence or smart testing algorithms embedded within red cell laboratory analysers (reflex testing) are now available and can include specific recommendations for further management to primary care,including referral to a dedicated electronic IDA clinical assessment service which supports appropriate clinical interaction between primary and secondary care before any further investigation.Given the increasing fragmentation of care across providers, this should include a facility for interrogating electronic healthcare records for any previously documented diagnosis of IDA, and the results of prior investigations including oesophago-gastroduodenoscopy, colonoscopy and CT colonography. For a dedicated IDA service to deliver highly effective care, the four essential components are 1 confirmation of IDA, 2 timely access to appropriate investigation (if not already investigated) 3 ensuring appropriate IRT (with long-term therapy when needed) and 4 strong clinical leadership. IDA services can also provide an alternative pathway for patients found to have more severe anaemia, and who otherwise might have been referred for emergency hospital admission. Estimates based on data from Hospital Episode Statistics 2017 suggest that up to 97 781 patients are admitted in England each year with IDA as the primary diagnosis, which is 72% higher than in 2012. Similar increases over the same period are seen for non-elective hospital spells (days in hospital) with IDA as a secondary diagnosis. ## Costs associated with ida The estimated costs incurred by the NHS in the management of IDA in secondary care in England rose from £65.8 million in 2012/2013 to £90.6 million in 2017/2018.The vast majority of these costs arose from patient managementoutpatient or emergency inpatient referral, and subsequent investigation-rather than from treatment of the iron deficiency. Clearly, treatment costs following the diagnosis of CD for example are very different to those associated following occult GI blood loss in patients taking anticoagulants. Few studies have analysed the investigation and management costs of IDA, but it is recognised from data collected as part of the national blood transfusion audits that costs arising from unnecessary emergency hospital admission could be substantially reduced if alternative patient referral pathways were readily available to support ambulatory care.While most oral iron supplements are cheap, they are not always well-tolerated, often due to GI side-effects. Newer oral iron supplements are better tolerated, but more expensive. Intravenous IRT is often necessary for patients with comorbidities which impair iron absorption. While there are several studies reporting the cost-effectiveness of intravenous iron preparations in comparison to oral IRT for specific conditions such as CKD, CHF and IBD, it is the associated comorbidity which accounts for the improved cost-effectiveness of intravenous iron in these circumstances. 218 ## Patient summary Iron is a nutrient essential to life. It is used in the body to produce many cellular proteins, and an important one is Hb, the oxygen-binding protein found in red blood cells. A shortage of iron in the body prevents the production of these proteins, and so one of the major consequences is that the rate and quality of red cell production in the bone marrow is reduced-a condition called IDA. IDA is common worldwide, and can result in many symptoms including extreme fatigue and breathlessness. It can generally be diagnosed by simple blood tests, and remedied by treatment with IRT given by mouth or injection. There are many causes of iron deficiency, including a poor dietary intake, and failure to absorb dietary iron in the upper bowel. Because blood is iron-rich, it can also result from the gradual loss of blood from the body over the course of a long period-and this is a common cause of IDA. Studies have shown that about a third of adults over the age of 50 with IDA in the UK have an underlying bleeding abnormality, most commonly in the stomach or lower bowel. In about a third of these, the abnormality proves to be a cancer. It is therefore recommended that unexplained IDA in this age group is investigated by examining these areas, even if there are no other relevant symptoms. This is usually done by endoscopy, though CT scanning is an alternative for assessing the lower bowel. ## Research recommendations Diagnosis ► New digital approaches to identifying IDA. Investigation ► FIT and risk stratification in IDA. ► Role of screening for atrophic gastritis by histology or serology (eg, Gastropanel). ► The role of newer diagnostic modalities for example, colon capsule. Treatment ► Optimal dosage regimes for oral IRT. ► Optimal target of treatment with oral IRT. ► Role of newer iron salts (eg, ferric maltol) when traditional salts have failed. ► Optimal place of intravenous iron in acute and chronic settings. ► The role of laboratory investigations in predicting nonresponse to oral IRT. Special situations ► Appropriate investigative strategies in menstruating women. ► Epidemiology, investigation and treatment of NAID.	None	https://gut.bmj.com/content/gutjnl/70/11/2030.full.pdf	Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA—for example, as a consequence of menstrual or GI blood loss. Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel. IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease— with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.
442a2ea780e36704ba66e53795ca2cae17aa51ec	pubmed	Recommendations for the management of adrenal incidentalomas: what is pertinent for radiologists?	Recommendations for the management of adrenal incidentalomas: what is pertinent for radiologists? Adrenal incidentalomas are unsuspected, asymptomatic adrenal masses detected on imaging. Most are non-functioning benign adrenocortical adenomas but can represent other benign lesions or lesions requiring therapeutic intervention including adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis. This review summarizes and highlights radiological recommendations within the recently issued guidelines for the management of adrenal incidentalomas from the European Society of Endocrinology Clinical Practice in collaboration with the European Network for Study of Adrenal Tumours. Four pre-defined clinical questions were addressed in the guidelines and two have specific relevance and implications for radiologists: (1) how to assess risk of malignancy on imaging and(2)what follow-up is indicated if an adrenal incidentaloma is not surgically removed? The guidelines also include recommendations for frequently encountered special circumstances, including bilateral incidentalomas, incidentalomas in patients with extra-adrenal malignancy and in the young and elderly patients. This review highlights radiological recommendations within the guidelines and evidence used for formulating the guidelines. # Introduction An adrenal incidentaloma is defined as a mass detected on imaging not performed for the purpose of investigating adrenal disease. The imaging is for evaluation of symptoms that are not obviously related to an adrenal aetiology. An adrenal tumour in patients with a pre-disposing hereditary syndrome detected on surveillance imaging is outside the definition of an adrenal incidentaloma. Adrenal masses discovered during staging investigations for other malignancies also do not meet the strict definition of an adrenal incidentaloma. However, as this is a frequent clinical scenario, it is addressed under special circumstances. The guidelines have included only adrenal incidentalomas larger than 1 cm. This arbitrary cut-off is in line with previous recommendations and reviews. [bib_ref] Risk factors and longterm follow-up of adrenal incidentalomas, Barzon [/bib_ref] [bib_ref] Prevalence and natural history of adrenal incidentalomas, Barzon [/bib_ref] [bib_ref] Recommended evaluation of adrenal incidentalomas is costly, has high falsepositive rates and..., Cawood [/bib_ref] [bib_ref] Management of incidentally discovered adrenal masses and risk of malignancy, Favia [/bib_ref] [bib_ref] Management of the clinically inapparent adrenal mass ("incidentaloma"), Grumbach [/bib_ref] [bib_ref] Incidentally discovered adrenal masses, Kloos [/bib_ref] [bib_ref] The clinically inapparent adrenal mass: update in diagnosis and management, Mansmann [/bib_ref] [bib_ref] Exploration and management of adrenal incidentalomas. French Society of Endocrinology Consensus, Tabarin [/bib_ref] [bib_ref] AME position statement on adrenal incidentaloma, Terzolo [/bib_ref] [bib_ref] Clinical practice. The incidentally discovered adrenal mass, Young [/bib_ref] [bib_ref] Imaging evaluation of the non-functioning indeterminate adrenal mass, Sahdev [/bib_ref] Adrenal incidentalomas are composed of benign and malignant lesions derived from the adrenal cortex, medulla or extra-adrenal origin. The vast majority, .90%, are benign adrenocortical adenomas. The reported frequency of malignant lesions in the literature varies according to the context of the study and the size inclusion criteria of the adrenal masses within these studies. Prevalence of malignant and functional lesions is overestimated as the prevalence is based on surgical studies where indeterminate adrenal masses are resected, as they not retain typically benign features. [bib_ref] Recommended evaluation of adrenal incidentalomas is costly, has high falsepositive rates and..., Cawood [/bib_ref] Autopsy studies suggest a prevalence of incidentalomas of around 2% (range 1.0-8.7%), increasing with age. [bib_ref] Management of the clinically inapparent adrenal mass ("incidentaloma"), Grumbach [/bib_ref] [bib_ref] Incidentally discovered adrenal masses, Kloos [/bib_ref] [bib_ref] The clinically inapparent adrenal mass: update in diagnosis and management, Mansmann [/bib_ref] Radiological studies report a frequency close to 3% in patients below the age of 50 years, increasing up to 10% in the elderly. [bib_ref] Prevalence and natural history of adrenal incidentalomas, Barzon [/bib_ref] [bib_ref] Management of the clinically inapparent adrenal mass ("incidentaloma"), Grumbach [/bib_ref] [bib_ref] Incidentally discovered adrenal masses, Kloos [/bib_ref] [bib_ref] The clinically inapparent adrenal mass: update in diagnosis and management, Mansmann [/bib_ref] [bib_ref] A survey on adrenal incidentaloma in Italy. Study group on adrenal tumors..., Mantero [/bib_ref] [bib_ref] Prevalence of adrenal incidentaloma in a contemporary computerized tomography series, Bovio [/bib_ref] [bib_ref] The optimal imaging of adrenal tumours: a comparison of different methods, Ilias [/bib_ref] Childhood incidentalomas are extremely rare. Target group and aim of the guidelines The European Society of Endocrinology (ESE) Clinical Practice Guideline was developed for endocrinologists, radiologists, surgeons and general physicians. The overall purpose of the guideline is to provide practical guidance for the management of patients with adrenal incidentalomas. # Methodology The detailed methodology is described within the guidance document. [bib_ref] Management of adrenal incidentalomas: European society of endocrinology clinical practice guideline in..., Fassnacht [/bib_ref] In summary, the guideline used the Grading of Recommendations Assessment, Development and Evaluation method, firstly defining the clinical question(s) and secondly performing a systematic literature search and rating the quality of the evidence. Recommendations by the guideline panel are worded as recommend (strong recommendation) and suggest (weak recommendation). When coming to a guideline recommendation, the quality of evidence, balance of desirable and undesirable outcomes, values and preferences (patient preferences, goals for health, costs, management inconvenience, feasibility of implementation etc.) were considered. [bib_ref] GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction..., Andrews [/bib_ref] Key information for radiologists The guidelines addressed four important clinical questions for review: (1) how to assess risk of malignancy on imaging, (2) how to define and manage low-level autonomous cortisol secretion, the so called "sub-clinical" Cushing's syndrome, (3) which patients should have surgical treatment and how should it be performed and (4) what follow-up is indicated if the adrenal incidentaloma is not surgically removed? Questions 1 and 4 are directly relevant to radiological practice and will be the main focus of this article. How to assess risk of malignancy on imaging? Question (1a): what is the most accurate diagnostic imaging procedure to determine whether an adrenal mass is benign in patients with unilateral or bilateral adrenal mass(es) on imaging with or without the history of other malignant lesions? The recommendations were guided by a recent meta-analysis conducted by some of the guideline panel members on the performance of imaging in differentiating benign from malignant adrenal incidentalomas. The included 37 studies in this systematic review were included using strict inclusion criteria. [bib_ref] Imaging for the diagnosis of malignancy in incidentally discovered adrenal massesa systematic..., Dinnes [/bib_ref] No randomized studies comparing the commonly used imaging modalities met the inclusion criteria of the review. The majority of included studies had moderate to high risk of bias due to unclear study population selection, retrospective selection of the diagnostic threshold and inadequate reference standards. The studies included and evaluated in the guidelines reviewed the performance of five commonly used radiological diagnostic criteria: (1) tumour density .10 Hounsfield units (HU) on noncontrast CT (2) contrast-enhanced CT including delayed intravenous contrast media washout, either absolute percentage washout or relative percentage washout (3) MRI chemical shift analysis: loss of signal intensity between in-phase and out-of-phase images (including both qualitative and quantitative estimates of signal loss) (4) fluorine-18 fludeoxyglucose ( 18 F-FDG) positron emission tomography (PET) or PET-CT, the maximum standardized uptake value (SUV max ) (5) ratio of SUV max in the adrenal gland compared with that of the liver (adrenal : liver ratio). 18 of the 37 studies were included but were small with a median sample size of 45 (range 12-181). Only 7 studies addressed true incidentalomas, whereas 11 studies included patients with known extra-adrenal malignancy. 2 studies with 102 true incidentalomas suggest that CT density .10 HU has 100% sensitivity for detection of adrenal malignancy (confidence interval 91-100%). In patients with a history of underlying malignancy, the performance is less reliable. Five studies evaluating the .10 HU cut-off as indicative of malignancy showed a 93% sensitivity for detection of malignancy as 7% of adrenal metastases were found to have a tumour density of #10 HU. The use of non-contrast CT attenuation ,10 HU therefore has a better performance in excluding malignancy in patients with no underlying malignancy. The overall performance of all other diagnostic criteria was poor and based on small numbers of studies with very few patients and accompanying wide confidence intervals. For true adrenal incidentalomas, two of three MRI studies reported sensitivities and specificities lower than CT using adrenal : liver and adrenal : spleen ratios for the loss of signal intensity. The performance of 18 F-FDG PET-CT for adrenal mass : liver ratio and SUV max in the two included studies was not clearly superior than noncontrast CT and was similar to MRI. In patients with a history of extra-adrenal malignancy, only one study included CT contrastenhanced washout and showed very poor 16% sensitivity. Four of the five studies reported high 89-99% sensitivity and high specificity 60-93% for measures of adrenal : liver, adrenal : spleen and adrenal : muscle ratios and of loss of signal intensity on MRI. Although there were more studies evaluating CT, MRI and PET in patients with known extra-adrenal malignancy than true incidentalomas, evaluation of test performance is still based on too small numbers to be able to discriminate between tests. ## Question (1b): what is the diagnostic accuracy of adrenal biopsy? The recommendations for adrenal biopsies were guided by a systematic review conducted by members of the guideline panel with experience of adrenal biopsy and its outcomes. [bib_ref] The diagnostic performance of adrenal biopsy: a systematic review and meta-analysis, Tamhane [/bib_ref] Only 8 of the 32 identified studies could be included. In the remaining studies, at least 50% of the patients lacked any or optimal reference standards. The included studies had moderate risk for bias due to limitations in biopsy techniques, patient selection, assessment of outcome and adequacy of follow-up of the study population. Pathology of adrenal lesion was reported for only 1600/2207 cases. Pooled overall complication rate derived from 1356 biopsies was 2.4% (range 5-12%), although likely underrepresented, as there were differences in assessment and reporting of complications. The most frequent complications following adrenal biopsy are haemorrhage and pneumothorax. Less common complications include pain, pancreatitis and rarely needle tract seeding. However, most are minor and self-limiting, and the rate for major complications necessitating further treatment is 0.4-2%. [bib_ref] Percutaneous adrenal biopsy: review of a 10-year experience, Welch [/bib_ref] The pooled non-diagnostic rate derived from 2030 adrenal biopsy procedures was 8.6%. The diagnostic performance of adrenal biopsy using 323 adrenal biopsy procedures had a sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of 87%, 100%, 229 and 0.13, respectively. Performance was lower for adrenocortical carcinoma sensitivity, specificity, positive likelihood ratio and negative likelihood ratio 70%, 98%, 100.43 and 30.9 respectively. On balance, therefore, the performance of adrenal biopsies provides no significant improvement over non-invasive imaging, but the overall complication rate is clinically significant. Question (4): what is the optimal follow-up in patients with an apparently benign adrenal incidentaloma in order to detect malignant transformation and/or development of overt hormone excess? Review of 14 studies assessing the natural course of 1410 pooled patients with apparently benign, non-functioning adrenal incidentalomas was performed. [bib_ref] Recommended evaluation of adrenal incidentalomas is costly, has high falsepositive rates and..., Cawood [/bib_ref] [bib_ref] Natural course of benign adrenal incidentalomas in subjects with extra-adrenal malignancy, Yener [/bib_ref] In the included studies, selection criteria were often not reported; information on radiological reevaluation was not always provided or standardized; duration of follow-up was heterogeneous across studies (medians ranging from 19 to 90 months) and completeness of follow-up was difficult to assess providing overall poor quality evidence. The pooled risk for developing malignancy in this review was 0.2%. [bib_ref] Recommended evaluation of adrenal incidentalomas is costly, has high falsepositive rates and..., Cawood [/bib_ref] In two studies, one case of adrenal non-Hodgkin lymphoma and one patient with renal cancer metastasis were reported. In the first case, imaging characteristics of the adrenal lesion at the presentation was not consistent with benign characteristics, and the lymphoma may have been misdiagnosed initially. [bib_ref] Long-term follow-up study of patients with adrenal incidentalomas, Libe [/bib_ref] In the second case, the patient had a history of renal cell carcinoma, and it is unclear whether the adrenal mass was found incidentally or during the follow-up for cancer. [bib_ref] Adrenal incidentaloma: clinical characteristics and comparison between patients with and without extraadrenal..., Tsvetov [/bib_ref] No case of malignancy was reported in the remaining patients, and no malignant transformation of a presumably benign incidentaloma was reported. ## Recommendations and rationale Risk of malignancy (1) The guidelines recommend establishing whether the mass is benign or malignant at the time of initial detection. This is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. Malignant lesions may need urgent surgical intervention and other therapies, and delay may cause harm. (2) The guidelines recommend all adrenal incidentalomas should undergo an imaging procedure to determine if the mass is homogeneous and lipid-rich and therefore benign. For this purpose, the guidelines primarily recommend the use of non-contrast CT. (3) The guidelines suggest if non-contrast CT demonstrates a homogeneous mass with #10 HU, appearances are consistent with a benign adrenal mass and no further imaging is required. Rationale In patients presenting without known malignancy, a non-contrast CT with HU of #10 was only found in benign disease, whereas in patients with extra-adrenal malignancy, 7% were malignant. [bib_ref] Imaging for the diagnosis of malignancy in incidentally discovered adrenal massesa systematic..., Dinnes [/bib_ref] Although MRI with chemical shift imaging is based on the lipid content of masses, quantitative assessment of loss of signal intensity is not well standardized and the evidence is insufficient to make strong recommendation for its use. [bib_ref] Combined chemical shift imaging with early dynamic serial gadolinium-enhanced MRI in the..., Rodacki [/bib_ref] [bib_ref] Characterization of lipid-poor adrenal adenoma: chemical-shift MRI and washout CT, Seo [/bib_ref] Qualitative interpretation of MRI is more subjective and dependent on the experience of the radiologist than quantitative CT assessment. The guideline panel felt confident about the negative-predictive value of non-contrast CT to recommend no additional imaging when benign characteristics were found in an adrenal mass ,4 cm. Additional imaging may also risk false-positive results and significant psychological and financial burden for patients and health systems. The cut-off of 4 cm is not based on good evidence from clinical studies, but the panel felt it is necessary to provide clear guidance based on expert clinical experience. MRI with chemical shift should be the first choice only where CT is less desirable (e.g. pregnancy, children). However, if MRI with chemical shift has already been performed and the results are unambiguous, a multidisciplinary expert team (MDT) might judge this as sufficient for the individual patient. The recommendations are summarized in [fig_ref] Figure 1: Management of patients with adrenal incidentalomas [/fig_ref]. (4) If the adrenal mass is indeterminate on non-contrast CT (.10 HU) and results of hormonal work-up do not indicate significant hormone excess, three options should be considered by a MDT acknowledging the patient's clinical context: immediate additional imaging with another modality interval imaging in 6-12 months (non-contrast CT or MRI) or surgery without further delay. Rationale Evidence for "secondor third-line" imaging modality for indeterminate adrenal mass is collectively very poor, but the guideline panel provides some guidance for clinical practice [fig_ref] Table 1: Imaging criteria of a benign adrenal mass [/fig_ref] and emphasizes discussions which need to be individualized within a MDT setting. Contrast washout CT is widely available, but there is huge variability in protocols and therefore it has poor comparability. [bib_ref] GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction..., Andrews [/bib_ref] F-FDG PET-CT has a low risk of missing a malignant adrenal tumour, limited to lymphoma and renal cell carcinoma. [bib_ref] Role of fluorine-18 fluorodeoxyglucose positron emission tomography scan in the evaluation and..., Karam [/bib_ref] [bib_ref] The usefulness of (18)F-fluorodeoxyglucose positron emission tomography [(18)F-FDG-PET] and a comparison of..., Tsukamoto [/bib_ref] [bib_ref] PET/CT and renal pathology: a blind spot for radiologists? Part 1, primary..., Zukotynski [/bib_ref] It is more expensive, not always easily available and several benign adrenal tumours may have 18 F-FDG uptake resulting in falsepositive lesions (e.g. functional adenomas or benign pheochromocytoma). [bib_ref] 18F-FDG PET/CT in the characterization and surgical decision concerning adrenal masses: a..., Ansquer [/bib_ref] [bib_ref] Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the..., Timmers [/bib_ref] [bib_ref] 18)F-FDG-PET/CT imaging of ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) demonstrating increased (18) F-FDG..., Alencar [/bib_ref] (5) The guidelines recommend against the use of adrenal biopsy in diagnostic work-up of patients with adrenal masses, unless there is a history of extra-adrenal malignancy and all of the following criteria are fulfilled: (i) The lesion is hormonally inactive (in particular, a pheochromocytoma has been excluded); (ii) The lesion has not been conclusively characterized as benign by imaging; (iii) Management would be altered by the knowledge of the histology. Rationale Adrenal biopsy has a limited role mainly in confirming metastases from extra-adrenal malignancy, lymphoma or inflammatory/infectious processes. In patients with no other obvious metastatic lesions and when surgical removal of the adrenal lesion is considered, 18 F-FDG PET-CT should be considered to exclude extra-adrenal metastases not visualized on CT or MRI. Only an experienced radiologist should perform adrenal biopsy and only when it is required to guide further management. The panel particularly recommends against a biopsy if the adrenal mass is likely to be an adrenocortical carcinoma, which runs a low risk of biopsy track seeding and tumour dissemination precluding a complete (R0) resection and has a significant non-diagnostic rate. [bib_ref] The diagnostic performance of adrenal biopsy: a systematic review and meta-analysis, Tamhane [/bib_ref] [bib_ref] Transcutaneous biopsy of adrenocortical carcinoma is rarely helpful in diagnosis, potentially harmful,..., Williams [/bib_ref] The only exception is a formal confirmation of histological diagnosis in an inoperable tumour for oncological management or as part of a clinical trial. Recommendations for imaging follow-up (1) The guidelines recommend against further imaging for follow-up in patients with an adrenal mass ,4 cm with clear benign features on imaging studies. (2) In patients with an imaging indeterminate adrenal mass opting not to undergo adrenalectomy following initial assessment, a repeat non-contrast CT or MRI after 6-12 months can exclude significant growth. The guidelines suggest surgical resection if the lesion enlarges by .20% (in addition to at least a 5-mm increase in maximum diameter) during this period. If there is growth of the lesion below this threshold, additional imaging after 6-12 months should be performed. ## Rationale Amongst .2300 patients in follow-up studies, there is no reported occurrence of adrenal malignancy in incidentalomas displaying typical features of benign adrenocortical adenomas at initial imaging studies. [bib_ref] Recommended evaluation of adrenal incidentalomas is costly, has high falsepositive rates and..., Cawood [/bib_ref] [bib_ref] AME position statement on adrenal incidentaloma, Terzolo [/bib_ref] Therefore, the guideline panel did not support repeating imaging investigations if the initial investigations are unequivocally consistent with a benign lesion. However, patients with adrenal incidentalomas .4 cm in diameter have undergone adrenalectomy in the past, and the literature on follow-up of non-operated large adrenal incidentalomas is scarce. As the risk of malignancy in this category is undetermined, some panel members favoured one follow-up imaging (non-contrast CT or MRI) after 6-12 months in patients not undergoing resection, as both primary adrenal malignancies or adrenal metastases are likely to increase in size whilst lack of growth may be taken as an indicator of benignity. In cases with a low likelihood of a malignant tumour, the guideline panel favoured a time interval of 12 months. As there are no published or any evidence-based size or volume cut-off to support growth suggestive of malignancy, the panel proposed adaptation of the Response Evaluation Criteria in Solid Tumors v. 1.1 criteria. [bib_ref] New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eisenhauer [/bib_ref] Although Response Evaluation Criteria in Solid Tumors v. 1.1 criteria are not validated for the differentiation between benign and malignant adrenal tumours, the 20% cut-off together with an absolute increase of at least 5 mm in diameter in 6-12 months may serve as a warning for significant growth and reconsideration for surgical resection. Exceptional cases of malignant adrenal tumour without significant growth for several years can be considered a very rare exception and does not justify follow-up of all patients with an incidentaloma with repeated imaging. [bib_ref] Radiographic characteristics of adrenal masses preceding the diagnosis of adrenocortical cancer, Nogueira [/bib_ref] [bib_ref] Preexisting adrenal masses in patients with adrenocortical carcinoma: clinical and radiological factors..., Ozsari [/bib_ref] In masses with no demonstrable growth, no further imaging follow-up is recommended, and only in masses with measurable growth ,20%, should additional follow-up imaging be considered. The clinical necessity and interval of follow-up imaging should be discussed by a MDT. ## Special circumstances Patients with bilateral adrenal incidentalomas (1) The guidelines recommend for patients with bilateral adrenal masses that each adrenal lesion should be assessed at the time of initial detection according to the same imaging protocol as for unilateral adrenal masses to establish if either or both masses are benign or malignant. (2) The same recommendations regarding the indication for surgery and follow-up should be used as for patients with unilateral adrenal incidentalomas. Rationale Bilateral adrenal masses usually represent benign adenomas, macronodular hyperplasia or distinct bilateral nodules. In the relevant clinical setting, metastases (especially in patients with known malignancy), lymphoma or pheochromocytomas should also be considered. Each lesion should be evaluated individually as bilateral adrenal masses can represent co-occurrence of different lesions. Adrenal incidentalomas in young or elderly patients (1) The guidelines recommend urgent assessment of adrenal mass in children, adolescents, pregnant females and adults younger than 40 years of age because of a higher likelihood of malignancy. (2) MRI rather than CT is suggested if dedicated adrenal imaging is required in children, adolescents, pregnant females and adults younger than 40 years of age. (3) The guidelines recommend imaging investigations and management of patients with poor general health and a high degree of frailty should be tailored in proportion to potential clinical gain. ## Rationale Benign adrenal incidentalomas increase with age, with the majority of patients presenting in the fifth to seventh decade of life. Although 10% or more of individuals older than 70 years harbour an adrenal mass, adrenal nodules in individuals younger than 40 years are much less prevalent and are rare in children and young adults. Consequently, investigation of adrenal masses in young patients including pregnant females should be pursued with urgency, as the risk of malignancy is much higher. In the young patient, MRI is the preferred imaging technique. However, adapted low-dose unenhanced CT protocols can limit radiation exposure and offer an alternative (especially if availability of MRI is limited). Conversely, small adrenal incidentalomas in elderly patients have a very low pre-test probability of malignancy and investigations should only be expedited where suspicion of malignancy is high ## Rationale Both qualitative and quantitative performance of 18 F-FDG PET-CT varies considerably. In 2 studies with 117 lesions in patients with history of extra-adrenal malignancy, adrenal lesion : liver ratio of 1.53-1.8 was investigated and found to have a sensitivity of 82% and specificity of 96% to detect malignant disease. [bib_ref] What parameters from 18F-FDG PET/CT are useful in evaluation of adrenal lesions?, Kunikowska [/bib_ref] For adrenal lesions characterized as benign by non-contrast CT, the same rationale as for patients with no history of underlying malignancy applies. However, the currently available data suggest a false-negative rate of up to 7% in this population. In patients with advanced metastatic extra-adrenal malignancy, characterizing an adrenal incidentaloma will not alter clinical management. If, however, clinical management would be altered by the demonstration of a solitary adrenal metastasis, then further imaging, biopsy or resection should be performed. The recommendations are summarized in [fig_ref] Figure 2: Evaluation of adrenal mass in patients with known extra-adrenal malignancy [/fig_ref]. # Multidisciplinary team discussion The guidelines recommend that patients with adrenal incidentalomas should be discussed in a MDT, if at least one of the following criteria is met: (1) Imaging is not consistent with a benign lesion; (2) There is evidence of hormone excess (including "autonomous cortisol secretion"); (3) There is evidence of significant tumour growth during follow-up imaging; (4) Adrenal surgery is considered. ## Rationale This is based mainly on expert opinion, aiming to identify subgroups of patients who would be most likely to benefit from MDT discussion. The panel recommends that the core multidisciplinary team should consist of at least a radiologist, endocrinologist and surgeon, all with significant experience in adrenal tumours. This team should have access to anaesthetists and an endocrine pathologist, who are also experienced in adrenal tumours. Overall comment Several guidelines exist to assist radiologists and physicians in the investigation and management of adrenal incidentalomas. [bib_ref] Adrenal incidentalomas: clinical controversies and modified recommendations, Garrett [/bib_ref] [bib_ref] ACR Committee on Appropriateness Criteria. ACR appropriateness criteria on incidentally discovered adrenal..., Choyke [/bib_ref] [bib_ref] Work-up of the incidental adrenal mass, Baltzera [/bib_ref] In practice, it is critical to ensure that appropriate previous imaging is reviewed in the decision-making process separating benign from malignant lesions. The panel developed this guideline after critical evaluation of the studies available at the time of analysis. Several studies had to be excluded, as these did not meet the required Grading of Recommendations Assessment, Development and Evaluation selection criteria. When compared with other guidelines such as the American Appropriateness Criteria, less weight is placed on the second line of imaging investigations in view of the weak data. In line with the European Urology guidelines, this guideline emphasizes the important role of a MDT in ensuring an expert team manages indeterminate and malignant lesions. The guideline therefore emphasizes and provides the physician clear criteria for lesions that require referral for MDT discussion and management. Unlike several existing guidelines, these guidelines also aim to reduce the imaging follow-up burden. Long-term follow-up of lesions should be limited to lesions not unequivocally characterized as benign, ,4 cm and with ,20% increase in size over 12 months. This maintains a safe approach to the management of adrenal incidentalomas. A critical question not addressed within these guidelines is how or whether the radiologist, at first detection of an adrenal incidentaloma, should instigate biochemical investigations and further follow-up. Should all incidental adrenal lesions be referred for clinical and biochemical endocrine evaluation? These specific considerations were outside the remit of the current guidelines and the evidence to make any recommendation was not reviewed. # Conclusion This targeted summary of the recent guidelines from the European Society of Endocrinology and ENSAT developed to aid the management of adrenal incidentalomas provides a management strategy for an increasingly frequent clinicoradiological problem. The guidelines aim to provide a safe, simple, costeffective algorithm based on the evidence available, minimizing the need and psychological stress experienced by patients undergoing repeated imaging for an incidentaloma. An attenuation value of ,10 HU on non-contrast-enhanced CT to confirm a benign adrenal lesion has the strongest evidence base. For these lesions, if no adrenal cortical hyperfunction is demonstrated, the lesions are homogeneous and ,4 cm in size, no further imaging follow up is recommended. The evidence base for the second-and third-line imaging modalities to exclude malignancy is weak, and there is a need for clinical trials in all areas. [fig] Figure 1: Management of patients with adrenal incidentalomas. Based on the European Society of Endocrinology and the European Network for the Study of Adrenal Tumours adrenal incidentaloma guideline. CSI, chemical shift imaging; MDT, multidisciplinary expert team. [/fig] [fig] 18 F: -FDG, fluorine-18 fludeoxyglucose; HU, Hounsfield units; PET, positron emission tomography; ROI, region of interest. These criteria can be applied only to homogeneous masses or masses with clear features consistent with benign disease, e.g. myelolipoma. Guidelines & recommendations: Imaging recommendations for the management of adrenal incidentalomas BJR and kept in proportion to the clinical performance status of the individual and the expected clinical gain. Patients with a newly diagnosed adrenal mass and a history of extra-adrenal malignancy (1) The guidelines suggest -FDG PET-CT if performed as part of investigations for the underlying malignancy can replace other dedicated adrenal imaging techniques. (2) Adrenal lesions characterized as benign by non-contrast CT require no further specific adrenal imaging follow-up. (3) For indeterminate lesions, the guidelines recommend imaging at the same time interval as for the primary malignancy for assessing the growth of the lesion. Alternatively, -FDG PET-CT, surgical resection or biopsy can be considered if distinction is essential to influence treatment decisions for the primary tumour. [/fig] [fig] Figure 2: Evaluation of adrenal mass in patients with known extra-adrenal malignancy. Based on the European Society of Endocrinology and the European Network for the Study of Adrenal Tumours adrenal incidentaloma guideline. (1) Always take life expectancy into consideration. (2) If there is hormone excess, treatment individualized. (3) Fluorine-18 fludeoxyglucose ( 18 F-FDG) positron emission tomography (PET)/CT to exclude other metastatic deposits in patients with no other obvious metastatic lesions and for whom surgical removal of the lesion is an option. [/fig] [table] Table 1: Imaging criteria of a benign adrenal mass [/table]	None	None	Adrenal incidentalomas are unsuspected, asymptomatic adrenal masses detected on imaging. Most are non-functioning benign adrenocortical adenomas but can represent other benign lesions or lesions requiring therapeutic intervention including adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis. This review summarizes and highlights radiological recommendations within the recently issued guidelines for the management of adrenal incidentalomas from the European Society of Endocrinology Clinical Practice in collaboration with the European Network for Study of Adrenal Tumours. Four pre-defined clinical questions were addressed in the guidelines and two have specific relevance and implications for radiologists: (1) how to assess risk of malignancy on imaging and (2) what follow-up is indicated if an adrenal incidentaloma is not surgically removed? The guidelines also include recommendations for frequently encountered special circumstances, including bilateral incidentalomas, incidentalomas in patients with extra-adrenal malignancy and in the young and elderly patients. This review highlights radiological recommendations within the guidelines and evidence used for formulating the guidelines.
e21577df71e72fdd3e8e4722c55be52c792423f3	pubmed	All India Ophthalmological Society - Oculoplastics Association of India consensus statement on preferred practices in oculoplasty and lacrimal surgery during the COVID-19 pandemic	All India Ophthalmological Society - Oculoplastics Association of India consensus statement on preferred practices in oculoplasty and lacrimal surgery during the COVID-19 pandemic ## I. definitions a. Infectious Aerosols: These are defined as particles suspended in gas, less than 100 µm and can be respired. Aerosols between 10-100 µm are usually deposited in the upper respiratory tract, whereas less than 10 µm can penetrate deep into the lungsb. AGP (Aerosol Generating Procedures): Medical procedures or interventions that has the potential to generate aerosols and expose the healthcare worker to the pathogens. Examples are endotracheal intubation, mechanical ventilation, suctioning of body fluids, etc.c. PPE (Personal Protective Equipment): PPE refers to the equipment worn to minimize hazards of exposure to the pathogens and includes protective clothing, masks, goggles, face masks, face shields, helmets with or without respirators d. FFP (Filtering Face Piece mask): FFP or simply called a respirator is a protective face mask known to filter dust particles and viruses. They are of three types based on the filtration capacity and inward leakage. The FFP2 (N-95) or FFP3 masks are commonly recommended for the virusese. PAPR (Powered Air Purifying Respirators): PAPR or positive pressure masks are a specialized respirator designed to filter contaminated air. They are considered superior to N-95 mask; however, its use is limited by the cost and availability factorsf. Ideal PPE (Type A): This would comprise of Hazmat suit + N-95 mask + Visor + Shoe coverg. Minimum PPE (Type B): This would comprise of Surgical gown + N-95 mask + Visor + Shoe cover + cap +/-monkey hood or cap +/-plastic apron +/-goggles/surgical loupes.II. COVID screening in practices When resuming services, it would be ideal to screen every patient who comes for a consult. An easy way to perform it during demanding situations like a pandemic is the use of a simple questionnaire []. In addition, make a note of the patient's residential address and the colour code of the zone of the location. This questionnaire would then form the basis for pre-surgical screening subsequently []. The use of these two simple methods would allow the surgeon to make decisions with regards to proceeding with clinical examination, surgery where needed, and the degree of logistical needs. III. General pre-operative, intra-operative and post-operative guidelines for SARS-Cov-2 positive or suspected patients 1. PPE for all medical and non-medical personnel involved in the surgery (at least minimum PPE described as above)2. Only minimum necessary anaesthetic, surgical and allied health personnel should be present inside the operating room3. Use of aerosol protection devices is encouraged during intubation and extubation to limit spread of aerosols away from the patient. An oxygen mask/aerosol protection device should be placed over the face after the tube is removed to mitigate aerosolization with coughing4. Non-anaesthetic manpower should be outside the operating room during intubation and extubation5. The surgical operating team should be outside the door ideally for 20 minutes following intubation before entering the operating theatre. The team may then enter with appropriate PPE (N95 or PAPR)6. Povidine Iodine (PVP-I) disinfection for endonasal lacrimal and orbital procedures: PVP-I has viricidal activity on coronaviruses related to SARS-Cov-2. Studies suggest 0.5% PVP-I preferably in atomised form for disinfection of nasal mucosa and nasopharynyx for both the medical personnel involved in surgery and the patient. Alternatively, 2% PVP-I oral solution can be used for oral mucosal dis-infection of medical personnel before surgery and 5% PVP-I solution in the case of the patient. The method of instillation depends on the availability, region and institution where surgery is being performed7. An interval of 20-30 minutes between cases is essential during the time of this crisis to give enough time for aerosols generated during the previous procedure to clear. The exact interval timing will depend on operating theatre air exchange rates-which should be decided by individual hospitals.IV. ## Role of respirators-use of n95 respirators vs powered air-purifying respirators (paprs) There is enough evidence in literature of superior protection of N95 respirators and PAPRs compared to regular 3-ply face masks especially against Influenza virus and SARS-CoV (the virus responsible for the previous SARS outbreak) making them indispensable during this present pandemicIn one significant comparative study, N95 respirators had 30 times more protective factor than the regular 3-ply masks.For emergency proceduresPlease score the above sheet, but can go ahead with surgery with full PPE in designated operating rooms. A pre or post-operative consultation from an infectious disease (ID) specialist or General Physician. It is also advised that nasopharyngeal swab/ blood be sent preferably for COVID-19 testing* pre-operatively. Operating team may not be able to wait for results before proceeding with surgery. For semi urgent/elective procedures 1. If the answer to all the questions above is NO, then may proceed with surgery with preferably testing for COVID-19.* 2. If the answer to any of the above is YES -please consult infectious diseases specialist before proceeding. *Either RT-PCR of nasopharyngeal swab OR protective serum IgG level. Experiences from Wuhan, China and Northern Italy suggest that PAPR (FFP3) were deemed to have accorded better protection than N95 respirators (FFP2) and helped in keeping infection rates among medical personnel in control.There are issues of comfort and physiological effects on medical personnel using N95 masks. Earlier studies have reported decreased concentrations of inhaled oxygen (O2) and increased concentrations of inhaled carbon dioxide (CO2) associated with use of N95 respirators for long periods.With expected prolonged mask wearing, long term health implications of the medical personnel needs be carefully considered. In a long-term study, the subjects consistently reported headache, dizziness, feeling tired and communication obstacles.In many surgeries, mask wearing time may be significantly longer and there may be increased O2 utilisation rate than in experimental settings. These issues are obviated by PAPRs making them the respirators of choice. Though PAPRs are preferred over N95 respirators, considering the cost factor involved and availability of PAPRs, the choice of respirators may be left to the individual institutions, hospitals and practices in the present time. Full Face-shield Respirators with better air ventilation and N95 specifications can be considered as an alternative to N95 respirators. There are suggestions for disinfection of respirators to conserve expensive respirators in this period of crisis. Ultraviolet irradiation, atomised hydrogen peroxide and moist heat are the most promising decontamination procedures, but there is not enough literature to support its specific efficacy against SARS-CoV-2. Reusing respirators after disinfection may reduce its efficacy over time.V. General guidelines for oculoplastic surgery 1. Avoid general anaesthesia (intubation, extubation) whenever possible2. Avoid monopolar cautery for cutting/coagulation3. Use cutting blade for skin and mucosal incisions whenever possible4. Use bipolar cautery for haemostasis in lowest power setting5. Practise minimal handling of tissues especially mucosal surfaces6. Avoid repeated irrigation and suctioning of tissues7. Avoid/minimize drills, oscillating osteotomes and other powered instruments8. Consider closed reduction if fracture is stable for zygomatico-maxillary complex (ZMC) fractures. Avoid intra-oral incision, if two-point fixation (rim and ZF) is sufficient for stabilization9. Self-drilling screws preferred over self-tapping ones that require pre-drilling10. An optional use of a smoke and suction evacuator device having fluid suction high-efficiency particulate air (HEPA) filter compartment and an ultra-low penetrating air (ULPA) efficiency rating will keep the aerosol and smoke dispersion in check11. To plan orbital decompression surgery avoiding endo-nasal endoscopic approach and only utilising an orbital approach, so that there is minimal to no breach of sinus mucosa. The operating surgeon can even consider-in a known COVID-19 positive patient-a single wall, aggressive lateral wall decompression as a temporising procedure to protect the optic nerve or/and reduce orbital congestion. The surgeon can plan for a more complete decompression at a later date.VI. Donning and doffing of complete and minimum PPEThe decision to use either complete (Type A) and ideal PPE versus minimum PPE (Type B) depends upon the nature of the risk and availability of the protective suits. The donning and doffing techniques of each type is described. ## Vii. classification of clinical and surgical procedures [14,17,18,22] This classification offers a broad time line but is not sacrosanct and may be modified based on individual or institutional discretion. Level A -Emergency/Urgency -The need to operate within 4-72 hours. Level B -May be deferred for up to 4 weeks with or without conservative management. Level C -May be deferred beyond 6 weeks without adversely affecting the outcomes. ## Viii. risk stratification for oculoplastic surgeries The risk classifications of orbital surgeries are shown in, eyelid and facial procedures inand that of Ocular Oncology inand lacrimal procedures in. In addition, certain specifics of eyelids, orbital and lacrimal malignancies are dealt within the respective risk stratification tables. ## Ix. lacrimal surgeries Unlike other oculoplastic surgeries, lacrimal procedures involves various interventions into the nasal cavity which enhances the risks for a lacrimal surgeon. Hence it requires a brief discussion on the intricacies of clinical examinations like lacrimal irrigation and nasal endoscopy and common surgical procedures. ## A. lacrimal irrigation This is a basic clinical examination in any ophthalmic clinic. However, it is potentially an aerosol generating procedure -especially in the setting of an obstructed lacrimal drainage system. This can be compounded by the controversy of presence of virus in the tears.The previous guideline was to avoid lacrimal irrigation and instead rely more on Fluorescein dye disappearance test (FDDT).In the immediate aftermath of lockdown, this view may not be entirely valid. One, because of inherent sensitivity and specificity of the test and second, FDDT is neither confirmatory test for any lacrimal obstruction nor does it reflect the level of obstruction. Hence decisions to operate cannot be confidently taken. Irrigation, when necessary, should be performed ideally with at least a minimum PPE and preferably with a low capacity syringe (1 cc) and straight 25 or 27 G cannulas. This is to reduce the force generated to minimum and allow a more controlled and slower rate of fluid flow. This is likely to reduce the generation of aerosols. Since a straight canula is used on a slim syringe, the same canula can also be used to assess the level of canalicular obstruction if needed. The usual second intervention of using a probe to assess the level of obstruction can be avoided. ## B. nasal endoscopy Routine nasal endoscopies prior to any lacrimal surgery is best avoided while the pandemic lasts. Yet it may be needed for a subset of patients, for example, in congenital dacryocystocele with signs of airway compromise, to assess intranasal cyst or in cases of acute lacrimal drainage trauma or malignancies. It is to be borne in mind that the nasal tissues harbour high viral load with higher risk for the examining surgeon. This can be complicated by an unexpected sneeze reflex that it may occasionally induce. In addition, since the SARS-CoV-2 virus can be stable on the surfaces for long periods,effective disinfection of the telescope before using it for another patient can be a dilemma. While disposable endoscopes can be an alternative, it is not an economically feasible option in the developing world. When performing nasal endoscopy, carefully decongest and anesthetize the nose. It is preferable to avoid the use of atomizers and suctions. Perform the procedure in a quick yet controlled manner, preferably with PPE. ## C. stent extubation Stent extubation is not an emergency. It may be warranted on a priority basis where clinical examination reveals complications like internal common opening threatening tubal granulomas. Endoscopy route is the quickest to remove it. In the presence of concerns for endoscopy either because of logistic reasons or patient related factors, a careful external approach removal can be an alternative. However, for obvious reasons, there is no scope for its removal by sneezing manoeuvre as is the practice in some centres. ## D. probing for congenital nasolacrimal obstruction (cnldo) Routine probing is to be avoided till the decline of the pandemic. However, exceptional circumstances like congenital dacryocystocele or dacryocystopyocele may require endoscopic decompression. In such an eventuality, all precautions for a surgery as mentioned earlier including PPE is warranted. ## E. dacryocystorhinostomy Routine dacryocystorhinostomy (DCR) by any approach is to be avoided till the decline of the pandemic. However, there may be certain indications that come under level A surgical classification may require it, for example recurrent lacrimal abscess with extraocular complications in younger individuals. The surgery would mandate a pre-operative testing for COVID-19 as described earlier and PPE. If an urgent DCR is planned, it is preferable to use the external route, use blades for incisions, avoid cautery, powered instruments like drills or ultrasonic aspirators and suction (use gauze instead). One needs to be very careful while fashioning the nasal mucosal flap. Use a direct decongestion on the nasal mucosa before incising it. Avoid suction here as it is a potentially aerosol generating step. A direct pack compression is preferable in case of troublesome bleeding. Use at least a PPE at minimum during the post-operative follow-ups of these patients. ## F. dacryocystectomy Dacryocystectomy is comparatively a safer procedure than a DCR and mandates all the general precautions as elucidated above. It has certain absolute indications in the present eraand any other indications need to be weighed against the risk of persistent epiphora. For all extended DCTs, PPE is mandatory. # X. conclusion While all attempts have been made to make this a comprehensive document, these guidelines must be put into practice taking into consideration the rules and regulations laid down by the local state/municipal authorities. As a subspecialty, oculoplastic surgery will come out of this crisis but not without fundamental changes to the way we practice, and the new normal may be completely different. In reality, the bulk of surgeries in ophthalmic plastic surgery are elective surgeries, and it is evident that resumption of elective and aesthetic procedures is not on the cards in the immediate foreseeable future. How much of these changes that our practice has undergone will become permanent remains to be seen; and the guidelines presented in this document are likely to change over time. Until an effective treatment against COVID-19 or a vaccine is developed, it is hoped that this set of guidelines can help oculoplastic surgeons in resuming clinical duties and serving society at large in an optimal and secure way, without compromising on both their safety as well as their patients. ## Financial ## Financial support and sponsorship Nil. ## Conflicts of interest There are no conflicts of interest. ## Disclaimer The authors of this document would like to declare that these guidelines are based on the information issued by various relevant organizations, and State and Central Governments as on the date of their release. These guidelines are provided for informational and educational purposes only. Adherence to any recommendations included in this document may not ensure a successful outcome in every situation. Furthermore, the recommendations contained in this document should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. These guidelines reflect the best available information at the time the document was prepared. The results of future studies may require revisions to the recommendations to reflect new data. The guidelines do not replace or override existing national/regional/ local statutory requirements. The guidelines are to be tempered with the regional, local and individual hospital guidelines and expertise. The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient considering all the circumstances presented by the individual patient, and the known variability and biological behavior of the medical condition. This expert panel does not warrant the accuracy or completeness of the guidance and assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this guidance or for any errors or omissions. We will not be a party to/for medico legal implications arising out of following or not following these recommendations.	None	None	Oculoplastic surgeries encompass both emergency surgeries for traumatic conditions and infectious disorders as well as elective aesthetic procedures. The COVID-19 pandemic has brought about a drastic change in this practice. Given the highly infectious nature of the disease as well as the global scarcity of medical resources; it is only prudent to treat only emergent conditions during the pandemic as we incorporate evidence-based screening and protective measures into our practices. This manuscript is a compilation of evidence-based guidelines for surgical procedures that oculoplastic surgeons can employ during the COVID-19 pandemic. These guidelines also serve as the basic framework upon which further recommendations may be based on in the future, as elective surgeries start being performed on a regular basis.
65319914ac5ccbc81f9708a2f096fde86d7a97f3	pubmed	APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing	APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on ''APASL consensus statements and recommendations for management of hepatitis C'' in March 2015 to revise the ''APASL consensus statements and management algorithms for hepatitis C virus infection'' (Hepatol Int 6:409-435, 2012). The working party consisted of expert hepatologists from the Asian-Pacific region gathered at the Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed, and debated during the course of drafting a revision. Participants of the consensus meeting assessed the quality of the cited studies. The finalized recommendations for hepatitis C prevention, epidemiology, and laboratory testing are presented in this review. # Introduction The prevalence rates of hepatitis C virus (HCV) and HCV genotype (GT) distribution around the Asia-Pacific region were well described in a recent study [bib_ref] Features of hepatitis C virus infection, current therapies and ongoing clinical trials..., Omata [/bib_ref]. Estimated HCV infection rates in the general populations were 0.1-14.7 % in the Asia-Pacific region [bib_ref] Features of hepatitis C virus infection, current therapies and ongoing clinical trials..., Omata [/bib_ref]. HCV GTs vary, such as HCV GT-1, GT-2, GT-3, and other GTs, in the Asia-Pacific region [bib_ref] Features of hepatitis C virus infection, current therapies and ongoing clinical trials..., Omata [/bib_ref]. The absolute numbers of currently HCVinfected both globally and in the Asia-Pacific region may recently have been scaled down, since better seroprevalence studies demonstrated lower rates of active infection in China than previously believed [bib_ref] Seroprevalence of transfusion-transmissible infectious agents among volunteer blood donors between, Zheng [/bib_ref] [bib_ref] Prevalence and trend of major transfusion-transmissible infections among blood donors in Western..., Song [/bib_ref]. In this article, we mainly aim to introduce the natural history of HCV infection and recent advances in hepatitis C prevention, epidemiology, and laboratory testing in Asian-Pacific countries. Grading of evidence and recommendations are shown in . ## Natural history of hcv infection The natural history of hepatitis C is quite variable. The majority of patients who acquire HCV do not spontaneously clear the virus and develop chronic HCV infection. Chronic infection results in liver fibrosis and ultimately cirrhosis in a subset of patients, although the rate of disease progression is variable. Patients who develop cirrhosis are at further risk for complicating events (such as variceal hemorrhage, ascites, and encephalopathy) and hepatocellular carcinoma, although many patients with compensated cirrhosis remain stable for years [bib_ref] APASL consensus statements and management algorithms for hepatitis C virus infection, Omata [/bib_ref] [bib_ref] Asian Pacific Association for the Study of the Liver consensus statements on..., Mccaughan [/bib_ref]. ## Acute hcv infection Around 3-4 million people are newly infected with hepatitis C annually, and this phenomenon is not limited to developing countries, as 18,000 new HCV infections occur annually in the USA alone [bib_ref] The hidden epidemic of hepatitis C virus infection in the United States:..., Ward [/bib_ref]. Populations at risk for acute hepatitis C are patients who received blood transfusions, blood products or anti-D-immunoglobulin during pregnancy prior to routine screening of blood products for HCV, intravenous drug users, intranasal cocaine users, patients with tattoos or body piercings, healthcare workers, dialysis patients, and those involved in high-risk sexual activities. The introduction of routine screening of blood products and sterile injection needles has changed the principal cohorts of newly infected patients in developed countries, although these factors are still the leading cause of newly acquired HCV infection in Asian countries [bib_ref] Acute hepatitis C in HIV infected men who have sex with men:..., Van De Laar [/bib_ref]. Acute hepatitis C infection is infrequently diagnosed because most patients are asymptomatic. Approximately 20-30 % of adults may develop clinical symptoms, which are usually mild and nonspecific. Onset of symptoms occurs 3-12 weeks after exposure. Symptoms may include malaise, weakness, anorexia, and jaundice. Jaundice appears in only 15-20 % of acutely infected individuals, and fulminant liver failure is rare except in those with concomitant chronic hepatitis B infection [bib_ref] a rare cause of fulminant hepatitis in Chiba, Kanda [/bib_ref]. HCV RNA can be detected in the serum within 1-2 weeks after exposure. The level of HCV RNA rises rapidly during the first few weeks and then peaks between 10 5 and 10 7 IU/mL, shortly before the peak of serum alanine aminotransferase (ALT) levels and onset of symptoms [bib_ref] Determinants of viral clearance and persistence during acute hepatitis C virus infection, Thimme [/bib_ref]. Serum ALT levels start rising 2-8 weeks postexposure and often reach levels more than 10 times the normal upper limits. Anti-HCV antibodies (anti-HCV), as detected by enzyme-linked immunosorbent assay (ELISA), become positive near the onset of symptoms, approximately 1-3 months after exposure. Up to 30 % of patients will test negative for anti-HCV at the onset of their symptoms, making anti-HCV testing unreliable for diagnosis of acute infection. Almost all patients eventually develop antibodies; however, titers can be low or undetectable in immunodeficient patients. Approximately 10-15 % of subjects may have fluctuating infection, with marked variation in the levels of ALT in association with marked changes in HCV RNA levels, including periods of HCV RNA negativity followed by reappearance of HCV RNA. In most patients, fluctuations are present only during the first 24 weeks after exposure, but they may also continue beyond 24 weeks [bib_ref] The natural history of acute hepatitis C: clinical presentation, laboratory findings and..., Loomba [/bib_ref]. The risk of chronic infection after hepatitis C acquisition is high because the virus has a tendency toward rapid mutation, leading to extensive viral diversity among the viral population infecting a single host. This can contribute to viral persistence because the viral diversity allows HCV to escape immune recognition [bib_ref] The outcome of acute hepatitis C predicted by the evolution of the..., Farci [/bib_ref]. In most studies, 50-85 % of patients chronically remain HCV RNA positive following infection and seroconversion, depending on the population and the source of infection. These studies are heterogeneous in terms of their study populations, and the majority are clinic-based acute hepatitis C case series using descriptive methodologies. Discrepancies in these estimates have been attributed to a number of factors. First, the asymptomatic nature of early infection means that detection of acute infection is uncommon. Second, there are currently no diagnostic tests to differentiate between acute and chronic infection. Third, the majority of HCV infections occur in marginalized populations, such as injecting drug users (IDUs), who may be difficult to recruit into studies and maintain in follow-up. Finally, the statistical methods and definitions used to determine clearance estimates vary among studies. Of those who are able to spontaneously clear HCV, most do so within 12 weeks of seroconversion, although spontaneous clearance after a longer period of follow-up has also been described [bib_ref] The effects of female sex, viral genotype, and IL28B genotype on spontaneous..., Grebely [/bib_ref]. The HCV RNA clearance rate is higher when clearance is defined as a single negative HCV RNA result compared with two negative HCV RNA results, which should be the preferred definition of RNA clearance [bib_ref] Potential biases in estimates of hepatitis C RNA clearance in newly acquired..., Amin [/bib_ref]. High spontaneous HCV clearance in the Asia-Pacific region may be due to the high prevalence of the favorable IL28B genotype [bib_ref] Genetic variation in IL28B and spontaneous clearance of hepatitis C virus, Thomas [/bib_ref]. ## Effects of treatment of acute hepatitis c The transition between acute hepatitis C and its progression to chronic HCV infection is poorly defined. Reported estimates of time to clearance range from 1-2 weeks up to 1-3 years. Although treatment is indicated in acutely infected patients likely to develop chronic HCV, the acute phase is frequently unrecognized. Peginterferon with or without ribavirin for 24 weeks induces high rates of viral clearance [bib_ref] Acute Hepatitis C Study Group. Acute hepatitis C: a 24-week course of..., Santantonio [/bib_ref]. Response rates are lower in patients treated more than 20 weeks postinfection, and it is often recommended to initiate the therapy if HCV RNA remains positive after 12 weeks of observation. This strategy also negates the risk of loss to follow-up in at-risk patients. Newer antiviral agents may alter this thinking [bib_ref] APASL consensus statements and management algorithms for hepatitis C virus infection, Omata [/bib_ref] [bib_ref] Asian Pacific Association for the Study of the Liver consensus statements on..., Mccaughan [/bib_ref]. ## Chronic hcv infection There have been extensive studies focusing on the natural course of the disease progression of chronic hepatitis C, including fibrosis progression and the development of cirrhosis and hepatocellular carcinoma (HCC). ## Natural progression of liver disease in chronic hcv infection The natural history of chronic HCV is described variably. Published estimates of fibrosis progression and time to cirrhosis are dependent on the study design and the patient population investigated. Retrospective studies have often been based on large tertiary referral centers and may reflect ascertainment bias because individuals with advanced liver disease are more likely to be referred. The timing of the initial infection is based on the patient's recall of first contact with blood products or intravenous drug abuse, which can often be inaccurate. In retrospective studies, cirrhosis rates have been reported to be between 17 and 55 %, HCC rates 1 and 23 %, and liver-related death 1 and 23 % over an estimated infection period of 20-30 years [bib_ref] Clinical presentation, outcome, and response to therapy among patients with acute exacerbation..., Sagnelli [/bib_ref] [bib_ref] The natural course of chronic hepatitis C: a comparison between patients with..., Kobayashi [/bib_ref]. Additionally, estimates from retrospective studies (17-55 %) have been higher than those from prospective studies (7-16 %), possibly reflecting referral bias in the former. Even prospective studies are limited by relatively short follow-up periods and are only available in well-defined patient cohorts, thus failing to provide information on longer-term outcomes. These studies typically show lower complication rates, as shown in a cohort of female infected with hepatitis C following administration of anti-D-immunoglobulin during pregnancy. Over a follow-up period of 18-20 years, the incidence of histologically confirmed cirrhosis was reported to be between 1 and 2 %, and bridging fibrosis between 2 and 10 % [bib_ref] Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish..., Kenny-Walsh [/bib_ref]. An alternative approach is retrospective prospective studies in which the precise time at which past infection with acute hepatitis C occurred can be defined retrospectively and the subjects are subsequently followed prospectively. In early retrospective prospective studies, the interval from exposure ranged from 9 to 50 years, and development of cirrhosis occurred in 0.3-15 % of patients, HCC developed in 0-1.9 %, and liver-related death occurred in 0-2.8 % [bib_ref] Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors, Missiha [/bib_ref]. Cumulatively, these studies suggest that there is a variable rate of disease progression to cirrhosis and its complications, likely due to multiple factors. Genomewide association studies revealed variants associated with the progression of liver fibrosis in HCV-infected patients [bib_ref] A genomewide association study of HCV-induced liver cirrhosis in the Japanese population..., Urabe [/bib_ref]. Further studies will be needed to clarify this point. The progression of chronic hepatitis C is accelerated in human immunodeficiency virus (HIV)-infected patients. Hepatitis C and HIV can share routes of transmission. Coinfection with HIV has a negative impact on the natural history of HCV. Among those with persistent HCV infection, HIV coinfection has been associated with higher HCV plasma RNA viral loads and, according to most studies, with more rapid progression to cirrhosis, liver failure, and HCC. In a meta-analysis of eight cohorts of HIV/HCVcoinfected individuals, Graham et al. [bib_ref] Influence of human immunodeficiency virus infection on the course of hepatitis C..., Graham [/bib_ref] demonstrated that HIV coinfection increased the risk of cirrhosis by a factor of 2.1 and clinically decompensated liver disease by a factor of 6.1. ## Development of cirrhosis and its complications HCV infection causes slowly progressive disease characterized by persistent hepatic inflammation, leading to development of cirrhosis in approximately 10-20 % of patients over 20-30 years of HCV infection. However, the published data vary considerably, with reported progression rates to cirrhosis from as low as 2-3 % to as high as 51 % over 22 years [bib_ref] Clinical outcomes after transfusion associated hepatitis C, Tong [/bib_ref] [bib_ref] Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak..., Wiese [/bib_ref]. The progression to cirrhosis is often clinically silent, and some patients are not known to have HCV infection until they present with the complications of end-stage liver disease. Cirrhosis rates begin to become significant after 20 years of infection. The time from HCV infection to cirrhosis depends on multiple factors and cannot be predicted in an individual patient. Multiple studies have attempted to measure the time interval from infection to cirrhosis and HCC. Frequently, the initial time of infection is not known and therefore must be estimated. Individuals who contracted HCV through a single blood transfusion or surgery are able to provide more precise time intervals from infection to cirrhosis and HCC. Although the mean time to cirrhosis in chronic HCV patients is estimated at 20 years, only 10-20 % of patients will actually develop cirrhosis within this time period [bib_ref] Natural history of chronic hepatitis C, Seeff [/bib_ref]. A systematic review of 111 studies analyzing the natural history of HCV estimated that the prevalence of cirrhosis 20 years after infection was 16 % [95 % confidence interval (CI) 14-90 %] [bib_ref] Estimation of stagespecific fibrosis progression rates in chronic hepatitis C virus infection:..., Thein [/bib_ref]. Overall, once cirrhosis has developed, there is a 1-5 % annual risk of HCC and a 3-6 % annual risk of hepatic decompensation. Five-and ten-year survival rates of compensated cirrhosis are 90-95 and 70-80 %, respectively. The cumulative probability of an episode of clinical decompensation is 5-10 % at 1 year, increasing to 30-40 % at 10 years from the diagnosis of cirrhosis. Once decompensated cirrhosis occurs, the 5-year survival rate falls to 40-50 % [bib_ref] on behalf of the Trent Hepatitis C Study Group. A comparison of..., Lawson [/bib_ref]. Achievement of viral eradication is associated with a marked decrease in decompensation and the incidence of bacterial infection [bib_ref] Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12..., Trinchet [/bib_ref]. ## Development of hcc The risk of HCC occurrence varies among HCV patients. It is a function of the degree of liver fibrosis and the time after acquisition of the infection. In a meta-analysis of 21 case-control studies, the risk for HCC increased 17-fold in HCV-infected patients compared with HCV-negative controls [bib_ref] A meta-analysis of epidemiological studies on the combined effect of hepatitis B..., Donato [/bib_ref]. Virtually all cases of HCV-related HCC occur among patients with cirrhosis. Once cirrhosis is established, HCC develops at an annual rate of 1-4 % and is increased in patients with raised alpha-fetoprotein levels at baseline. Higher estimates, in the range of 5-7 %, have been reported from Japan. The higher proportion of elderly patients infected with HCV in Japan may explain the higher incidence rate in that country because older age accelerates the development of HCC. Patients with lower degrees of fibrosis exhibit HCC development at rates of 0.5-2.6 % [bib_ref] Trend of liver cirrhosis as precancerous lesions, Kiyosawa [/bib_ref]. In the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial, the overall rate of HCC development in cirrhotic patients was 7 % over 4.8 years. Importantly, a significant number of patients with Ishak grade 3 or 4 fibrosis also developed HCC, raising questions regarding what defines the need for screening in cirrhotic and noncirrhotic patient cohorts. The risk of HCC appears to be greater with HCV GT-1b compared with HCV GT-2a/2c [bib_ref] Hepatitis C virus genotype 1b as a major risk factor associated with..., Bruno [/bib_ref]. In contrast to hepatitis B virus (HBV) infection, HCC in patients with hepatitis C occurs almost exclusively in those with cirrhosis, suggesting that cirrhosis is the major risk factor. There is also suggestive experimental evidence that HCV infection itself can promote development of HCC. In addition, obesity is an independent risk factor for HCC development in chronic hepatitis C patients [bib_ref] Obesity is an independent risk factor for hepatocellular carcinoma development in chronic..., Ohki [/bib_ref]. HCV GT-3 is also associated with a significantly increased risk of developing cirrhosis and HCC compared with HCV GT-1 . Recent study demonstrated that patients with diabetes or HCV GT-3 infection were significantly more likely to develop HCC after sustained virologic response (SVR) in veterans with HCV infection in the USA. ## Survival Survival is decreased in patients with HCV, especially in those who have developed cirrhosis. Compared with uninfected patients, patients with chronic HCV infection are more likely to die at a younger age and, as expected, from liver-related causes . In the large prospective HALT-C trial, which included 1050 patients with advanced fibrosis or cirrhosis who were followed for a median of 5.7 years, 122 patients (12 %) died and an additional 74 patients (7 %) underwent liver transplantation . In a series of 384 patients with compensated cirrhosis, the 3-, 5-, and 10-year survival rates were 96, 91, and 79 %, respectively . Once decompensated cirrhosis occurred, the 5-year survival declined substantially to approximately 50 %. Survival may also be worse in patients who develop cryoglobulinemia. Causes of death among patients with HCV vary with the age group being examined. In a population study from Denmark, the primary cause of death among patients aged 20-39 years was unnatural (reported as death due to mental and behavioral disorders related to psychoactive substance use and death resulting from external causes). The 10-year risk of unnatural death in patients between the ages of 20 and 29 years was 13 %. In patients between the ages of 40 and 59 years, deaths were equally distributed among liver-related, non-liver-related, and unnatural causes. In patients 70 years of age or older, the most common causes of death were non-liver related. Patients with HCV were at increased risk of death compared with non-HCV-infected individuals at all ages, ranging from an 18-fold increase for 20-29-year-olds to a 1.6-fold increase for patients aged 70 years or greater . Mortality in patients with HCV is not always related to liver disease. A population-based study from Australia found that most deaths in young patients with HCV were due to continued drug use rather than the infection . ## Hcv infection and extrahepatic manifestation Some patients with chronic HCV infection may suffer from extrahepatic illnesses, with a symptomatic spectrum varying from fatigue to permanent organ damage. These illnesses resolve following SVR by antiviral treatment [bib_ref] APASL consensus statements and management algorithms for hepatitis C virus infection, Omata [/bib_ref]. Interferon-free treatment appears safe and effective in HCV patients with certain extrahepatic manifestations . ## Hepatitis c virus genotype 3 infection and hepatic steatosis Patients infected with HCV often have hepatic steatosis. Several studies reported that HCV GT-3 infection was associated with hepatic steatosis compared with HCV GT-1 infection . HCV GT-3 is the most prevalent HCV GT in patients with chronic HCV infection in North and Central India, where HCV GT-3 is also associated with significant hepatic steatosis and fibrosis . Among patients infected with HCV GT-3, SVR significantly reduced steatosis, but there was no change in steatosis among those without SVR . Expression of steatosisassociated HCV GT-3 core protein produces intracellular lipid accumulation in primary and cultured hepatocytes , and polymorphisms in HCV GT-3 core protein could produce increased intracellular lipid levels . These facts may indicate the direct cytopathic effect of HCV core protein. ## Chronic hcv infection and insulin resistance/diabetes mellitus Several studies have shown a higher prevalence of HCV antibodies in patients with diabetes mellitus than in the general population . HCV infection is associated with insulin resistance/diabetes mellitus in adult patients with cirrhosis undergoing assessment for liver transplantation . Allison et al. reported that the prevalence of diabetes mellitus was 50 % in cirrhotic patients infected with HCV, and it was 9 % in those without HCV. Although there are several basic associations between HCV infection and insulin resistance/diabetes mellitus , it might be difficult to cure insulin resistance/diabetes mellitus in patients with HCV and advanced liver fibrosis with interferon-free regimens. ## Chronic hepatitis c virus infection in patients with normal versus high serum aminotransferase levels HCV infection with normal ALT is defined by detectable HCV RNA and a serum ALT concentration that is persistently within the normal range. Using this definition, approximately 25-40 % of patients with chronic HCV infection have persistently normal serum ALT. It has been proposed that the upper limit of normal may be set too high because of unrecognized fatty liver disease among apparently healthy individuals who were included in the cohorts used to establish the normal range. This is supported by a study in which a decrease in ALT levels was noted in patients with ''normal'' ALT levels who achieved a SVR after undergoing treatment [58]. Many anti-HCV-positive patients with normal serum ALT concentrations have an abnormal liver biopsy, although the changes are usually mild. Patients with a persistently normal ALT are more likely to be female and generally have milder disease, a lower serum HCV RNA level, and a relatively favorable prognosis, although up to 10 % of patients have bridging fibrosis, suggesting that the relatively favorable prognosis is not universal . A significant proportion of patients (20-30 %) experience ALT flares that may be associated with enhanced disease progression [60]. ## Predictive models for disease progression Many multivariate models that can help predict disease progression in individual patients have been developed. Baseline data collected as part of the HALT-C trial were used to develop predictive models for both clinical and histological outcomes. The 1050 patients in the HALT-C trial were previous nonresponders to standard interferon therapies who had advanced fibrosis on liver biopsy. Clinical outcomes were defined as an increase in Child-Pugh score to seven or greater, variceal bleeding, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, and liver-related death. The histological outcome for the study was an increase in Ishak fibrosis score of two or more points (biopsies taken at 1.5 and/or 3.5 years after randomization). Factors predictive of clinical outcomes on multivariable analysis were elevated aspartate aminotransferase (AST)/ ALT ratio, elevated total bilirubin, low albumin, low platelet count, and increasing Ishak fibrosis score. Factors predictive of histological progression were increasing body mass index, low platelet count, and hepatic steatosis [61]. In another study, clinical and laboratory variables among 247 patients with varying degrees of HCV histologic severity were analyzed. Death from liver failure, development of HCC, and liver transplantation were considered together in the statistical analysis. History of hepatic decompensation (defined as at least one episode of ascites, jaundice, hepatic encephalopathy, or gastrointestinal bleeding of variceal origin) and serum albumin concentration were independent predictors of the above outcomes. Patients without history of decompensation and serum albumin concentration greater than 4.1 mg/dL (41 g/L) had only a 3 % chance of developing one of the endpoints within 5 years versus approximately 6 % in patients with one of these factors and 40 % in patients with both factors . In a third study of 455 patients who were followed for a median of 4.7 years, the only independent predictors of progression on multivariable analysis were sporadic transmission, advanced fibrosis, and low albumin . ## Spontaneous resolution of chronic hepatitis c Spontaneous resolution of chronic hepatitis C is relatively rare and has been reported in only a few longitudinal or retrospective studies. Rates of 0.5 % resolution per year per person have been observed . However, HCV RNA can persist at very low levels in the serum, peripheral lymphoid cells, and brain for many years after apparent resolution of chronic hepatitis C. ## Effect of antiviral therapy and natural history of hcv infection Recent data demonstrate that antiviral therapy, particularly among those achieving a SVR, is associated with long-term persistence of a SVR, improved fibrosis and inflammation scores, reduced incidence of HCC, and prolonged life expectancy [bib_ref] APASL consensus statements and management algorithms for hepatitis C virus infection, Omata [/bib_ref]. This reduction in the rate of progression has also been demonstrated in patients with chronic hepatitis C and cirrhosis in some studies. The impact on slowing progression is greatest in patients with a SVR, less in relapsers, and equivocal in nonresponders [bib_ref] APASL consensus statements and management algorithms for hepatitis C virus infection, Omata [/bib_ref]. With the most recent approval of direct-acting antivirals (DAAs), the rates of SVR and virological cure have greatly increased across all HCV GTs for both treatment-naïve and treatment-experienced patients [bib_ref] APASL consensus statements and management algorithms for hepatitis C virus infection, Omata [/bib_ref]. ## Antiviral therapy and effect on hepatic fibrosis and inflammation Most of the studies on the effect of treatment of fibrosis have been limited by a lack of long-term follow-up after treatment versus untreated patients. Ongoing cofactors such as alcohol and metabolic syndrome are likely to play a significant role. The majority of patients (57-94 %) demonstrate marked improvements in their necroinflammation and fibrosis scores following a SVR [65-68]. However, a small minority (1-14 %) of patients demonstrated fibrosis progression following a SVR [bib_ref] Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients..., Poynard [/bib_ref]. Young age and platelet count at the SVR are predictive of fibrosis regression [bib_ref] Histologic improvement of fibrosis in patients with hepatitis C who have sustained..., Shiratori [/bib_ref]. The HALT-C study showed that long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who did not have a response to initial treatment with peginterferon and ribavirin. Patients with HCV cirrhosis who achieve a SVR have a reduction in their portal pressure measurements compared with nonresponders [bib_ref] Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis..., Rincon [/bib_ref]. Although achieving a SVR prevents development of esophageal varices in the majority of patients with compensated HCV cirrhosis, a recent prospective study showed that, although the risk of developing varices post-SVR was vastly reduced, it was not eliminated, with a small number of patients developing small esophageal varices (2/57) [bib_ref] Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh..., Bruno [/bib_ref]. A meta-analysis of data from 1013 patients from three large randomized trials demonstrated that peginterferon treatment reduced inflammation and fibrosis in patients with a SVR or who relapsed, but not in nonresponders. This improvement was more prominent with the use of peginterferon than with interferon [bib_ref] Effect of peginterferon alfa-2a on liver histology in chronic hepatitis C: a..., Cammà [/bib_ref]. Even in patients with advanced fibrosis or cirrhosis, inflammation and fibrosis are improved with interferon monotherapy, peginterferon monotherapy, or peginterferon plus ribavirin combination therapy [bib_ref] Histological benefits of virological response to peginterferon alfa-2a monotherapy in patients with..., Everson [/bib_ref]. Overall, studies of antiviral therapy with interferon monotherapy, peginterferon monotherapy, or peginterferon plus ribavirin combination therapy demonstrated improvement in inflammation and fibrosis in patients with a SVR, to a lesser extent in relapsers, and uncertain benefit in nonresponders. Overall, progression of liver fibrosis to cirrhosis is rare but can occur despite a SVR. Based on a large pooled dataset from 3010 naïve patients, one study estimated the prevalence at 7 % [bib_ref] Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients..., Poynard [/bib_ref]. However, another study of 121 patients with pre-and posttreatment liver biopsies reported fibrosis progression in 12 % of patients after ruling out de novo infections or existence of occult HCV via polymerase chain reaction (PCR) of liver tissue [bib_ref] Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis..., Maylin [/bib_ref]. The presence of significant liver comorbidities or risk factors such as alcohol consumption or fatty liver disease are likely causes for many of the cases in which progression of liver diseases occurs post-SVR. In general, the combination of more than one liver disease, for example, hemochromatosis with alcohol consumption, or chronic viral hepatitis with alcoholic liver injury, can drive fibrosis progression in HCV patients [bib_ref] Hepatitis C and liver fibrosis, Schuppan [/bib_ref]. ## Antiviral therapy and effect on incidence of hepatocellular carcinoma Among those with chronic HCV infection without advanced fibrosis or cirrhosis, the incidence of HCC is decreased in patients with a SVR and probably also in relapsers when compared with nonresponders [bib_ref] Transient biochemical response in interferon therapy decreases the development of hepatocellular carcinoma..., Okanoue [/bib_ref]. Several studies and a meta-analysis have concluded that eradication of HCV with antiviral therapy reduces the risk of HCC in patients with chronic hepatitis C, independent of fibrosis stage [bib_ref] Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of..., Yoshida [/bib_ref] [bib_ref] Outcome of sustained virological responders with histologically advanced chronic hepatitis C, Morgan [/bib_ref]. However, a reduction in the risk of HCC does not necessarily indicate improvement in overall survival, and interferon is less effective in patients with cirrhosis. In addition, cirrhotic patients tend to be older, and liver-unrelated mortality may be significant and obscure any potential benefit of interferon therapy. A few studies have shown that, in patients with advanced fibrosis and/or cirrhosis who achieved a SVR, the age-adjusted hazard ratio for developing HCC and death is significantly reduced. The failure to achieve a SVR was associated with a higher risk of liver-related complications, HCC, and liver-related mortality compared with those who achieved a SVR [bib_ref] Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival..., Cardoso [/bib_ref]. However, several studies have demonstrated no beneficial effect of interferon therapy on the prognosis of cirrhotic patients. A recent meta-analysis that included 30 studies comprising 31,528 patients from 17 countries reported a 4.6 % absolute reduction in developing HCC following a SVR [bib_ref] Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma:..., Morgan [/bib_ref]. Furthermore, in patients with advanced liver disease, achieving a SVR reduced the overall risk of developing HCC from 17.8 to 4.2 %, with a reduction in incidence from 3.3 % per person-year to 1.05 % (CI 0.7-1.5 %) per person-year. Prospective data extracted from the HALT-C cohort also suggested that, following a SVR, the incidence of HCC decreased from 8.8 to 1.1 % over approximately 7 years of follow-up. A recently published meta-analysis demonstrated that antiviral treatment was associated with a reduced risk of HCC in patients who attained a SVR, compared with nonresponders; the best outcomes were observed in patients treated with ribavirin-based regimes [bib_ref] Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C..., Singal [/bib_ref]. The attainment of a SVR also demonstrated prevention of the development of esophageal varices [bib_ref] Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh..., Bruno [/bib_ref]. There have been case reports and long-term follow-up studies that have shown development of HCC in patients with advanced hepatic fibrosis after achievement of a SVR. These observations underscore the continued risk of HCC and the need for ongoing surveillance with imaging and alpha-fetoprotein (AFP) testing in patients with chronic hepatitis C and advanced hepatic fibrosis or cirrhosis, even after a SVR. A recent study tried to risk-stratify patients further by creating a scoring system based on age, platelets, AFP, and fibrosis score [bib_ref] A novel predictive score for hepatocellular carcinoma development in patients with chronic..., Chang [/bib_ref]. Patients were identified as low, medium, or high risk depending on their score. In the low-risk group, 9 out of 657 patients developed HCC over 9 years, equating to a 0.17 % risk per annum, an incidence rate that is well below that where screening is deemed cost effective. If this score is validated, it may help identify which patients should be recommended for long-term HCC surveillance. Achievement of eradication of HCV was associated with a marked decrease of HCC [bib_ref] Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12..., Trinchet [/bib_ref]. ## Antiviral therapy and effect on life expectancy It is expected that long-term durability of a SVR, improvement in fibrosis and inflammation, and a reduced incidence of HCC translate into prolonged life expectancy. Interferon treatment decreases the risk ratio for overall death and liver-related death, particularly in patients with a SVR, while the risk of liver-unrelated death remains unchanged [bib_ref] Interferon treatment improves survival in chronic hepatitis C patients showing biochemical as..., Kasahara [/bib_ref] [bib_ref] Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development..., Shiratori [/bib_ref]. ## Prevention of hcv infection in asia The World Health Organization estimates that more than 185 million people worldwide might be infected with HCV. These are crude estimates with significant differences in prevalence, from 2.0 % in South East Asia to 3.7-3.8 % in East and Central Asia [bib_ref] Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody..., Hanafiah [/bib_ref] , and the highest of approximately 15 % in Egypt [bib_ref] Towards realistic estimates of HCV incidence in Egypt, Breban [/bib_ref]. The prevalence of hepatitis C infection varies significantly in different areas and different populations among or within countries, implying different routes of transmission and different strategies needed to prevent HCV transmission [bib_ref] Distribution and clinical correlates of viral and host genotypes in Chinese patients..., Rao [/bib_ref] [bib_ref] Prevalence and characterization of hepatitis B and C virus infections in a..., Xu [/bib_ref]. Effective prevention of HCV can occur through the use of a prophylactic vaccine, but vaccine trials are still in early phases or progressing slowly [bib_ref] Progress in the development of preventive and therapeutic vaccines for hepatitis C..., Torresi [/bib_ref]. Therefore, the current approach for the prevention of HCV infection is to reduce transmission by reducing the risk of exposure to the virus, potentially by treatment with newly developed DAAs. In addition to a universal prevention strategy to reduce transmission by blood transfusion and other unsafe medical procedures including unsafe injection, unsafe dental management, hemodialysis, acupuncture, catheters, and other medical equipment, specific risk populations should be identified to develop population-specific prevention strategies, such as for people who inject drugs (PWID) using contaminated injection equipment, people with skin or mucous membrane inoculation, or with exposure of broken skin to contaminated blood such as through use of intranasal drugs or cosmetic procedures [bib_ref] Hepatitis C: who is at risk and how do we identify them?, Goldberg [/bib_ref]. Sexual transmission occurs particularly in the HIV coinfected population, but is at low or no risk in heterosexual couples. Meanwhile, male who have sex with male (MSM) were recently shown to be an at-risk population. Higher prevalence of HCV among HIV-positive than HIV-negative male was observed in the Asia-Pacific region [bib_ref] HIV and hepatitis C virus co-infection among men who have sex with..., Lea [/bib_ref]. The majority of acute hepatitis C in HIV-infected patients were MSM [bib_ref] Acute hepatitis C in HIV-1 infected Japanese cohort: single center retrospective cohort..., Ishikane [/bib_ref] [bib_ref] National trend and characteristics of acute hepatitis C among HIV-infected individuals: a..., Lo [/bib_ref]. Transmission from an infected mother to infant depends on the activity status of HIV coinfection during pregnancy. Due to the few clinical manifestations of chronic HCV infection, screening is important based on the geographical region and risk population. It would be more helpful to identify HCV infection earlier than to reduce transmission and the infection pool by initiating treatment. ## Blood safety In 1992, the introduction of second-generation anti-HCV ELISA largely eliminated HCV transmission via donated blood by screening out infected donors. Third-generation anti-HCV enzyme immunoassay (EIA) further reduced the window period by at least 1 week. Nucleic acid testing (NAT) can further reduce the risk of HCV transmission to 0.1-2.33 per million donations by mini-pool or individual donation testing [bib_ref] APASL consensus statements and management algorithms for hepatitis C virus infection, Omata [/bib_ref] [bib_ref] Impact of individual-donation nucleic acid testing on risk of human immunodeficiency virus,..., Vermeulen [/bib_ref] [bib_ref] A multi-Chinese blood center study testing serologic-negative donor samples for hepatitis C..., Shan [/bib_ref]. NAT was applied to donor HCV screening in Germany in 1997. In the Asia-Pacific region, NAT has been used for blood screening in Japan since 1999, Australia and HCV antigen assays, another method of detection of active HCV infection, have been commercially available for a couple of years and can detect both free antigen and antibody-combined antigen. A few studies have shown that they can shorten the window period. Therefore, this was applied in blood testing to enhance the overall effectiveness of serological HCV screening in some countries [bib_ref] Detection of HCV core antigen in HCV RNA positive, anti-HCV negative blood..., Brojer [/bib_ref] [bib_ref] Simultaneous detection of hepatitis C virus (HCV) core antigen and anti-HCV antibodies..., Laperche [/bib_ref] [bib_ref] Hepatitis C virus (HCV) core antigen detection in HCV RNA-positive/anti-HCV-negative Polish blood..., Letowska [/bib_ref]. However, the Global Database on Blood Safety shows that testing with anti-HCV ELISA is insufficient, particularly in countries with a low human development index-only 51.3 % of units of blood are tested for HCV [bib_ref] Transmission of hepatitis C virus by blood transfusions and other medical procedures:..., Prati [/bib_ref]. Blood donations are still not routinely tested for infectious markers including HCV in 39 countries. Overall, 47 % of donations are tested in laboratories without quality assurance; most were in Asia. Even the testing technologies varied by country, from all technologies in Egypt to a few blood centers in India, with the number of voluntary unpaid blood donations increasing from 3.6 million in 2007 to 4.6 million in 2008. ## Prevention in healthcare settings HCV infections are more likely to occur in healthcare settings with low compliance with universal precautions, associated with social imbalance, inequity of income, and inequity of health, particularly in low-and middle-income countries. The risks of HCV infection in healthcare settings include unsafe injection, dental management, medical procedures, and hemodialysis, and sometimes acupuncture in certain countries or areas. In a meta-analysis, unsafe injection practices were found to be widespread in the developing world, accounting for more than 50 % of infections. It was estimated that each person in the developing world receives 1.5 injections per year on an average. However, at least 50 % of injections were unsafe in 14 of 19 #2 Consensus statements and recommendations on blood safety 1. All countries must establish a national system for blood donor selection for the donation of blood or blood components. (A1) 2. Regular audit procedures should be implemented to ensure compliance at blood-testing facilities. (B2) 3. Anti-HCV antibody tests must be quality-assured with third-generation EIA or chemiluminescence immunoassay (CIA). (A1) 4. Application of HCV antigen assays and/or nucleic acid testing for the universal screening of blood products should be country specific based on availability and cost. (B2) countries [bib_ref] Unsafe injections in the developing world and transmission of bloodborne pathogens: a..., Simonsen [/bib_ref]. Moreover, 82 % of administered injections in Asia were considered unnecessary [bib_ref] Transmission of hepatitis C virus by health care workers in a rural..., Hayashi [/bib_ref]. Reuse of needles and reuse of syringes remain a common practice in Bangladesh and Pakistan [bib_ref] HCV in Pakistani: a systematic review of prevalence genotypes and risk factors, Waheed [/bib_ref] [bib_ref] Health care risk factors among women and personal behaviors among men explain..., Janjua [/bib_ref]. Unsafe injections have been estimated to transmit 2.3-4.7 million HCV infections every year [bib_ref] Transmission of hepatitis B, hepatitis C and human immunodeficiency viruses through unsafe..., Kane [/bib_ref]. It was estimated that 40 % of new HCV infections are associated with unsafe injections globally [bib_ref] Use of injections in healthcare settings worldwide, 2000: literature review and regional..., Hutin [/bib_ref]. The average incidence of anti-HCV seroconversion after accidental percutaneous exposure from HCV-positive source is 1.8 %. Unfortunately, unsafe injections remain a problem in developing areas, where 75 % of unsafe injections are still conducted with insufficiently sterilized equipment [bib_ref] Use of injections in healthcare settings worldwide, 2000: literature review and regional..., Hutin [/bib_ref]. Other risks of HCV infection involve acupuncture and needle-stick injury, which account for up to 7 % of HCV infections [bib_ref] APASL consensus statements and management algorithms for hepatitis C virus infection, Omata [/bib_ref] [bib_ref] Estimation of the global burden of disease attributable to contaminated sharps injuries..., Prüss-Ü Stün [/bib_ref]. Medical procedures associated with HCV infection are inevitable due to low compliance with universal precautions [bib_ref] Transmission of hepatitis C virus by blood transfusions and other medical procedures:..., Prati [/bib_ref] including surgical procedures [bib_ref] Outbreak of hepatitis C virus infection during sclerotherapy of varicose veins: long-term..., De Ledinghen [/bib_ref] , gastrointestinal endoscopy [bib_ref] Multiple clusters of hepatitis virus infections associated with anesthesia for outpatient endoscopy..., Gutelius [/bib_ref] , radiopharmaceuticals [bib_ref] Hepatitis C virus infections from a contaminated radiopharmaceutical used in myocardial perfusion..., Patel [/bib_ref] , and oncology procedures. Low compliance with universal precautions also contributed to hemodialysisassociated HCV infection [bib_ref] Lack of de novo hepatitis C virus infections and absence of nosocomial..., Ross [/bib_ref]. Mishandling of parenteral medication vials is a major risk for HCV infection outbreaks in dialysis units. In Egypt, the HCV infection rate was as high as 50-90 % among dialysis patients [bib_ref] The epidemiology of hepatitis C virus in Egypt: a systematic review and..., Mohamoud [/bib_ref]. The Centers for Disease Control and Prevention (CDC) recommends that all single-use injectable medications and solutions be dedicated for use on a single patient. Medications packaged as multidose should be assigned to a single patient whenever possible. The occurrence of HCV infection in healthcare settings varies depending upon the frequency of injections, medical procedures, etc. and the level of compliance with universal precautions. High frequency of injections and low compliance with universal precautions is strongly associated with a high prevalence of HCV in the general population. Compliance with universal precautions varies in the Asia-Pacific region; it is lowest in Turkey at 33.6 % [bib_ref] Occupational Infections Study Group. Healthcare workers' compliance with universal precautions in Turkey, Hosoglu [/bib_ref] , 40 % in India [bib_ref] Knowledge and practices about hospital waste disposal and universal safety precautions in..., Megha [/bib_ref] , and 64.7 % in China [bib_ref] Factors impacting compliance with standard precautions in nursing, China, Luo [/bib_ref]. The knowledge of universal precautions was inadequate in some countries in Asia [bib_ref] Knowledge and practices about hospital waste disposal and universal safety precautions in..., Megha [/bib_ref] [bib_ref] Factors impacting compliance with standard precautions in nursing, China, Luo [/bib_ref] [bib_ref] Risk of infection among primary health workers in the Western Development Region,..., Timilshina [/bib_ref] [bib_ref] Knowledge of blood-borne infectious diseases and the practice of universal precautions amongst..., Hamid [/bib_ref]. The factors influencing compliance were irregular supply of materials, lack of other high-level disinfection equipment, and lack of training [bib_ref] Knowledge and practices about hospital waste disposal and universal safety precautions in..., Megha [/bib_ref] [bib_ref] Risk of infection among primary health workers in the Western Development Region,..., Timilshina [/bib_ref] [bib_ref] Knowledge of blood-borne infectious diseases and the practice of universal precautions amongst..., Hamid [/bib_ref] [bib_ref] Thai nursing students' knowledge and health beliefs about AIDS and use of..., Earl [/bib_ref]. Body piercing, tattooing, and cosmetology are also associated with potential HCV infection [bib_ref] Body piercing as a risk factor for viral hepatitis: an integrative research..., Hayes [/bib_ref] [bib_ref] Tattooing and the risk of transmission of hepatitis C: a systematic review..., Jafari [/bib_ref]. Tattoo-associated HCV infection is one of the greatest risks in some Asian countries such as Bangladesh, India, and Japan [bib_ref] Features of hepatitis C virus infection, current therapies and ongoing clinical trials..., Omata [/bib_ref]. These data show that non-healthcare transmission routes should also be noted. ## Prevention for persons who inject drugs (pwid) PWID are important sources of HCV infection, particularly in middle-and high-income countries. Most HCV prevalence studies are based on anti-HCV because PCR-based tests are rarely used in epidemiological studies. The estimated HCV prevalence rates varied among PWID in the Asia-Pacific region. Recently, a systematic review showed that midpoint reports ranged from 36.0 % in Afghanistan to 89.8 % in Thailand. China has the largest estimated population of PWID and had midpoint estimates of anti-HCV prevalence amongst PWID of 67.0 % [bib_ref] Global epidemiology of hepatitis B and hepatitis C in people who inject..., Nelson [/bib_ref]. Due to the common transmission route of sharing contaminated injecting equipment, the prevention strategy for HCV infection should be the same as that for prevention of HIV infection. ''Needle and syringe'' programs, including other drugusing paraphernalia, should be recommended, and ''condom'' programs for people who inject drugs and their sexual partners are advisable. In addition to HIV infection prevention, HCV transmission-specific strategies should be advocated. Those strategies include implementing sterile needle and syringe programs that provide low-dead-space syringes for distribution to people who inject drugs, offering peer interventions to people who inject drugs to reduce the incidence of viral hepatitis, offering opioid substitution therapy to treat opioid dependence, reducing HCV risk behavior and transmission through injecting drug use, and increasing adherence to HCV treatment, although a meta-analysis showed that there was insufficient evidence that interventions with needle and syringe programs were effective [bib_ref] Evidence for the effectiveness of sterile injecting equipment provision in preventing hepatitis..., Palmateer [/bib_ref]. Another systematic review showed no clear association of HCV prevalence with duration of injection use or age of users [bib_ref] Injecting alone among young adult IDUs in five US cities: evidence of..., Hagan [/bib_ref]. Unfortunately, many countries do not provide sterile needle and syringe programs, and the same countries do not provide sufficient coverage even if they do have those programs. It is estimated that only 22 syringes are provided per year per person who injects drugs. In the Asia-Pacific region, Australia had by far the greatest rate of needle-syringe distribution at 202 needle-syringes per #3 Consensus statements and recommendations on prevention in healthcare settings 1. In healthcare settings, universal precautions should be followed for healthcare and cosmetology workers and strictly carried out. (A1) 2. Regular audit should be implemented for hand hygiene, safe handling and disposal of sharp objects and waste, and safe cleaning of equipment. (B2) 3. Unnecessary injections should be avoided. PWID per year; however, the rate of needle-syringe distribution is only 0.5 needle-syringes per PWID per year in the Middle East [bib_ref] HIV prevention, treatment, and care services for people who inject drugs: a..., Mathers [/bib_ref]. In addition to injected drugs, a systematic review suggested that noninjection drug use is also associated with a higher risk of HCV infection, such as sharing of inhalation equipment for cocaine [bib_ref] Non-injection drug use and hepatitis C virus: a systematic review, Scheinmann [/bib_ref]. ## Prevention of infection via sexual transmission Based on a cross-sectional study of sexual transmission of HCV among monogamous heterosexual couples, the maximum incidence rate of HCV transmission by sex was as low as 0.07 % per year or approximately one per 190,000 sexual contacts. No specific sexual practices were related to HCV positivity among couples [bib_ref] Sexual transmission of hepatitis C virus among monogamous heterosexual couples: the HCV..., Terrault [/bib_ref]. However, another Asian study showed that the seroprevalence rates of anti-HCV were 5.5 % in HIV-positive MSM and 0.4 % in HIV-negative MSM [bib_ref] Seroprevalence of hepatitis virus infection in men who have sex with men..., Tseng [/bib_ref]. This result is similar to that of a community survey conducted in London, UK that showed that the seroprevalence of anti-HCV was more common in the HIV-infected population (7.7 %) than in those without HIV infection (1.2 %) [bib_ref] Hepatitis C in men who have sex with men in London-a community..., Price [/bib_ref]. Therefore, the risk of sexual transmission is strongly associated with preexisting HIV infection and unsafe sex [bib_ref] Unsafe sex and increased incidence of hepatitis C virus infection among HIV-infected..., Rauch [/bib_ref] , and there is low or no risk of sexual transmission of HCV among HIV-uninfected heterosexual couples. ## Mother-to-infant transmission Mother-to-infant transmission (also called vertical transmission) is significantly affected by coinfection with HIV. The transmission rate varied from 4 to 8 % among mothers without HIV coinfection; however, it increased to 17-25 % among mothers coinfected with HIV [bib_ref] Perinatal transmission of hepatitis C virus from human immunodeficiency virus type 1-infected..., Thomas [/bib_ref] [bib_ref] Risk factors for perinatal transmission of hepatitis C virus (HCV) and the..., Mast [/bib_ref] [bib_ref] Effect of cesarean section on the risk of perinatal transmission of hepatitis..., Chehreh [/bib_ref]. Breastfeeding was not significantly associated with transmission [bib_ref] Reducing risk for mother-to-infant transmission of hepatitis C virus: a systematic review..., Cottrell [/bib_ref] , and cesarean section did not decrease perinatal HCV transmission from mothers to infants [bib_ref] Effect of cesarean section on the risk of perinatal transmission of hepatitis..., Chehreh [/bib_ref]. Therefore, no specific prevention method can be recommended for this population. The safety and potential efficacy of reducing mother-toinfant transmission by recently developed DAAs or those under development, particularly in HIV coinfection, require more research. ## Reinfection in pwid HCV reinfection occurs commonly in PWID. PWID with previous infection with HCV clearance are half as likely to be reinfected compared with those who had not been infected previously. However, other studies suggested that previous spontaneous clearance of HCV infection might not reduce the risk of new infection [bib_ref] Hepatitis C virus clearance, reinfection, and persistence, with insights from studies of..., Grebely [/bib_ref]. Ongoing highrisk behaviors among PWID can lead to repeated exposure to HCV, resulting in reinfection [bib_ref] Mixed HCV infection and reinfection in people who inject drugs-impact on therapy, Cunningham [/bib_ref]. Although reinfection is common, it does not always lead to persistent infection. Spontaneous clearance of HCV reinfection has also been frequently reported with a different HCV GT from that of the initial infection [bib_ref] Hepatitis C virus clearance, reinfection, and persistence, with insights from studies of..., Grebely [/bib_ref]. Reinfection rates for PWID receiving opioid substitution therapy (OST) are the most well studied. The rate of reinfection in this population is low [bib_ref] Hepatitis C virus infection and injection drug users: prevention, risk factors, and..., Backmund [/bib_ref]. In essence, HCV reinfection after spontaneous or treatment-induced clearance can occur. However, the rate of HCV reinfection might be as low as 0-5 cases per 100 person-years, even among persons who continue injected drug use during and after treatment [bib_ref] Mixed HCV infection and reinfection in people who inject drugs-impact on therapy, Cunningham [/bib_ref] [bib_ref] Treatment of hepatitis C virus infection among people who are actively injecting..., Aspinall [/bib_ref] [bib_ref] Hepatitis C virus reinfection following treatment among people who use drugs, Grady [/bib_ref]. Due to the low reinfection rate and potential clearance after reinfection, antiviral treatment should not be withheld for these populations. ## Reinfection following liver transplantation Reinfection following liver transplantation has been observed, and it leads to liver disease in approximately 30 % of patients. However, newly developed DAAs make it easy to achieve a SVR both among compensated liver transplant recipients with no fibrosis or mild fibrosis [bib_ref] An interferon-free antiviral regimen for HCV after liver transplantation, Kwo [/bib_ref] [bib_ref] Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection..., Charlton [/bib_ref] and before liver transplantation [bib_ref] Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an..., Curry [/bib_ref]. ## Hcv laboratory testing before and after svr serologic assays Exposure to HCV is determined by testing for anti-HCV antibodies using an approved enzyme (EIA) or chemiluminescent immunoassay (CIA). The presence of anti-HCV antibodies indicates a current or previously resolved HCV infection. The absence of anti-HCV antibodies usually shows that the patient has not been infected. However, anti-HCV antibodies might not be detectable in the first few weeks after the initial infection (window period) in immunosuppressed patients, or in patients who resolve their infection many years later [bib_ref] Laboratory diagnostics for hepatitis C virus infection, Kamili [/bib_ref] [bib_ref] American Association for the Study of Liver D. Diagnosis, management, and treatment..., Ghany [/bib_ref]. Several countries in the Asia-Pacific region have developed their own individual testing algorithms for anti-HCV antibody testing. A high signal-to-cutoff ratio for a sample in a specific EIA is highly predictive of an authentic anti-HCV antibody reactive result. The recombinant immunoblot HCV assays recommended for supplemental testing are no longer available. Molecular testing for HCV RNA is currently the only supplemental testing [bib_ref] APASL consensus statements and management algorithms for hepatitis C virus infection, Omata [/bib_ref]. Recently, rapid assays for detecting HCV antibodies in fingerstick capillary blood and venipuncture whole blood were shown to provide high sensitivity and specificity of . Given their very high accuracy, convenience, and quick turnaround time, rapid diagnosis tests (RDT) and point-of-care tests (POCT) may be useful in nontraditional settings such as emergency departments, outreach clinics, and community-based organizations. The currently available HCV core antigen quantitative assay has a sensitivity of 90 % for samples with HCV RNA [10,000 IU/mL and a specificity of near 100 % across HCV GT-1-6 [bib_ref] Clinical utility of hepatitis C virus core antigen quantification in patients with..., Chevaliez [/bib_ref]. There is good correlation between HCV core antigen and HCV RNA levels. However, it is probably not suitable for on-treatment monitoring due to its limited sensitivity. The major role these assays might play is in the identification of blood donors in the seroconversion window. ## Molecular assays Nucleic acid testing (NAT) for HCV RNA detection NATs remain the gold standard for diagnosing HCV viremia, determining acute or chronic infection, and monitoring/assessing virologic responses to antiviral therapy. HCV RNA testing should be strongly considered in patients at high risk of infection but who might be anti- ## #7 consensus statements and recommendations on prevention of reinfection in pwid In high-risk HCV-reinfection populations (PWID), frequent testing is recommended. Education and counseling about the risk of reinfection are advised for this population. (B1) ## #8 consensus statements and recommendations on prevention of reinfection in liver transplant recipients Liver transplant recipients with HCV reinfection should be treated with highly efficacious DAAs. (B1) #9 Consensus statements and recommendations on anti-HCV testing 1. Anti-HCV antibody testing should be performed using approved anti-HCV third-or fourth-generation EIA or CIA. (A1) 2. Samples negative in an approved EIA/CIA can be reported as anti-HCV negative. However, it should be noted that individuals on hemodialysis or coinfected with HIV might be HCV RNA positive but anti-HCV negative. (A1) 3. Samples reactive in an approved single EIA can be reported as anti-HCV positive provided the signalto-cutoff ratio is sufficiently high to be predictive of a true positive.* (B1) 4. Noninstrumented point-of-care tests (POCT) with rapid anti-HCV testing could serve as first-line screening for hepatitis C (B2). *The ratio is calculated by dividing the optical density (OD) value of the test sample by the OD of the assay cutoff. An example of the calculation of the ratio: Sample OD = 2.991, cutoff OD = 0.377, therefore S/CO ratio = 7.934. For most standard EIAs (i.e., those not using chemiluminescence), S/CO ratio greater than 3-4 should be indicative of the presence of true anti-HCV antibodies. HCV negative because they are in the early phase of acute HCV infection or immunosuppression. The assays used for qualitative HCV RNA testing include endpoint PCR and transcription-mediated amplification (TMA), which have detection limits of 50 and 10 IU/mL, respectively. Although negative TMA results are more predictive of a SVR, a single positive TMA result should be interpreted with caution because patients with positive TMA results may achieve a SVR [bib_ref] Interpretation of positive transcription-mediated amplification test results from polymerase chain reaction-negative samples..., Morishima [/bib_ref]. Recently, with the introduction of more sensitive quantitative realtime PCR assays, qualitative NATs may be only useful in mass screening of blood donors [bib_ref] Comparative analysis of triplex nucleic acid test assays in United States blood..., Stramer [/bib_ref]. HCV viral loads, although not associated with disease activity or progression to chronicity, have been associated with disease progression [bib_ref] Development and validation of a clinical scoring system for predicting risk of..., Lee [/bib_ref] , development of HCC [bib_ref] Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: long-term predictors..., Lee [/bib_ref] , and the treatment outcome of anti-HCV therapy with both interferon-based regimens [bib_ref] Treatment of chronic hepatitis C in Asia: when East meets West, Yu [/bib_ref] [bib_ref] Interleukin-28B genetic variants in identification of hepatitis C virus genotype 1 patients..., Huang [/bib_ref] and new, powerful DAA interferon-free regimens [bib_ref] Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without..., Kowdley [/bib_ref]. Monitoring of viral loads during therapy has proven to be useful in individualized HCV therapy. Futility rules and responseguided therapy (RGT) based on in-treatment virologic responses at treatment weeks 4, 8, 12, and 24 could provide information for optimal treatment durations to avoid unnecessary therapy, maximize cost-effectiveness, and minimize adverse events with interferon-based therapy [bib_ref] A randomised study of peginterferon and ribavirin for 16 versus 24 weeks..., Yu [/bib_ref] [bib_ref] Rapid virological response and treatment duration for chronic hepatitis C genotype 1..., Yu [/bib_ref] [bib_ref] Response-guided peginterferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of..., Martino [/bib_ref] [bib_ref] Revisiting the stopping rule for hepatitis C genotype 1 patients treated with..., Yu [/bib_ref]. Commercial signal amplification (e.g., branched-DNA assay) and target amplification assays (e.g., real-time PCR assays) are available for quantification of HCV RNA. Inhouse testing with traditional endpoint PCR for viral loads, which is used widely across the Asia-Pacific region, is not encouraged due to its limited dynamic range compared with commercial, sensitive PCR assays. Such assays should be calibrated to the World Health Organization (WHO) International Standard [bib_ref] Establishment of the first international standard for nucleic acid amplification technology (NAT)..., Saldanha [/bib_ref]. With recent advances in RGT strategies and new treatment regimens with DAAs, only assays with a lower limit of quantification of B25 IU/mL and a lower limit of detection of 15 IU/mL are recommended. The presence of detectable but not quantifiable HCV RNA is clinically important because this condition reflects true viremia [bib_ref] Clinical relevance of detectable but not quantifiable hepatitis C virus RNA during..., Harrington [/bib_ref]. Therefore, several real-time PCR assays, which have a broad dynamic range of quantification and are sensitive, specific, precise, and reproducible, are preferred [bib_ref] Multi-center evaluation of the Abbott RealTime HCV Assay for monitoring patients undergoing..., Vermehren [/bib_ref] [bib_ref] Second-generation Cobas AmpliPrep/Cobas TaqMan HCV quantitative test for viral load monitoring: a..., Zitzer [/bib_ref] [bib_ref] Performance of the novel Qiagen artus QS-RGQ viral load assays compared to..., Drexler [/bib_ref] [bib_ref] Performance evaluation of the new Roche cobas AmpliPrep/cobas TaqMan HCV test, version..., Pas [/bib_ref]. In contrast, the bDNA assay, with its low sensitivity, has limited applicability in monitoring treatment. The traditional primary endpoint of assessing anti-HCV therapy is SVR24 (HCV RNA \50 IU/mL 24 weeks after end of treatment), which indicates that HCV RNA remains negative during long-term follow-up [bib_ref] Sustained hepatitis C virus clearance and increased hepatitis B surface antigen seroclearance..., Yu [/bib_ref]. Recent studies demonstrated that SVR12 (HCV RNA \25 IU/mL 12 weeks after end of treatment) had positive predictive values (PPV) of [98 % for SVR24, regardless of whether therapy was interferon based or DAA interferon free [bib_ref] Earlier sustained virologic response end points for regulatory approval and dose selection..., Chen [/bib_ref] [bib_ref] Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with..., Yoshida [/bib_ref]. SVR12 is currently widely used as the primary endpoint of clinical trials and regulatory approval for DAA-containing regimens. SVR12 was suitable for predicting persistent virologic response in almost all cases. In certain DAA-including regimens, SVR12 could not always predict persistent virologic response. Further study of the difference between SVR12 and SVR24 will be needed in interferon-free regimens. ## Hcv genotyping HCV genotyping is helpful in epidemiological studies and necessary for the clinical application of personalized therapy for chronic hepatitis C [bib_ref] New treatments for HCV: Perspective from Asia, Yu [/bib_ref]. Currently, HCV has been classified into seven major GTs, which can be further divided into subtypes [bib_ref] Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes:..., Smith [/bib_ref]. HCV GT-1, GT-2, and GT-3 are widely distributed in the Asia-Pacific region [bib_ref] Global epidemiology and genotype distribution of the hepatitis C virus infection, Gower [/bib_ref] , whereas HCV GT-4 and GT-6 are mainly restricted to the Middle East and South East Asia, respectively, and are increasing in prevalence among IDUs [bib_ref] Hepatitis C virus infection among injection drug users with and without human..., Hsieh [/bib_ref]. RGT with interferon (IFN)-based therapy is HCV GT specific, and the currently available DAAs are GT and/or subtype specific. Several methods targeting different regions [5 0 -untranslated region (UTR), core, NS5A, and NS5B] for HCV genotyping vary from country to country, potentially depending on approval by the relevant health authorities and/or available funding. Methods include direct sequencing, reverse-phase hybridization (e.g., line probe assay), type-specific PCR, restriction fragment length polymorphism analysis after PCR amplification, melting curve analysis after real-time PCR amplification, detection of HCV GT-specific antibodies, and restriction fragment mass polymorphism analysis. Genotyping methods with accurate determination of HCV GT-1 to GT-6 and distinction of HCV GT-1a from GT-1b are required for certain DAA-containing therapies [bib_ref] New treatments for HCV: Perspective from Asia, Yu [/bib_ref]. ## Detection of hcv resistance-associated variants (ravs) RAVs are naturally occurring HCV quasispecies in the viral life cycle whose frequency mainly depends on their replicational fitness. RAVs may be associated with inferior treatment efficacy, such as the resistance of HCV GT-1a with Q80K mutation to simeprevir, a nonstructural protein 3/4A (NS3/4) protease inhibitor, plus peginterferon/ribavirin [bib_ref] Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir..., Lenz [/bib_ref] , and HCV GT-1b with NS5A-L31F/ I/M/V and/or NS5A-Y93H mutation resistance to the daclatasvir/asunaprevir all-oral regimen [bib_ref] All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational,..., Manns [/bib_ref]. Excluding patients with preexisting RAVs could enhance treatment efficacy [bib_ref] High sustained virologic response to daclatasvir plus asunaprevir in elderly and cirrhotic..., Mcphee [/bib_ref]. ## Host genetic testing Host single-nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B, IFN-lambda 3) gene are associated with spontaneous and peginterferon/ribavirin treatment-induced viral clearance in HCV GT-1/GT-4 patients [bib_ref] Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance, Ge [/bib_ref] [bib_ref] Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy..., Tanaka [/bib_ref] but have a limited role in HCV-2/3 patients [bib_ref] Role of interleukin-28B polymorphisms in the treatment of hepatitis C virus genotype..., Yu [/bib_ref]. Combined with baseline viral loads, viral kinetics, and previous treatment responses [bib_ref] New treatments for HCV: Perspective from Asia, Yu [/bib_ref] , the IL28B genotype could provide important information for decision-making in clinical practice, including: (1) identification of HCV GT-1 treatment-naïve patients who are eligible for 24-week peginterferon/ribavirin (IL28B favorable genotype with baseline viral loads \400,000 IU/mL) [bib_ref] Interleukin-28B genetic variants in identification of hepatitis C virus genotype 1 patients..., Huang [/bib_ref] , (2) early identification of HCV GT-1 nonresponders (IL28B unfavorable genotype with HCV RNA [1000 IU/mL at treatment week 4) [bib_ref] Revisiting the stopping rule for hepatitis C genotype 1 patients treated with..., Yu [/bib_ref] , and (3) exclusion of retreatment with peginterferon/ribavirin for treatment-experienced HCV GT-1 patients who carry the IL28B unfavorable genotype [bib_ref] Clinical utility of host genetic IL-28B variants in hepatitis C virus genotype..., Huang [/bib_ref]. ## Assessment of liver fibrosis Acute assessment of liver fibrosis is of clinical importance in decision-making, especially in the era of DAA and IFN-free regimens. Patients with cirrhosis with or without other unfavorable factors, such as HCV GT-1a, HCV GT-3, and prior null responses, require intensified treatment [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] Sofosbuvir and ribavirin in HCV genotypes 2 and 3, Zeuzem [/bib_ref] [bib_ref] All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C..., Nelson [/bib_ref]. Although liver biopsy remains the gold standard to assess liver fibrosis, alternative noninvasive approaches for liver fibrosis have assumed great importance. Approaches include the following [bib_ref] Liver fibrosis: consensus recommendations of the Asian Pacific Association for the Study..., Shiha [/bib_ref] [bib_ref] Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis..., Lin [/bib_ref] [bib_ref] Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: a systematic..., Singh [/bib_ref] : - Noninvasive imaging (e.g., transient elastography and magnetic resonance elastography/spectroscopy). - Noninvasive blood marker panels [e.g., aspartate aminotransferase-platelet ratio index (APRI), fibrosis-4 (FIB-4), FibroTest, FIBROSpect II, Hepascore, FibroMeter, and FibroFast]. These tests can provide areas under the curve of [0.7 for identifying clinically significant fibrosis and [0.8 for identifying cirrhosis [bib_ref] Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis..., Chou [/bib_ref]. Although noninvasive markers and transient elastography are only useful for identifying those patients with no fibrosis or with advanced fibrosis, a stepwise algorithm incorporating noninvasive markers and/or transient elastography may enhance the accuracy of diagnosis and significantly reduce the number of liver biopsies [bib_ref] SAFE biopsy: a validated method for large-scale staging of liver fibrosis in..., Sebastiani [/bib_ref] [bib_ref] Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis..., Castera [/bib_ref]. However, application of the algorithm in clinical practice remains to be validated. Furthermore, accumulating data provide evidence that noninvasive methods for liver fibrosis can be applied at a single point or repeatedly to provide prognostically meaningful distinctions in predicting clinical outcomes, with or without antiviral therapy, in chronic hepatitis C patients [bib_ref] Liver stiffness identifies two different patterns of fibrosis progression in patients with..., Carrion [/bib_ref] [bib_ref] Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients..., Vergniol [/bib_ref] [bib_ref] Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest) and..., Poynard [/bib_ref]. A recent study demonstrated that the 3-year evolution of the results of serial noninvasive assessment of hepatic fibrosis strongly predicts the long-term outcome in chronic hepatitis C patients [bib_ref] Evolution of noninvasive tests of liver fibrosis is associated with prognosis in..., Vergniol [/bib_ref]. ## #11 consensus statements and recommendations on hcv genotyping HCV GT-1a/GT-1b testing is important for assessing treatment regimens and duration and the efficacy of antiviral therapy. (A1) ## #12 consensus statements and recommendations on hcv rav detection Identification of baseline resistance-associated variants is helpful in certain DAA-containing regimens. (B2) ## #13 consensus statements and recommendations on host il28b genotyping In interferon-based treatment, IL28B genotyping could help in determining the treatment strategy. (A1) ## Laboratory testing after hcv cure Long-term complications of chronic hepatitis C, including HCC and decompensation, and all-cause mortality are largely reduced after achieving a SVR [bib_ref] A sustained virological response to interferon or interferon/ribavirin reduces hepatocellular carcinoma and..., Yu [/bib_ref] [bib_ref] Sustained virological response to interferon reduces cirrhosis in chronic hepatitis C: a..., Huang [/bib_ref] [bib_ref] Association between sustained virological response and all-cause mortality among patients with chronic..., Van Der Meer [/bib_ref] [bib_ref] Postoperative peginterferon plus ribavirin is associated with reduced recurrence of hepatitis C..., Hsu [/bib_ref]. Nevertheless, SVR patients remain at risk of HCC development, especially those with old age, high baseline gamma-glutamyltransferase levels, advanced liver fibrosis or comorbidity such as diabetes [bib_ref] Baseline gamma-glutamyl transferase levels strongly correlate with hepatocellular carcinoma development in non-cirrhotic..., Huang [/bib_ref] [bib_ref] Impact of diabetes mellitus on incidence of hepatocellular carcinoma in chronic hepatitis..., Hung [/bib_ref] [bib_ref] Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma..., Arase [/bib_ref]. High APRI 6 months after the end of treatment [bib_ref] A simple noninvasive index for predicting long-term outcome of chronic hepatitis C..., Yu [/bib_ref] and high posttreatment ALT or AFP levels [bib_ref] Alpha-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis..., Asahina [/bib_ref] were independent factors significantly associated with HCC development. These data indicate that regular monitoring for HCC screening and good control of comorbidities after achieving a SVR are mandatory for HCV patients. Older age, male gender, advanced fibrosis, severe steatosis, lower serum albumin levels, non-SVR, and higher post-interferon-treatment ALT or AFP levels are identified as independent factors significantly associated with HCC development [bib_ref] Alpha-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis..., Asahina [/bib_ref]. Occurrence of HCC is not a rare event during and after antiviral treatment in older HCV patients [bib_ref] Occurrence of hepatocellular carcinoma was not a rare event during and immediately..., Kanda [/bib_ref] or HCV patients with advanced fibrosis [bib_ref] Alpha-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis..., Asahina [/bib_ref]. Further studies will be needed regarding this point after interferon-free treatment [bib_ref] Ledipasvir/Sofosbuvir with ribavirin is safe and efficacious in decompensated and post liver..., Manns [/bib_ref] [bib_ref] Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection:..., Omata [/bib_ref] [bib_ref] Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks..., Mizokami [/bib_ref] [bib_ref] High coverage of ART associated with decline in risk of HIV acquisition..., Tanser [/bib_ref]. ## Compliance with ethical standards All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki 1975, as revised in 2008 [bib_ref] Asian Pacific Association for the Study of the Liver consensus statements on..., Mccaughan [/bib_ref]. Informed consent was obtained from all patients included in the study. This article does not contain any studies with animal subjects. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://crea tivecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. ## Conflict of interest ## #14 consensus statements and recommendations on noninvasive assessment of fibrosis Noninvasive methods for assessing liver fibrosis are useful for identifying patients with no/minimal fibrosis or advanced fibrosis and can provide prognostically meaningful distinctions in predicting clinical outcomes in chronic hepatitis C patients before and after successful treatment. A stepwise algorithm incorporating the results of noninvasive methods may enhance the accuracy of diagnosis. Liver biopsies are not always recommended for the diagnosis of hepatitis C or the decision for the treatment of hepatitis C. [fig] #4: Consensus statements and recommendations on HCV prevention for persons who inject drugs (PWID) 1. Because transmission of HCV via injecting drug users (IDUs) is an increasing trend in the Asia-Pacific region, effective strategies to reduce HCV transmission in this group should be explored. (B2) 2. Harm reduction including ''sterile needle and syringe programs'' should have increased coverage. (B2) #6 Consensus statements and recommendations on mother-to-infant transmission 1. No specific precaution is needed for breastfeeding to prevent vertical transmission. (B2) #5 Consensus statements and recommendations on prevention of sexual transmission 1. There is low or no risk of sexual transmission of HCV among HIV-uninfected heterosexual couples. (A2) 2. It is recommended that correct and consistent condom use be applied in MSM with HIV infection. (B2) [/fig] [fig] #10: Consensus statements and recommendations on HCV RNA testing 1. For all samples positive for anti-HCV, HCV RNA should be determined by sensitive nucleic acid testing (NAT). (A1) 2. HCV RNA quantitation should be reported in IU/ mL (optionally including copies/mL). DAA-containing regimens should use assays with a lower limit of quantification of B25 IU/mL and a lower limit of detection of B15 IU/mL. (B1) 3. Monitoring of HCV loads during treatment is important for response-guided therapy to determine futility, treatment protocol, and duration. (A1) [/fig] [table] B1: #15 Consensus statements and recommendations on laboratory testing after HCV cure 1. Regular HCC screening after achieving a SVR is mandatory for HCV patients at high risk such as patients with advanced fibrosis, older patients, or male patients. (A1) 2. Comorbidities should be evaluated and well controlled to reduce their impact on the disease progression of chronic hepatitis C (B1).De Nicola S, Aghemo A, Rumi MG, Colombo M. HCV genotype 3: an independent predictor of fibrosis progression in chronic hepatitis C. J Hepatol 2009;51:964-966 35. Nkontchou G, Ziol M, Aout M, Lhabadie M, Baazia Y, Mahmoudi A, Roulot D, Ganne-Carrie N, Grando-Lemaire V, Trinchet JC, Gordien E, Vicaut E, Baghad I, Beaugrand M. HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis. J Viral Hepat 2011;18:e516-e522 36. Kanwal F, Kramer JR, Ilyas J, Duan Z, El-Serag HB. HCV genotype 3 is associated with an increased risk of cirrhosis and hepatocellular cancer in a national sample of US veterans with HCV. Hepatology 2014;60:98-105 37. El-Serag HB, Kanwal F, Richardson P, Kramer J. Risk of hepatocellular carcinoma after sustained virologic response in veterans with HCV-infection. 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Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997;127:875-881 66. Poynard T, Moussalli J, Munteanu M, Thabut D, Lebray P, Rudler M, et al. Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C. J Hepatol 2013;59:675-683 67. Maylin S, Martinot-Peignoux M, Moucari R, Boyer N, Ripault MP, Cazals-Hatem D, et al. Eradication of hepatitis C virus in [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs12072-016-9736-3.pdf	None
a3d8fbf5039ba5f7ce9f114b872221f4cea1fa2e	pubmed	Guidelines for the Acute Treatment of Cerebral Edema in Neurocritical Care Patients	Guidelines for the Acute Treatment of Cerebral Edema in Neurocritical Care Patients Background: Acute treatment of cerebral edema and elevated intracranial pressure is a common issue in patients with neurological injury. Practical recommendations regarding selection and monitoring of therapies for initial management of cerebral edema for optimal efficacy and safety are generally lacking. This guideline evaluates the role of hyperosmolar agents (mannitol, HTS), corticosteroids, and selected non-pharmacologic therapies in the acute treatment of cerebral edema. Clinicians must be able to select appropriate therapies for initial cerebral edema management based on available evidence while balancing efficacy and safety.Methods:The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacy to create a panel in 2017. The group generated 16 clinical questions related to initial management of cerebral edema in various neurological insults using the PICO format. A research librarian executed a comprehensive literature search through July 2018. The panel screened the identified articles for inclusion related to each specific PICO question and abstracted necessary information for pertinent publications. The panel used GRADE methodology to categorize the quality of evidence as high, moderate, low, or very low based on their confidence that the findings of each publication approximate the true effect of the therapy.Results:The panel generated recommendations regarding initial management of cerebral edema in neurocritical care patients with subarachnoid hemorrhage, traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, bacterial meningitis, and hepatic encephalopathy.Conclusion:The available evidence suggests hyperosmolar therapy may be helpful in reducing ICP elevations or cerebral edema in patients with SAH, TBI, AIS, ICH, and HE, although neurological outcomes do not appear to be affected. Corticosteroids appear to be helpful in reducing cerebral edema in patients with bacterial meningitis, but not ICH. Differences in therapeutic response and safety may exist between HTS and mannitol. The use of these agents in these critical clinical situations merits close monitoring for adverse effects. There is a dire need for high-quality research to better inform clinicians of the best options for individualized care of patients with cerebral edema. # Introduction Cerebral edema is a non-specific pathological swelling of the brain that may develop in a focal or diffuse pattern after any type of neurological injury. The underlying cause of this brain swelling is highly variable and relates to multiple physiological cellular changes. The simplest description of cerebral edema is an accumulation of excessive fluid within either brain cells or extracellular spaces. Cerebral edema can be secondary to disruption of the blood brain barrier, local inflammation, vascular changes, or altered cellular metabolism. The identification and treatment of cerebral edema is central to the management of critical intracranial pathologies. Measurement of cerebral edema is indirect and generally relies on surrogate markers seen on imaging studies, such as tissue shifts or structural changes, or via intracranial pressure (ICP) monitoring devices. It is considered one of the more common contributors to elevated ICP, which has been identified as a predictor of poor outcome in patients with TBI, stroke, and other intracranial pathologies. The literature describes multiple treatment modalities including hyperosmolar therapy, acute hyperventilation, temperature modulation, diversion of CSF, surgical decompression, and metabolic suppression. These treatments are often administered without consideration of the underlying disease process, when in fact their efficacy may hinge upon the pathophysiology at hand. Recent guidelines for the management of AIS, ICH, and TBI, among others, discuss the treatment of cerebral edema. However, practical recommendations regarding the selection and monitoring of therapies for optimal efficacy and safety are generally lacking. This guideline primarily evaluates the role of hyperosmolar agents (mannitol, HTS), corticosteroids, and selected non-pharmacologic therapies in the acute treatment of cerebral edema; strategies used for refractory cerebral edema or increased ICP (e.g., barbiturates, therapeutic hypothermia) are not highlighted. The term cerebral edema was used preferentially as a representative term encompassing elevated intracranial pressure, brain swelling, herniation syndromes, and cerebral edema (intracranial pressure may not be known in many patients, but symptoms of this intracranial abnormality may be present). In references where intracranial pressure was specifically evaluated, the results are stated as such. It should be emphasized that the recommendations in this guideline are based on available medical literature, which may not reflect all aspects of clinical expertise and practical experience. # Methods This work was commissioned and approved by the Neurocritical Care Society (NCS) Board of Directors. The NCS Guidelines Committee tasked two Chairs (AC, LS) to form a panel of experts in neurocritical care, pharmacotherapy, and nursing to execute the guideline. A GRADE methodologist was also included in the panel. Beginning in October 2017, the panel drafted sixteen questions relevant to the treatment and monitoring of cerebral edema in neurocritical care patients using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework . Questions were drafted using the PICO format and aligned with specific neurocritical care populations (e.g., TBI) so as to render recommendations relevant to underlying pathologies and not the neurocritical care population as a whole. Individual outcomes of interest related to cerebral edema, ICP, neurological status, or other evaluated parameters are listed on the applicable tables that are included as electronic supplementary material. Of note, the response of intracranial pressure or cerebral edema was separated from neurological outcomes such as modified Rankin Score or mortality as the authors were uncertain that treatment response of intracranial pressure or cerebral edema is directly related to neurological outcome. Interventions were specifically identified by name and formulation in most instances. In some PICO questions, various sodium salts with differing concentrations were evaluated. Throughout the document, "hypertonic saline" was referred to as "hypertonic sodium solutions" to account for the differences in sodium salt formulation. In cases where a specific sodium salt or concentration was evaluated, it was identified as stated in the study if the specific formulation was pertinent for the results. A research librarian executed a comprehensive, independent literature search using Ovid Medline and EMBASE from inception (1947) to July 5, 2018. The searches were peer reviewed by a second librarian at St. Michael's Hospital in Toronto, ON. Additional articles were identified from the bibliographies of the publications included in the literature search, as well as a supplementary PubMed searches of publications and personal files of members of the panel up to February 2019 once data abstraction began. The literature search excluded articles that were not available in English, pediatric studies, animal studies, and unpublished works. The panel included systematic reviews, meta-analyses, randomized, controlled trials, observational studies, and case series of five or more patients. Studies with prospectively collected data which were retrospectively evaluated were consistently considered retrospective observational studies in our quality of evidence assessment. Studies with mixed populations (e.g., SAH, TBI, and ICH) were included if the population relevant to the specific PICO question had a sample size of five or more. Meta-analyses were included only if their patients were representative of the population of neurocritical care patients identified in the specific PICO question. If the meta-analysis included a mixture of multiple populations, the results were only included if they were differentiated by neurological injury. All meta-analyses that were excluded due to an inability to differentiate results by specific neurological injury are listed as footnotes on the applicable evidentiary tables that are included as electronic supplementary material. A systematic review software was used for screening and abstraction of the available literature (DistillerSR, Evidence Partners, Ottawa, Canada). Initial article screening for inclusion criteria was performed by one individual reviewer. Once screened for inclusion, data abstraction from each of the pertinent articles was performed by a minimum of two panel members pertaining to each PICO question . The panel used the GRADE methodology to evaluate the quality of evidence as high, moderate, low, or very low. These designations denote the degree of certainty that the estimate of effect in each study approximates the true effect. Recommendations generated from this literature review and the subsequent quality of evidence rating accounted for efficacy, risks, potential sources of bias, and treatment effect. The Cochrane Risk of Bias Assessment tool was used to evaluate bias in sequence generation, allocation, blinding, missing outcome data, selective outcome reporting, and other sources of bias. The panel classified recommendations as strong ("We recommend") when they are the preferred treatment for most patients and should be adopted as policy in the majority of situations. Conditional recommendations ("We suggest, " "Clinicians should consider") should be further considered based upon the clinical scenario and carefully evaluated by stakeholders before being implemented as policy. Areas where there is insufficient evidence to support recommendations are identified, and, in some instances, "good practice statements" are provided. These statements are meant to state guidance where there may be a lack of published evidence, but the practice is commonly accepted as beneficial. The panel met in person on September 26-27, 2018, in Boca Raton, FL, and again on January 17-18, 2019, in Chicago, IL. Other meetings were virtual. Members assigned to specific PICO questions presented a summary of the GRADE evidence on each topic, and recommendations were discussed, revised, and validated by the entire panel. Internal experts within the Neurocritical Care Society and external stakeholders reviewed the final guideline. ## Treatment of cerebral edema in patients with subarachnoid hemorrhage In patients with SAH, does sodium target-based dosing with hypertonic sodium solutions (sodium chloride, lactate, or bicarbonate) improve ICP/cerebral edema compared to intermittent, symptom-based bolus doses of hypertonic sodium solutions? In patients with SAH, does sodium target-based dosing with hypertonic sodium solutions (sodium chloride, lactate, or bicarbonate) improve neurological outcomes at discharge compared to intermittent, symptom-based bolus doses of hypertonic sodium solutions? ## Recommendations 1. We suggest using symptom-based bolus dosing of hypertonic sodium solutions rather than sodium target-based dosing for the management of ICP or cerebral edema in patients with SAH (conditional recommendation, very low-quality evidence). Rationale: In making this recommendation, the panel felt that while the quality of evidence was very low, the consistency of the literature justified symptom-based bolus dosing of HTS as an effective means of reducing ICP and cerebral edema in patients with SAH. The data on sodium target-based HTS dosing regimens for ICP control were extremely limited and provided only indirect evidence and thus could not be recommended. 2. Due to insufficient evidence, we cannot recommend a specific dosing strategy for HTS to improve neurological outcomes in patients with SAH. The panel first evaluated the relative merits of symptom-based bolus dosing of HTS as opposed to HTS administration titrated to a target sodium concentration in patients with SAH , Questions 1 and 2). A small number of publications have addressed this specific issue, and the panel did not identify any studies that directly compared the two administration strategies. Nine studies addressed the two infusion strategies independently: two targeted a sodium level of 145-155 mEq/L and seven used symptom-based bolus administration of HTS. The overall quality of evidence was very low . The panel assessed seven studies of symptom-based bolus administration of HTS. One key study for many of the topics in this guideline is Koenig, et al., which was a retrospective cohort analysis that evaluated the percentage of neurocritical care patients who experienced clinical reversal of TTH after receiving a 30-60 mL dose of 23.4% NaCl. The investigators observed clinical TTH reversal in 75% of cases and 22 patients (32.4%) survived to hospital discharge. Only 16 of 68 patients included had SAH and the results were only reported for the full cohort (i.e., not subdivided to show the SAH patient data specifically), so the direct effects on patients with SAH could not be discerned. Overall, reversal of TTH was associated with a > 5 mEq/L rise in serum sodium concentration (p < 0.001) or an absolute serum sodium of > 145 mEq/L (p < 0.007) within 1 h after 23.4% HTS administration. It should be noted that while changes in sodium values were observed, specific targets had not been pre-determined. In a prospective study, Al-Rawi et al. administered 2 ml/kg of 23.5% NaCl to 44 patients with poor-grade SAH. Patients who demonstrated a robust and durable response to the NaCl infusion were more likely to have a favorable outcome (mRS < 4). Bentsen and colleagues published three studies using 7.2% NaCl with 6% HES, a formulation which is currently not available in the USA, in patients with SAH. One of these was a prospective, randomized, placebo-controlled trial of 22 patients that found modest reductions in ICP using 7.2% HTS/6% HES compared to placebo. The other studies were of lower quality with similar results. Two studies explored the effects of titrating HTS to a targeted serum sodium concentration of 145-155 mEq/L. Tseng, et al. prospectively observed 35 patients who received 2 ml/kg doses of 23.5% NaCl. They concluded that HTS administration in this manner decreased ICP and improved CBF, though their results were obtained via logistic regression analysis of dose-dependent effects of HTS on CBF as measured by CT scan perfusion studies. The panel deemed that these measures were too indirect to be considered outcomes as defined by the PICO question, which downgraded the rating of this study. A second study retrospectively compared patients who received a 3% NaCl continuous infusion titrated to a goal serum sodium of 145-155 mEq/L to a group of historical controls who did not receive HTS. While the total sample size was robust (n = 215), only 38 patients had SAH. This subgroup was underpowered, and there was not a statistically significant difference in episodes of critically elevated ICP or neurological outcomes. Given both studies were underpowered and used different administration methods to achieve the target sodium concentration, the panel felt the available data prevented endorsement of HTS use to target a specific serum sodium concentration in order to improve ICP, cerebral edema, or neurological outcomes. While the overall quality of the evidence in this area is very low, the panel felt there was enough consistency across the published studies to suggest symptom-based bolus dosing of HTS as an effective means of reducing ICP and cerebral edema in patients with SAH. In addition, HTS bolus administration may also raise serum sodium, improve brain pH, and increase brain tissue oxygenation. At present, there are insufficient data to support the use of HTS to improve neurological outcome, regardless of the administration strategy. We did not identify any substantial evidence to support targeting a specific serum sodium concentration in order to reduce ICP or improve neurological outcome in patients with SAH, demonstrating the need for future research regarding the impact of specific sodium targets on ICP and neurological outcomes. ## Treatment of cerebral edema in patients with traumatic brain injury In patients with TBI, does the use of hypertonic sodium solutions improve cerebral edema compared to mannitol? In patients with TBI, does the use of hypertonic sodium solutions for cerebral edema improve neurological outcomes compared to mannitol? Recommendations 1. We suggest using hypertonic sodium solutions over mannitol for the initial management of elevated ICP or cerebral edema in patients with TBI (conditional recommendation, low-quality evidence). We suggest that neither HTS nor mannitol be used with the expectation for improving neurological outcomes in patients with TBI (conditional recommendation, low-quality evidence). Rationale: In making this recommendation, the panel felt that while the quality of evidence was low, the consistency of the literature suggested HTS was at least as safe and effective as mannitol. In addition, the panel agreed that the putative advantages of HTS over mannitol for fluid resuscitation and cerebral perfusion justified the suggestion to use HTS over mannitol. Although treatment effect of these agents on elevated ICP or cerebral edema may be expected based on the literature, neither agent has been demonstrated to improve neurological outcomes. 2. We suggest that the use of mannitol is an effective alternative in patients with TBI unable to receive hypertonic sodium solutions (conditional recommendation, low-quality evidence). Rationale: Although HTS was recommended over mannitol, the quality of evidence was low and the literature consistently suggests that mannitol is also a safe and effective option for the initial management of elevated ICP or cerebral edema in patients with TBI, particularly those with concomitant severe hypernatremia or volume overload. 3. We recommend against the use of hypertonic sodium solutions in the pre-hospital setting to specifically improve neurological outcomes for patients with TBI (strong recommendation, moderate-quality evidence). Rationale: Acute treatment of cerebral edema and herniation syndromes is often necessary in the pre-hospital setting. However, well-designed clinical trials did not suggest any benefit from the use of HTS in the pre-hospital setting on long-term outcomes in patients with TBI. 4. We suggest against the use of mannitol in the prehospital setting to improve neurological outcomes for patients with TBI (conditional recommendation, very low-quality evidence). Rationale: In making this recommendation, the panel felt that the quality of evidence was very low and did not suggest any potential benefit in the pre-hospital setting on long-term outcomes in patients with TBI. The panel evaluated several studies to inform recommendations on the use of HTS and/or mannitol to improve ICP, cerebral edema, or neurological outcomes , Questions 3 and 4). These two agents have been compared in at least eight randomized, controlled trials of patients with elevated ICP from a variety of causes, including TBI. A number of uncontrolled, retrospective, and non-comparative studies have also evaluated either HTS or mannitol in patients with TBI. These studies all support the notion that both hyperosmolar therapies effectively reduce ICP . The available data are limited by patient heterogeneity, low sample size, and inconsistent methods among studies. For example, several studies utilized a crossover study design where patients served as their own control, sequentially receiving HTS and then mannitol or vice versa, whereas others randomized patients to receive one agent or the other. In addition, several of the early studies evaluating HTS used a combination product which included HES. The overall quality of evidence was low (Evidentiary of Electronic Supplementary Material). The panel discussed at length the lack of high-quality evidence supporting preferential use of one hyperosmolar agent as first line treatment of elevated ICP in TBI. Several meta-analyses have reached conflicting conclusions; some found no difference in ICP-related outcomes in TBI patients, whereas others favored HTS. Differences in the statistical analysis across these metaanalyses may have accounted for the variance in results. Some advantages of HTS over mannitol have been observed in direct comparison, crossover, and rescue therapy randomized studies. HTS may have a quicker onset of action, a more robust and durable ICP reduction, and may be advantageous in patients in whom mannitol failed. Hypertonic sodium solutions with either a chloride, lactate, or bicarbonate salt seem to all be effective. The panel felt that there was consistency across the numerous, lower-quality studies that HTS was more effective than mannitol for reducing ICP or cerebral edema in this population. Several meta-analyses and RCTs have demonstrated no significant difference in neurological outcomes when comparing various hyperosmolar therapies. It is notable that two of the RCTs used equi-osmolar doses of HTS and mannitol, whereas the third used twofold higher osmolar dose of 7.5% NaCl compared to mannitol. Another prospective study pooled data from three separate trials and evaluated target-based infusions of 20% NaCl compared to standard care. Overall there was no difference in long-term neurological outcomes between groups, but patients who received 20% NaCl exhibited a reduced mortality rate at 90 days in a propensity-score-adjusted analysis (HR 1.74, 95% CI 1.36-2.23). Nevertheless, the weight of the current evidence does not support the use of hyperosmolar therapies for the specific purpose of improving neurological outcomes. Studies have also evaluated emergent, pre-hospital resuscitation with HTS or mannitol in patients with TBI. A phase II feasibility study evaluated 229 TBI patients with a GCS < 9 and those who were hypotensive (SBP < 100 mm Hg) and randomized each to receive prehospital 250 mL 7.5% NaCl or 250 mL Ringer's lactate. Survival to hospital discharge was similar in both groups, as was GOSE and survival at 6 months. Bulger et al. performed a prospective, double-blind trial of 1282 TBI patients who received a 250 mL bolus of 7.5% NaCl/6% dextran 70, a 250 mL bolus of 7.5% NaCl, or a 250 mL 0.9% NaCl in the pre-hospital setting. No significant differences in distribution of GOSE category, Disability Rating Score, or mortality by treatment group were found. Sayre et al. evaluated the use of mannitol in the pre-hospital setting in patients with TBI and also found no benefit on mortality. While the overall quality of the evidence in this area is low, the panel felt there was enough consistency across the published studies to suggest that both HTS and mannitol are effective in reducing ICP elevations and cerebral edema. The panel noted that the evidence supporting HTS is more robust, but mannitol is also an effective option. The decision regarding which agent to use should be based on available resources, the patient's individual characteristics, and local practice patterns. While either agent can address the physiological abnormalities of ICP elevations and cerebral edema, there is evidence that neither agent directly influences long-term neurological outcome, particularly when used in the pre-hospital setting. ## Treatment of cerebral edema in patients with acute ischemic stroke In patients with ischemic stroke, does the use of hypertonic sodium solutions improve cerebral edema compared to mannitol? In patients with ischemic stroke, does the use of hypertonic sodium solutions for cerebral edema improve neurological outcomes compared to mannitol? ## Recommendations 1. We suggest using either hypertonic sodium solutions or mannitol for the initial management of ICP or cerebral edema in patients with acute ischemic stroke (conditional recommendation, low-quality evidence). There is insufficient evidence to recommend either hypertonic saline or mannitol for improving neurological outcomes in patients with acute ischemic stroke. Rationale: In making this recommendation, the panel felt that the quality of evidence was low and the literature in patients with AIS was not compelling to recommend one agent over the other for initial management of elevated ICP or cerebral edema. Patient-specific factors may be employed to aid clinicians in selecting the appropriate initial agent in patients with either measured elevated ICP or symptoms of cerebral edema. 2. We suggest that clinicians consider administration of hypertonic sodium solutions for management of ICP or cerebral edema in patients with acute ischemic stroke who do not have an adequate response to mannitol (conditional recommendation, low-quality evidence). Rationale: In making this recommendation, the panel felt that the quality of evidence was low, but the literature in patients with AIS suggested that patients who do not have an adequate treatment response to mannitol may still respond to HTS. 3. We suggest against the use of prophylactic scheduled mannitol in acute ischemic stroke due to the potential for harm (conditional recommendation, low-quality evidence). Rationale: In making this recommendation, the panel felt that while the quality of evidence was low, the lack of benefit and the potential association with worse neurological outcomes justified avoiding prophylactic mannitol in patients with acute ischemic stroke. The panel evaluated whether the use of HTS or mannitol improves ICP, cerebral edema, or neurological outcomes in patients with AIS. The panel did not identify any RCTs that directly compared these agents in AIS using neurological outcomes as an endpoint. Therefore, we included observational studies that either compared mannitol or HTS with no hyperosmolar therapy or that reported on hyperosmolar therapy use without a control group , Questions 5 and 6). The overall level of evidence was low . The panel identified 11 studies that evaluated hyperosmolar therapy for reducing ICP or cerebral edema in patients with AIS. Of these, three were prospective, randomized trials that compared mannitol directly with HTS. The remainder were prospective or retrospective cohort studies that evaluated one or both hyperosmolar therapies with or without a control group. The majority of these studies suggested that both HTS and mannitol were efficacious in reducing ICP in AIS, although some of these studies had a mixed patient population. In two prospective, randomized studies, the reduction in ICP from HTS was quicker, more pronounced, and more sustained compared to mannitol. In addition, two studies suggested that HTS may be effective even in patients in whom mannitol has failed. While the use of a continuous infusion of HTS titrated to sodium goals is a common practice in neurocritical care, use of this strategy in AIS has only been evaluated in two studies which had conflicting results. One evaluation suggested that the use of continuous HTS to target a serum sodium concentration of 145-155 mEq/L may be associated with fewer ICP crises per patient, while the other demonstrated no difference. Based on the available evidence, the use of 3% NaCl to target a specific serum sodium concentration does not consistently demonstrate reductions in ICP crises and does not appear to improve neurological outcome in patients with AIS. Overall, both mannitol and HTS appear to be effective in reducing ICP and cerebral edema in patients with AIS. Given the limitations of the above studies (small sample size, heterogeneous populations, insufficient information on osmolar load), we cannot definitively conclude that one hyperosmolar therapy agent is clearly superior to the other for ICP reduction. However, it appears HTS may have a more rapid onset of action, a more robust and durable ICP reduction, and may be advantageous for patients in whom mannitol failed. After having established the potential benefits of hyperosmolar therapy in improving intracranial pressure, the panel next evaluated 10 studies that focused on hyperosmolar therapy to improve neurological outcome in AIS. Of these studies, only one was an RCT (which compared mannitol to no hyperosmolar therapy). Only two other studies classified outcomes separately between mannitol and HTS in AIS; however, these studies did not directly compare these treatments and therefore an analysis of the relative efficacy was not possible. Of these studies, hyperosmolar therapies were administered in a number of different ways, ranging from scheduled daily dosing, dosing to a specific serum sodium target (in the case of HTS), or intermittent dosing over the period of several days. The indication for hyperosmolar therapy was also variable: ICP elevation, cerebral edema, or prophylactic. Overall, the data are weak and contradictory when evaluating the effect of hyperosmolar agents on neurological outcome after AIS. An analysis of a prospective registry of patients reported improved mortality and 3-month mRS in AIS treated with 5.1-7.6% NaCl, but this was not compared with another therapy or control group. Another small case series reported improvement in GCS or pupillary reactivity in some patients after a single mannitol dose, but, with only seven patients and no control group, definitive conclusions are not possible. The Koenig study was also included to address this PICO question, but the potential benefit of 23.4% NaCl in AIS patients is not discernable from this report. The only RCT is an outdated study of 77 patients with AIS which found no change in neurological outcome after a single daily dose of 0.8 to 0.9 g/kg mannitol for 10 days. The majority of the observational studies also reported no difference in neurological outcome after hyperosmolar therapy administration. Conversely, some reports have suggested harm with prophylactic hyperosmolar therapy with mannitol after AIS. Two large, retrospective, cohort studies reported an increased risk of death at 30 days and/or greater functional dependency with prophylactic use of scheduled mannitol doses. However, the findings of both of these studies may have been skewed by the potential for dosing mannitol more frequently in the most critically ill patients. This potential treatment bias could not be fully accounted for after multivariable adjustment. While the overall quality of evidence in this area is low, the panel felt there was enough consistency across published studies to suggest that both HTS and mannitol are effective in reducing ICP elevations and cerebral edema in AIS. In contrast, the overall evidence does not support routine hyperosmolar therapy to improve neurological outcome following AIS, and in fact, the use of prophylactic mannitol may be associated with harm. ## Treatment of cerebral edema in patients with intracerebral hemorrhage In patients with ICH, does the use of hypertonic sodium solutions improve cerebral edema compared to mannitol? In patients with ICH, does the use of corticosteroid therapy improve neurological outcomes compared to placebo/control? ## Recommendations for hyperosmolar therapy 1. We suggest using hypertonic sodium solutions over mannitol for the management of ICP or cerebral edema in patients with intracerebral hemorrhage (conditional recommendation, very low-quality evidence). Rationale: In making this recommendation, the panel felt that while the quality of evidence was very low, the consistency of the literature suggested HTS was at least as safe and effective as mannitol. In addition, the panel agreed that the putative advantages of HTS over mannitol for fluid resuscitation and cerebral perfusion justified the suggestion to use HTS over mannitol. 2. We suggest that either symptom-based bolus dosing or using a targeted sodium concentration is appropriate hypertonic sodium solution administration strategy for the management of elevated ICP or cerebral edema in patients with intracerebral hemorrhage (conditional recommendation, very low-quality evidence). Rationale: In making this recommendation, the panel felt that the quality of evidence was very low and the literature in patients with ICH was not compelling to recommend one method of administration of HTS over the other for initial management of elevated ICP or cerebral edema. Patient-specific factors may be employed to aid clinicians in selecting the appropriate initial agent. The panel evaluated the relative merits of HTS and mannitol in improving ICP, cerebral edema, or neurological outcomes in patients with ICH . The panel identified four studies examining HTS alone, one related to mannitol, and no studies comparing the two agents. The overall quality of evidence was very low . Three studies addressed the use of continuous infusion 3% NaCl adjusted to achieve a targeted sodium concentration of 145-155 mEq/L. Hauer et al. reported on a mixed neurocritical care patient population that included 120 patients with ICH. These patients received 3% NaCl infusions with a goal serum sodium of 145-155 mEq/L compared to a historical cohort, and the results are reported specific to patients with ICH. A prospective study of 26 ICH patients treated with 3% NaCl continuous infusion demonstrated a reduction in cerebral edema and number of ICP crises. Conversely, a retrospective cohort study with a subset of eight ICH patients who received 3% sodium acetate/ chloride continuous infusion (with additional boluses as needed) found no differences in ICP or mass effect at 12 h. Data from the aforementioned Koenig study was included to address this PICO question as patients with ICH were included even though they could not be separated out from the other patient populations. The data from these studies are conflicting, and clinicians should weigh the risks and benefits of targeting a sodium concentration in the short-term management of ICP and cerebral edema in ICH patients. The panel acknowledges that there are some commonly referenced articles reporting on the use of mannitol in patients with ICH that were not included in this guideline, as they did not address these specific PICO questions. Two recent publications, both of which demonstrated potential risk of hematoma expansion, were ultimately excluded from our assessment as the study outcomes did not directly address the PICO questions as written (though hematoma expansion is important clinically, the panel did not feel this variable was directly related to cerebral edema or ICP). However, the panel felt that their results may give providers some pause regarding the safety of mannitol in patients with ICH. Given these concerns, along with the lack of published articles assessing the impact of mannitol on short-term outcomes, the panel was unable to recommend use of mannitol in this population at this time. While the overall quality of evidence in this area is very low, the panel felt there was enough consistency across published studies to suggest that HTS is effective in reducing ICP elevations and cerebral edema. In contrast, the available published studies on mannitol were not directly related to the PICO question and they implied harm; thus, the panel favored HTS over mannitol. ## Recommendations for corticosteroids in patients with intracerebral hemorrhage 1. We recommend against the use of corticosteroids to improve neurological outcome in patients with intracerebral hemorrhage due to the potential for increased mortality and infectious complications (strong recommendation, moderate-quality evidence). The panel evaluated whether use of corticosteroids in patients with ICH impacts neurological outcome, including mortality or functional status at any designated time point. The panel included a Cochrane meta-analysis, two moderate-to high-quality studies, and several other lower-quality studies in their assessment , Question 8). The overall quality of evidence was moderate . A 2005 Cochrane Review assessed the impact of corticosteroids on neurological outcome in patients with ICH compared to placebo or standard of care controls. The review found no evidence to support the routine use of corticosteroids in patients with primary ICH and highlighted a potential for harm in these patients. One prospective, randomized, placebo-controlled trial (n = 93) of dexamethasone to placebo in patients with ICH was halted due to increased rates of infectious and diabetic complications, while another (n = 40) showed no difference in mortality or neurological outcomes. Sharafadinzadeh et al. published a placebo-controlled trial of 225 patients which found higher mortality in the dexamethasone group. Four other lower-quality studies all found no improvement in outcomes related to dexamethasone use, with two studies demonstrating increased mortality in the treatment group. ## Treatment of cerebral edema in patients with bacterial meningitis In patients with bacterial meningitis, does the use of hypertonic sodium solutions for cerebral edema improve CE compared to mannitol? In patients with bacterial meningitis, does the use of corticosteroid therapy improve neurological outcomes compared to placebo/control? ## Recommendations 1. We recommend dexamethasone 10 mg intravenous every 6 h for 4 days to reduce neurological sequelae (primarily hearing loss) in patients with communityacquired bacterial meningitis (strong recommendation, moderate-quality evidence). 2. We suggest dexamethasone 0.15 mg/kg intravenous every 6 h for 4 days as an alternative dose for patients with low body weight or high risk of corticosteroid adverse effects (good practice statement). 3. We recommend administering dexamethasone before or with the first dose of antibiotic in patients with bacterial meningitis (strong recommendation, moderate-quality evidence).. We recommend use of corticosteroids to reduce mortality in patients with tuberculosis meningitis (strong recommendation, moderate quality of evidence). We cannot make a recommendation for one specific corticosteroid or dose in patients with TB meningitis due to the inconsistency of agents and doses evaluated in the literature. 5. We suggest that treatment with corticosteroids should be continued for two or more weeks in patients with tuberculosis meningitis (conditional recommendation, low quality of evidence). Rationale: In making this recommendation, the panel felt that the quality of evidence was low and considerable variability exists within and across studies regarding the duration of corticosteroid treatment. Clinicians should use patient-specific response and clinical factors to optimize the duration of corticosteroid treatment in this setting. 6. There is insufficient evidence to determine whether hypertonic sodium solutions or mannitol is more effective to reduce ICP or cerebral edema in patients with community-acquired bacterial meningitis. The panel evaluated whether the use of corticosteroids improved neurological outcome in patients with community-acquired bacterial meningitis and TB meningitis. , Questions 9 and 10) The panel elected to focus on these two areas within the broader category of bacterial meningitis due to their acuity and worldwide prevalence. The literature describing corticosteroid use in community-acquired bacterial meningitis is broad and includes many studies that combined adult and pediatric populations, as well as mixed immunocompetent, immunocompromised, and unknown immune status patients. While various corticosteroids have been evaluated, the overwhelming majority administered dexamethasone. Specific antimicrobial use and the corticosteroid timing in relation to antibiotic dose were not always described but are noted in the applicable evidentiary table when the information was available. The overall quality of the evidence was moderate . ## Bacterial meningitis Three meta-analyses have shown varying effects of corticosteroid treatment on outcomes in community-acquired bacterial meningitis. These meta-analyses are disparate in their methodologies and assess patients over different time periods, but are similar in that they included several of the same randomized trials. Due to the high risk of heterogeneity across these meta-analyses and the low quality of some of the studies included in each meta-analysis, the overall quality of these metaanalyses was classified as low and the strength of these findings should be cautiously applied in practice. In addition, some overlap in the data and time periods exists; therefore, the panel took this into account so as to not over-emphasize specific studies in the recommendations. One meta-analysis by Brouwer et al. includedRCTs from 1963-2013 and evaluated children and adults with varying corticosteroid agents and doses. Overall, there were no significant differences in mortality or neurological sequelae, although corticosteroid use significantly lowered rates of hearing loss. Patients in high-resource areas who were treated with corticosteroids had decreased hearing loss compared to those in low-resource areas. In addition, a subset of patients with Streptococcus pneumoniae meningitis demonstrated a lower mortality rate with corticosteroid treatment. When seven studies from this meta-analysis were analyzed separately with only adult patient data, there was no difference in mortality between groups. Four of these studies included hearing loss as part of their neurological outcome measures and found it to be significantly lower in patients treated with corticosteroids. A second meta-analysis by Vardakas et al. included 10 RCTs published from 1963 to 2007 and determined that corticosteroids were not associated with decreased mortality overall. A subgroup analysis found that corticosteroid treatment was associated with lower mortality in laboratory-proven meningitis, Streptococcus pneumoniae meningitis, and in patients in high-resource areas. Further analysis of only the high-quality randomized controlled trials in the meta-analysis showed that corticosteroid use was associated with decreased hearing loss. An additional subgroup analysis removing primarily HIV-positive patients demonstrated that corticosteroid treatment was associated with lower mortality. Finally, Van de Beek et al. published a meta-analysis of five trials published between 2002 and 2007 using individual patient data. Overall, they found no difference in mortality, neurological disability, or severe hearing loss. A post hoc analysis suggested that, among survivors, corticosteroid use was associated with reduced hearing loss. Individual trials show similar trends. de Gans et al. published the landmark RCT for corticosteroid use in community-acquired bacterial meningitis, which randomized adult patients to dexamethasone 10 mg intravenous every 6 h for 4 days with the first dose of dexamethasone 15-20 min prior to or with antibiotics. Dexamethasone improved GOS and decreased mortality, but did not benefit other neurological sequelae including hearing loss. In a subgroup analysis of patients with Streptococcus pneumoniae meningitis, neurological outcomes and the rate of neurological sequelae were improved in the dexamethasone group compared with placebo. Other studies have also suggested patients with Streptococcus pneumoniae meningitis may exhibit reduced hearing loss and lower risk of mortality from corticosteroid therapy. Taken together, these three meta-analyses and multiple individual trials suggest that corticosteroids do not affect mortality overall, though some distinct patient subsets may gain mortality benefit. In addition, corticosteroids may play a role in mitigating hearing loss. Of note, the Infectious Disease Society of American Bacterial Meningitis Guidelines evaluated corticosteroid use in 2004. These guidelines included both adult and pediatric patients. The authors recommended use of dexamethasone in adults with suspected or proven Streptococcus pneumoniae meningitis and avoiding corticosteroid use if antimicrobials have already been initiated (both with a GRADE-equivalent to strong recommendation, high-quality evidence). They also noted that the data are inadequate to recommend dexamethasone in adults with meningitis due to an unknown or non-pneumococcal pathogen. The panel elected to recommend the dexamethasone dose used in the de Gans study as it was the seminal study and provides an easy, practical dosing regimen. There is a scarcity of the published literature addressing the use of HTS or mannitol for ICP elevation or cerebral edema in community-acquired bacterial meningitis . The panel identified one relevant study, which did not specifically evaluate the role of hyperosmolar therapy but rather determined that ICP control by a combination of methods improved mortality in communityacquired bacterial meningitis. Of note, only 40% of patients included in this study received hyperosmolar therapy. Multiple studies evaluate the use of glycerol for elevated ICP in community-acquired bacterial meningitis and did not show a mortality benefit. ## Tuberculous meningitis The panel evaluated the use of corticosteroid treatment in patients with TB meningitis separately from community-acquired bacterial meningitis , Questions 9 and 10). Tuberculous meningitis occurs in immunocompromised patients, is more frequent in lower-resource areas, and generally has a higher morbidity and mortality compared to community-acquired bacterial meningitis. The literature search identified a number of RCTs and one meta-analysis, as well as a number of other studies evaluating corticosteroids in TB meningitis. The overall quality of the evidence was moderate (Evidentiary of Electronic Supplementary Material). The meta-analysis by Prasad et al. included 1337 adult and pediatric patients with TB meningitis who received corticosteroids. Studies using a variety of agents and over different durations were also included in this analysis. At 3-18-month follow-up, corticosteroid use reduced mortality by almost 25%, but did not change overall neurological outcomes. These results are consistent with an RCT of moderate quality that evaluated a tapering dose of dexamethasone and found that it reduced mortality, but not neurological deficits. This treatment effect was consistent across subgroups of disease severity and HIV status. Conversely, other randomized trials in TB meningitis have shown no benefit on mortality or morbidity and were confounded by a variety of corticosteroid dosing strategies and agents used across the studies. The duration of corticosteroid therapy ranged from 1 to 8 weeks in these studies, and no definitive treatment duration has emerged from the available evidence. Overall, there is some suggestion that corticosteroids may reduce mortality in patients with tubercular meningitis and the duration of therapy is likely to be much longer than with community-acquired meningitis. ## Treatment of cerebral edema in patients with hepatic encephalopathy In patients with hepatic encephalopathy, does the use of hypertonic sodium solutions improve cerebral edema compared to mannitol? In patients with hepatic encephalopathy, does the use of hyperosmolar therapy improve neurological outcomes at discharge compared to ammonia-lowering agents? ## Recommendations 1. We suggest using either hypertonic sodium solutions or mannitol for the management of ICP or cerebral edema in patients with hepatic encephalopathy (conditional recommendation, very low-quality evidence). Rationale: In making this recommendation, the panel felt that the quality of evidence was very low and the literature in patients with hepatic encephalopathy was not compelling to recommend one form hyperosmolar therapy over the other. Thus, either agent could be used and patient-specific factors may be employed to aid clinicians in selecting the appropriate initial agent. 2. There is insufficient evidence to determine whether either hyperosmolar therapy or ammonia-lowering therapy improves neurological outcomes in patients with hepatic encephalopathy. The panel assessed whether the use of HTS reduced ICP or cerebral edema more effectively than mannitol in patients with HE . The panel identified five studies that evaluated either mannitol or HTS as monotherapy, but did not find any studies that directly compared the two agents. The overall quality of evidence was very low . Early studies evaluated various combinations of therapies (mannitol, dexamethasone) in patients with liver failure and elevated ICP. These studies were graded as low quality because they variably and inconsistently assessed the effect of mannitol on ICP. Nevertheless, the results suggested some benefits of mannitol in this context. One placebo-controlled study of 30 patients with acute liver failure and elevated ICP evaluated a 3% NaCl bolus to maintain a serum sodium of 145-155 mEq/L, which increased serum sodium and significantly decreased ICP compared to placebo. Retrospective analyses of patients with liver failure who received hyperosmolar therapy show conflicting results based on imaging: 23.4% NaCl reduced brain tissue volume (as measured by MRI or diffusion tensor imaging), whereas mannitol did not affect brain water or clinical status. The evidence identified by the panel suggests that hyperosmolar therapy can effectively treat elevated ICP or cerebral edema in the setting of fulminant liver failure and HE; however, more research is needed to determine optimal treatment strategies. The availability of a welldesigned prospective clinical trial comparing HTS and mannitol in this patient population would substantially change the strength of evidence in this area. In addition, a gap in the literature exists regarding the influence of ammonia-lowering therapy on ICP, cerebral edema, or neurological outcomes. ## Hyperosmolar therapy safety and infusion considerations In patients receiving mannitol, does osmolarity or osmolar gap best predict the likelihood for AKI? In patients receiving hypertonic sodium solutions, does the serum sodium concentration best predict toxicity [AKI, unwanted acidosis] compared to the serum chloride concentration? ## Recommendations for assessing the risk of renal injury after mannitol administration 1. We suggest using osmolar gap over serum osmolarity thresholds during treatment with mannitol to monitor for the risk of AKI (conditional recommendation, very low-quality evidence). Rationale: In making this recommendation, the panel felt that the quality of evidence was very low. While osmolar gap has not been definitively shown to predict AKI during mannitol treatment, the osmolar gap appears to correlate best with mannitol concentration and elevated mannitol concentration is best associated with toxicity. Thus, the physiological rationale for the use of osmolar gap is stronger than using an empiric osmolarity threshold. 2. There is insufficient evidence to recommend a cutoff value for osmolar gap when evaluating for the risk of acute kidney injury. Rationale: In making this recommendation, the panel felt that the quality of evidence was too low to make a definitive recommendation. While the panel recognizes that an osmolar gap of 20 mOsm/kg has been used in clinical practice, we were unable to identify evidence to support this threshold. Research suggests that serum mannitol concentrations are the most effective method to assess but AKI risk, but this laboratory measurement is not commonly available. We did identify one study that demonstrated an osmolar gap of 55 mOsm/ kg or higher being most correlated with serum mannitol concentration. 3. Renal function measures should be monitored closely in patients receiving mannitol due to the risk of AKI with hyperosmolar therapy (good practice statement). The panel evaluated whether osmolar gap was more predictive of AKI than osmolarity threshold in neurocritical care patients receiving mannitol , Question 13). Three publications have addressed this specific issue, though no studies directly compare the two measures. Because of this lack of direct comparison, we were unable to make a strong recommendation for one monitoring strategy over the other. The panel defined outcomes of interest as any related to renal dysfunction. The overall quality of evidence was very low . The incidence of AKI is estimated to be between 6 and 12% of patients treated with mannitol. Several specific risk factors have been identified in patients with mannitol-associated AKI, including heart failure, diabetes, higher severity of illness (APACHE II or NIHSS), and pre-existing renal dysfunction. The precise mechanism for mannitol-related AKI is not well defined, but appears to be concentration-related. Very limited evidence is available to guide clinicians in choosing an osmolarity parameter when administering mannitol. Clinicians commonly use a serum osmolarity of 320 mOsm/kg or an osmolar gap of 20-55 mOsm/kg to estimate the risk of AKI with mannitol; both are indirect surrogates of serum mannitol concentration. Serum mannitol concentration is possibly the best indicator of AKI risk based on animal models, however most clinical laboratories are not able to directly measure this. Of the clinical measures serum mannitol concentration appears to correlated best with osmolar gap. In one case series of eight patients with mannitolinduced AKI, an elevated osmolar gap was present in all but two patients (mean osmolar gap 74 mOsm/kg). Early publications describing a serum osmolarity threshold of 320 mOsm/L included variable mannitol dosing regimens under different treatment paradigms that may no longer apply to current therapy (e.g., continuous infusion). Recent studies have shown that an osmolarity threshold of greater than 320 mOsm/L does not affect the incidence of AKI. Clinicians should monitor intravascular volume status, renal function, and some measure of serum osmolarity closely when using mannitol in patients with cerebral edema. ## Recommendations for assessing the risk of toxicity (acute kidney injury or unwanted acidosis) after hypertonic sodium solution administration 1. We suggest that severe hypernatremia and hyperchloremia during treatment with hypertonic sodium solutions should be avoided due to the association with acute kidney injury (conditional recommendation, low-quality evidence). An upper serum sodium range of 155-160 mEq/L and a serum chloride range of 110-115 mEq/L may be reasonable to decrease the risk of acute kidney injury (conditional recommendation, very low-quality evidence). Rationale: In making this recommendation, the panel rated the quality of evidence as very low. The precise serum values associated with acute kidney injury varies across the literature. Clinicians should evaluate the appropriate sodium and chloride concentrations in individual patients based on renal function, acid-base balance, and the need for acute treatment for elevated ICP or cerebral edema. 2. Clinicians should routinely monitor both sodium and chloride serum concentrations to assess risk of AKI related to elevated concentrations (good practice statement). 3. Renal function should be monitored closely in patients receiving hypertonic sodium solutions due to the risk of AKI with hyperosmolar therapy (good practice statement). Rationale: In making these good practice statements on monitoring renal function, serum sodium, and serum chloride, the panel felt that the practice of routine monitoring for acute kidney injury was prudent given the potential risks of both HTS in this setting. Clinicians should use patient-specific factors to determine the frequency of monitoring with ranging from twice daily to every 2 h based on rapidity of change to interventions. The panel evaluated the safety of HTS as it relates to the development of AKI and unwanted metabolic acidosis , Question 14). Hypernatremia and hyperchloremia have both been linked to AKI and poor outcomes in a variety of critical care populations. A small number of publications directly compared serum sodium concentrations to serum chloride concentrations in terms of the risk of AKI. We identified six studies that evaluated the relationship between use of HTS, hypernatremia, and AKI. Varying concentrations of HTS, administration techniques, and serum sodium ranges (generally 155-160 mEq/L) have been described in the literature, which complicates interpretation. Also included in the panel's analysis were several studies that commented on the safety and/or side effects of hyperosmolar therapy in the neurocritical care setting but were not designed to specifically evaluate AKI. The panel defined outcomes of interest as any related to renal dysfunction or acid-base balance. The overall quality of evidence was very low . The only study which was designed to distinguish between serum sodium and serum chloride in predicting AKI retrospectively reviewed the use of continuous infusion 3% NaCl in a mixed neurocritical care population. Sixteen percent of patients developed AKI, which was associated with a longer intensive care unit (ICU) length of stay and a greater in-hospital mortality. Five independent risk factors for AKI were identified: severe hypernatremia (serum sodium > 155 mEq/L), male gender, African-American ethnicity, history of chronic kidney disease, or having received piperacillin/tazobactam. Hyperchloremia (serum chloride > 110 mEq/L), severe hypernatremia, and hyperosmolarity were more common in the AKI group. Other studies of neurocritical care patients who received HTS have conflicting results with regard to the relationship between hypernatremia and AKI. There is considerable variability in study design, population, statistical validity, and outcome reporting that precludes forming strong recommendations. Hyperchloremia has been implicated in the development of AKI in several observational studies. In one retrospective cohort study of patients with SAH, treatment with HTS was more common in the group of patients who developed AKI. Both increase in mean serum chloride level (OR 7.39 per 10 mEq/L increase) and use of HTS (OR 2.074) were found to be independently associated with AKI. In addition, five independent risk factors for AKI were identified: male gender, hypertension, diabetes mellitus, abnormal baseline creatinine, and degree of increase in mean serum chloride concentration. A separate, propensity-matched retrospective cohort study which included patients with ICH found that those who received continuous infusion 3% NaCl and developed hyperchloremia (Cl > 115 mEq/L) had significantly higher rates of AKI. One retrospective cohort comparison evaluated the effects of bolus dose and continuous infusion 3% NaCl on AKI. Hyperchloremia and AKI were more observed to be more frequent in the continuous infusion cohort. Three studies have described the effect of HTS on acid-base balance. Two retrospective cohort studies described the use of a sodium acetate and NaCl mix (to equal a 2 to 3% solution) which demonstrated no difference in the rate of metabolic acidosis. Tseng et al. reported on the use of 23.5% NaCl to achieve a goal serum sodium of 145-155 mEq/L in patients with SAH. No significant changes in serum bicarbonate concentration were noted. Despite the relative lack of studies demonstrating substantial acid-base imbalances with HTS use, clinicians should be mindful of the potential for hyperchloremia to induce metabolic acidosis, which may stimulate respiratory drive. Though the quality of the evidence is low, it suggests that severe hypernatremia and hyperchloremia from HTS are associated with AKI. In addition, the impact of HTS on acid-base balance is not well defined in studies including neurocritical care patients. Clinicians should monitor renal function, electrolytes, and acid-base balance closely when using HTS. ## Recommendations for the optimal administration method of hypertonic sodium solution In patients with cerebral edema, how does continuous infusion of hypertonic sodium solutions compare to bolus infusion of hypertonic sodium solutions in improving neurological outcomes? 1. There is insufficient evidence to support use of a continuous infusion of HTS targeting a serum sodium goal for the purpose of improving neurological outcomes. 2. Due to insufficient evidence, we cannot recommend a specific dosing strategy for HTS to improve neurological outcomes in patients with cerebral edema. 3. Clinicians should avoid hyponatremia in patients with severe neurological injury due to the risk of exacerbating cerebral edema (good practice statement). The panel evaluated whether titrating a continuous infusion of HTS to a target serum sodium concentration compared to the use of bolus/symptom-based dosing resulted in improved neurological outcomes in patients with cerebral edema across a variety of neurocritical care conditions , Question 15). Six publications have specifically addressed the issue of how HTS was administered to patients, but the panel only identified one that directly compared continuous infusion versus bolus administration for control of ICP that met the criteria for this PICO. The overall quality of evidence was very low . While the use of a continuous infusion of 3% NaCl is believed to be a common practice in neurocritical care, this strategy is not well studied. Maguigan et al. directly compared continuous versus bolus dose 3% NaCl for control of ICP elevations in a retrospective study of 162 patients with severe TBI to assess which method was the most effective. No significant difference was found in time to the goal osmolarity, although more patients receiving continuous 3% NaCl reached the goal serum osmolarity than patients receiving bolus dosing. There was no difference in ICP or mortality between the two groups. Given the lack of evidence comparing these dosing strategies, it is not clear whether continuous or bolus dosing is preferable when targeting a goal serum sodium concentration. Additionally, there is a significant gap in the literature regarding the value of targeting a specific serum sodium concentration in patients with cerebral edema, if it is in fact efficacious. While this discussion focuses on increasing sodium concentrations to treat elevated ICP and cerebral edema, clinicians must maintain awareness of the risk and benefits of sudden sodium changes, particularly in patients with chronic hyponatremia). ## Non-pharmacologic treatment of cerebral edema and elevated intracranial pressure In patients with cerebral edema, how do non-pharmacological interventions compare to pharmacological interventions for reduction of cerebral edema? ## Recommendations for the non-pharmacological treatment of cerebral edema 1. We suggest that elevating the head of the bed todegrees (but no greater than 45 degrees) be used as a beneficial adjunct to reduce intracranial pressure (conditional recommendation, very low-quality evidence). Rationale: In making this recommendation, the panel rated the quality of available evidence as very low. However, this intervention has been used extensively in the clinical setting and the risk of elevating the head of the bed is generally very low and may be beneficial. 2. We recommend that brief episodes of hyperventilation can be used for patients with acute elevations in intracranial pressure (strong recommendation, very low-quality evidence). Rationale: In making this recommendation, the panel rated the quality of available evidence was very low. However, a strong recommendation was felt to be appropriate given the extensive amount of practical experience with this therapeutic strategy. Clinicians should be mindful of the limitations of acute hyperventilation related to cerebral blood flow and the extent of PaCO 2 reduction. Clinicians should also maintain careful awareness of the duration of therapy to avoid deleterious changes in cerebral perfusion. 3. We suggest that the use of CSF diversion be considered as a beneficial adjunct to reduce intracranial pressure (conditional recommendation, very lowquality evidence). Rationale: In making this recommendation, the panel felt that the quality of evidence was very low. Clinicians should assess the risks and benefits of CSF diversion using patient-specific factors. 4. While non-pharmacological interventions may be effective for acute elevations in intracranial pressure, there is insufficient evidence that non-pharmacological interventions are effective for the treatment of any specific physiological changes that produce brain swelling related to cerebral edema. The panel evaluated whether non-pharmacologic therapies such as hyperventilation, head of the bed elevation, and CSF diversion can be used to reduce ICP and cerebral edema in neurocritical care patients , Question 16). It must be noted that these nonpharmacological interventions decrease ICP through mechanical or structural changes without actually having any impact on cerebral edema and brain swelling. Other non-pharmacologic therapies such as surgical decompression and therapeutic hypothermia were not included, as they are adequately addressed by other guidelines. The overall quality of evidence was very low . The panel identified nine studies which assessed ICP in relation to elevation of the head of the bed. Compared to supine positioning, ICP was consistently lower in patients at angles of 15 o to as high as 90 o . The effect of head of bed elevation may be attributable to cardiovascular physiology and cerebral blood volume, which can at times manifest as alterations in CPP. In fact, several studies suggest that CPP is slightly reduced as the extent of head of bed elevation increases, though not to a clinically significant degree. One prospective observational study of patients with TBI suggested that ICP was reduced and CPP was stable when elevating the patients' head of the bed from supine to 30 o. However, further increases in the angle of head elevation above 45 o may increase ICP and/or reduce CPP. The. There was no difference in long-term outcomes, and a subgroup analysis suggested that prophylactic hyperventilation may be harmful in patients with a motor subscore of 4-5 on the GCS. While the quality of the literature for transient hyperventilation is graded as very low, clinical experience with this practice as a temporizing treatment for elevated ICP is extensive. The use of transient hyperventilation in patients with symptoms suggesting acute cerebral edema or herniation has been a standard practice in multiple clinical settings (pre-hospital, emergency department, ICU and operating room), and clinicians have seen improvement in pupil diameter, physical examination, or ICP measurements in response to this intervention. In addition, the harm associated with hyperventilation is generally related to the risk for cerebral ischemia with prolonged vasoconstriction. Given the potential life-threatening nature of elevated ICP, lack of apparent associated harm, and possible short-term benefit with transient hyperventilation, we felt that virtually all clinicians would choose hyperventilation as an adjunctive treatment strategy given the possibility that it may decrease ICP. Thus, the panel felt that a strong recommendation was warranted. The panel identified four studies evaluating the efficacy of CSF diversion in reducing ICP. Physiologically, it may be reasonable to assume that CSF drainage can lower ICP by decreasing the volume of the intracranial compartment by shunting CSF from the ventricles (as opposed to decreasing cerebral edema). Overall, CSF diversion appeared to be effective at reducing the ICP in two separate prospective, observational cohort studies. There was a significant change in ICP immediately after drainage without a measurable improvement in other indices of cerebral perfusion. In addition, Nwachuku et al. found that continuous CSF drainage results in a lower mean ICP and overall ICP burden compared to intermittent drainage. ## Summary The pharmacologic treatment of cerebral edema should be guided whenever possible by the underlying pathology. The available evidence suggests hyperosmolar therapy may be helpful in reducing ICP elevations or cerebral edema in patients with SAH, TBI, AIS, ICH, and HE, although neurological outcomes do not appear to be affected. This finding is consistent with many other interventions used in the acute care of patients with neurological conditions in that treatments may affect an immediate abnormality, but outcomes are often influenced by multiple factors that may be beyond the awareness or control of the treating team (e.g., comorbidities, associated injuries, rehabilitation availability, etc.). Corticosteroids appear to be helpful in reducing cerebral edema in patients with bacterial meningitis, but not ICH. Differences in therapeutic response and safety may exist between HTS and mannitol. The use of these agents in these critical clinical situations merits close monitoring for adverse effects. The various treatments for ICP or cerebral edema reviewed in this guideline are used in patients with critical intracranial pathologies worldwide. Despite their ubiquity, the overall quality of the literature in this area is low and there is a paucity of rigorous prospective trials. The strength of the panel's recommendations was frequently downgraded due to the limited evidence available comparing the different treatments. The concepts of hyperosmotic therapy have been entrenched in the critical care management of patients with neurological injuries for years, yet there is limited evidence to guide clinicians on the optimal practical use of mannitol or hypertonic saline. There is a dire need for highquality research to better inform clinicians of the best options for the individualized care of patients with cerebral edema. The goals of research activities in this area should address specific questions, adequately reflect the scope of planned patient enrollment, and select reasonable outcome measures. Basic criteria of research efforts should include a definition of how cerebral edema is being measured, the specific purpose of any intervention (e.g., resuscitation, management of ICP, effect on physiological parameters), and what outcome measures will be assessed. In addition, research efforts should consider and report on the osmolar equivalents of agents used in the management of cerebral edema, assess the effects of specific ranges of sodium levels on markers of edema, evaluate the best duration of therapy, standardize and report basic care protocols, and consider the impact of all pharmacological and non-pharmacological interventions on designated outcomes. Finally, while the goal of all interventions in the management of neurological injuries is to improve survival and minimize disability, it must be acknowledged that a single intervention to address a specific physiological variable may have limited impact on the multiple factors that contribute to both short-and long-term outcomes. # Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1202 8-020-00959 -7) contains supplementary material, which is available to authorized users. ## Abbreviations AIS: Acute ischemic stroke; AKI: Acute kidney injury; APACHE: Acute physiology, age, and chronic health evaluation; CE: Cerebral edema; CNS: Central nervous system; CPP: Cerebral perfusion pressure; CSF: Cerebrospinal fluid; CT: Computerized tomography; GCS: Glasgow coma score; GOS: Glasgow outcome scale; GOSE: Glasgow outcome scale extended; HE: Hepatic encephalopathy; HES: Hydroxyethyl starch; HTS: Hypertonic sodium solution (usually referring to sodium chloride 3%, 7.5%, or 23.4%, but also inclusive of solutions ranging from 1.5 to 23.5% and various other sodium salts including lactate and bicarbonate); ICH: Intracerebral hemorrhage; ICP: Intracranial pressure; mRS: Modified Rankin scale; NaCl: Sodium chloride; NIHSS: National Institutes of Health Stroke Scale; PICO: Population, intervention, comparison, outcome; RCT : Randomized controlled trial; SAH: Subarachnoid hemorrhage; TB: Tuberculosis; TBI: Traumatic brain injury; TTH: Transtentorial herniation.	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1fea7d2c3113d3e4c13fb006891b9b58f93e253f	pubmed	Guidelines for the Diagnosis, Investigation and Management of Osteoarthritis of the Hip and Knee	Guidelines for the Diagnosis, Investigation and Management of Osteoarthritis of the Hip and Knee Osteoarthritis is a frequent medical problem. In general practice, musculoskeletal problems account for one in 10 of new consultations, 18% of them for osteoarthritis [1]. Many patients with osteoarthritis receive all the treatment they need from their general practitioner. Others require specialist rheumatological advice, and a few need joint replacement surgery. Guidelines for the care of this common problem as it affects the lower limbs will assist in the provision of the most appropriate care and help to identify areas where further research is necessary.Osteoarthritis is best considered as one potential cause of 'joint failure'. Osteoarthritis may be classified first by the joint sites involved, second by the severity of the individual radiological features and third by the presence or absence of clinical features. Clinically, the picture includes use-related pain, night pain, difficulty in initiating movement, and crepitus and 'bony' swelling, together with reduced range of movement in a joint.Radiologically, there is loss of inter-bone distance, subchondral sclerosis and cysts, and marginal osteophytes.Pathologically, there is initial defibrillation and softening which lead to local loss of cartilage, increased formation of subchondral bone, marginal osteophytes with altered bone contour, and a variable inflammatory synovitis[2].Epidemiology and natural historyStudies conducted in the UK by the Royal College of General Practitioners in 1981/2 showed an annual incidence of symptomatic osteoarthritis of 50/1,000 in Women and 29/1,000 in men over 75 years old [1].Prepared on behalf of the Joint Working Group by These figures, based on consultation rates, may be an underestimate of the true incidence of symptomatic osteoarthritis. A recent North American populationbased incidence study of symptomatic osteoarthritis suggested incidence rates of 50/100,000 patient years for hip osteoarthritis presenting for medical consultation, and 200/100,000 patient years for knee disease [bib_ref] Idiopathic symptomatic osteoarthritis of the hip and knee; a population based incidence..., Wilson [/bib_ref]. Osteoarthritis is rare before the age ofyears, but thereafter its frequency increases with age. It occurs most often in the distal interphalangeal joints, then in the knees, and is less common in the hips. Relatively little is known of the natural history of osteoarthritis. The disease progresses slowly and the pattern of progression at hip and knee differs [bib_ref] Analysis by age, sex, and distribution of symptomatic joint sites, Cushnaghan [/bib_ref]. Many people have radiological changes without symptoms, and symptoms of pain show considerable fluctuations with time. Although some patients improve after a symptomatic period due to osteoarthritis, most either remain static or have progressive disease. In many patients knee osteoarthritis remains static over 10 years [bib_ref] Radiological progression of osteoarthritis: an 11-year follow-up study of the knee, Spector [/bib_ref]. Clinical assessment Successful management centres on careful questioning and physical examination of the patient. Pain and physical disability are the principal clinical problems, and their causes and treatment usually require independent consideration. Periarticular pain syndromes are common in association with ostearthritis, though they must be differentiated from it and from intraarticular and bone causes of pain. Anxiety, depression, or fibromyalgia may be more relevant to an individual's pain and disability at a particular point in time than synovitis or mechanical dysfunction. Symptoms and functional impairment vary with time, reflecting the dynamic nature of osteoarthritis and the complexity of pain perception. Many elderly people have radiological changes of osteoarthritis; it is important to determine whether it is the cause of joint symptoms. Generalised arthropathies such as rheumatoid arthritis, psoriatic arthritis, and crystal arthritis should be considered [fig_ref] Table 1: Differential diagnosis of osteoarthritis [/fig_ref]. The main clinical assessments include: the presence of joint pain and tenderness; the presence of bony and soft tissue articular swelling; the distribution of joint involvement; the duration of morning stiffness; the presence of inactivity stiffness; and the presence of associated periarticular problems such as bursitis or tendinitis. Clinical signs which are more common in osteoarthritic joints than in other forms of arthritis include bony swelling and joint crepitus. Functional assessments are important, but are not often used in routine clinical practice. Standardised assessments such as the Health Assessment Questionnaire (HAQ) [bib_ref] Measurement of patient outcome in arthritis, Fries [/bib_ref] or the Arthritis Impact Measurement Scale (AIMS) [bib_ref] AIMS: an Anglicised version to assess the outcome of British patients with..., Hill [/bib_ref] can be used in osteoarthritis. 'Designer' instruments for osteoarthritis include the hip and knee scales of Lequesne, and associated measures [bib_ref] Indices of severity in osteoarthritis for weight-bearing joints, Lequesne [/bib_ref]. Investigation X-ray confirmation of the diagnosis of osteoarthritis is not always needed, especially in a general practice setting. X-rays should be taken if there is doubt about the diagnosis, if some other arthropathy is possible, or if joint replacement surgery is being considered. There is little advantage in using radiographs to determine the progress of osteoarthritis in routine clinical practice, but showing their radiographs to patients with osteoarthritis can help with patient education. Other investigations, such as rheumatoid factor titres or assessments of the acute phase response by measuring the ESR, will usually be negative or normal in osteoarthritis, and are only indicated in cases where there is diagnostic uncertainty. ## Treatment The goals of treatment are patient education, pain relief, and optimisation of function. A 'total patient' approach is appropriate. The treatment options are shown in . ## Patient education It is essential that patients understand the nature and likely effects of osteoarthritis, because this can help in their therapy [bib_ref] Reduction of joint pain in patients with knee osteoarthritis who have received..., Rene [/bib_ref]. They should be told about the disease itself and be reassured that it differs from rheumatoid arthritis. They should also be informed that it often stabilises and that surgery is usually not needed. General advice should include: explaining the Crystal arthritis (gout and pyrophosphate crystal (deposition disease) Seronegative arthritis, eg psoriatic arthritis Periarticular syndromes, eg bursitis and tendinitis advantages of losing weight if obese (giving help, if needed); discussing footwear, stressing the importance of shock-absorbing insoles (found in 'trainers' and other shoes); and emphasising the importance of regular exercise, such as walking every day. Simple aids such as walking sticks should be encouraged. Physcial and non-pharmacological treatments There are few prospective controlled evaluations of non-pharmacological therapies in osteoarthritis, though some, such as physiotherapy, are often used. An exercise programme for patients with osteoarthritis of the knee and hip increases activity and improves walking time without worsening pain or exacerbating arthritis-related symptoms [bib_ref] Efficacy of physical conditioning exercise in patients with rheumatoid arthritis and osteoarthritis, Minor [/bib_ref]. Pain lessens and muscle power is maintained. Other types of physiotherapy are frequently undertaken in patients with osteoarthritis. The simplest method of treatment involves teaching patients to perform quadriceps exercises, supervising them, and providing motivation [bib_ref] The medical management of osteoarthritis of the knee: an inflammatory issue?, Mcalindon [/bib_ref] [bib_ref] Supervised fitness walking in patients with osteoarthritis of the knee. A randomised,..., Kovar [/bib_ref]. Other methods of physiotherapy include the application of heat and cold, ultrasound, short-wave diathermy, and hydrotherapy, but they have not been subject to adequate critical appraisal to judge their benefits. The evidence that physiotherapy is of significant advantage for patients is weak, but it may help when combined with other procedures, such as arthroscopic lavage [bib_ref] Arthroscopic lavage of osteoarthritic knees, Livesley [/bib_ref] ; further studies are needed in this area. Hydrotherapy can be of value in rehabilitating patients disabled with osteoarthritis. It is often used to treat painful hips and to increase the range of movement of joints. It is conventional to recommend rest for an acutely painful osteoarthritic joint, though there is little evidence to support this contention; Bunning and Materson [bib_ref] A rational programme of exercise for patients with osteoarthritis, Bunning [/bib_ref] consider this advice to be an example of dogmatism in clinical practice. The case for repetitive exercise is more substantial. One study [bib_ref] Efficacy of physical conditioning exercise in patients with rheumatoid arthritis and osteoarthritis, Minor [/bib_ref] has shown a 44% improvement in patients after three months of aerobic pool exercises. The balance of evidence is in . Treatment options in osteoarthritis Analgesics Oral non-steroidal anti-inflammatory drugs Local non-steroidal anti-inflammatory drugs Local steroid injections Weight reduction Modification of mechanical factors (eg footwear, stick) Exercise Physiotherapy Arthroscopy, washout and debridement Replacement arthroplasty Osteotomy favour of exercise being beneficial in osteoarthritis, but further studies are needed to define the optimal approach [bib_ref] A rational programme of exercise for patients with osteoarthritis, Bunning [/bib_ref]. Quadriceps exercises are of considerable benefit in decreasing pain and increasing function in osteoarthritis of the knee [bib_ref] Physiotherapy in osteoarthritis of the knee, Chamberlain [/bib_ref] , and should be taught to patients. Obesity is a well-established risk factor for osteoarthritis of the knee. It can predict the development of knee osteoarthritis 36 years later [bib_ref] Obesity and knee osteoarthritis: The Framingham Study, Felson [/bib_ref]. Weight change significantly affects the risk for the development of knee osteoarthritis; among obese women with a high risk of developing osteoarthritis, weight loss decreased the risk [bib_ref] Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The..., Felson [/bib_ref]. At present there is no information as to whether or not weight loss is effective after symptomatic osteoarthritis has developed, though it is reasonable to expect that it has an effect. Various aids and appliances are provided for patients. A stick may reduce the load on a painful joint and improve both confidence and mobility; insoles reduce the impact forces transmitted to painful joints and favourably influence joint mechanics [bib_ref] The mechanisms of treatment of osteoarthritis of the knee with a wedged..., Yasuda [/bib_ref] ; simple aids for use within the home or garden, such as a bath stool, may substantially overcome handicap. ## Pharmacological treatments Drug therapy is an adjunct rather than a substitute for other treatments. Potential drug treatment includes analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), and local steroid injections; the concept of 'chondroprotection' by drugs remains controverisal and is currently unproven [bib_ref] Chondroprotection: myth or reality?, Brooks [/bib_ref]. Analgesics remain the first choice in drug therapy. The initial choice should be paracetamol, 0.5-lg given four to six hourly, up to a maximum of 4g/day. Nefopam hydrochloride, codeine phosphate, or combined preparations such as co-proxamol are often used, though evidence that they are better than paracetamol in osteoarthritis is scanty [bib_ref] Comparative effectiveness of five analgesics in patients with rheumatoid arthritis and osteoarthritis, Brooks [/bib_ref] , and any increase in efficacy may be offset by greater toxicity [bib_ref] Codeine plus paracetamol versus paracetamol in longer-term treatment of chronic pain due..., Kjaersgaard-Anderson [/bib_ref]. However, patients often prefer a combined analgesic. Stronger opioids should not be used; uncontrolled pain requires re-evaluation or an alternative approach. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used. Their superiority over simple analgesics is poorly documented. For example, a recent study showed no benefit over paracetamol for low (analgesic) or high (anti-inflammatory) doses of ibuprofen [bib_ref] Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen,..., Bradley [/bib_ref]. Although inflammation may be a feature of osteoarthritis, there is little evidence that NSAIDs are acting other than as analgesics. Nevertheless, for individual patients NSAIDs may offer better symptom control than pure analgesics. NSAIDs are associated with significant morbidity and mortality. Mortality from gastrointestinal complications (bleeding or ulceration of stomach, small bowel, and large bowel), cardiovascular sideeffects such as fluid retention, renal side-effects such as interstitial nephritis, and drug interactions, are particularly common and serious in elderly women, precisely the population with the highest requirement for control of osteoarthritic symptoms. NSAIDs should therefore only be considered when adequate doses of paracetamol have proved ineffective. When NSAIDs are used, it is advisable to prescribe the smallest effective dose, avoid repeat prescribing, and regularly reassess the need for NSAID therapy. This should be based on clinical assessment, vigilance for adverse reactions, and experience. Monitoring for adverse effects, particularly in elderly women, has been advocated [bib_ref] Renal complications of NSAIDs: identification and monitoring of those at risk, Blackshear [/bib_ref] , though the value of such monitoring has not yet been assessed. Similarly, prophylaxis of stomach (and possibly small bowel) complications by 'gastroprotective' agents such as misoprostol is being increasingly discussed [bib_ref] Prophylaxis of non-steroidal anti-inflammatory drug gastropathy; a clinical opinion, Roth [/bib_ref]. Such therapy does reduce endoscopic abnormalities but evidence that it reduces the rates of serious complications such as bleeding or perforation is still awaited [bib_ref] NSAID-associated gastropathy?a role for misoprostol?, Hopkinson [/bib_ref]. Patients vary greatly in their response to NSAIDs, and there are no convincing data to favour some NSAIDs more than others for use in osteoarthritis. ## Major differences in the safety profiles of different NSAIDs have yet to be established. Transcutaneous administration of NSAIDs may produce symptomatic relief equivalent to oral preparations [bib_ref] Topical non-steroidal anti-inflammatory drugs, Doogan [/bib_ref]. Their use is limited to superficial joints such as the knee. There is no evidence for their effectiveness in hip osteoarthritis. It is still unclear whether they are more effective than rubefacients, though there are few clinical trial data on this issue. Although certain NSAIDs show possible beneficial or detrimental effects on cartilage in experimental studies [bib_ref] Clinical aspects of chondroprotecdon, Huskisson [/bib_ref] , evidence that NSAIDs affect the osteoarthritic process in man is still being sought. However, there is some evidence that indomethacin may have deleterious effects on hip damage [bib_ref] Effect of non-steroidal anti-inflammatory drugs on the course of osteoarthritis, Rashad [/bib_ref]. This may be due to a number of mechanisms including damage to cartilage or bone. Until the results of further research are available indomethacin is best avoided in elderly osteoarthritic patients, especially as it is more often associated with other adverse effects, such as central nervous system toxicity and fluid retention, than are other NSAIDs. The use of corticosteroids remains controversial. Intraarticular steroids often produce symptomatic relief, but this is transient and there is a significant 'placebo' response [bib_ref] The effect of intra-articular steroids in osteoarthritis: a double blind study, Friedman [/bib_ref]. Different joints may show varying responses. Aspiration of synovial fluid with local steroid injection gives symptomatic benefits, and is mainly advantageous in allowing other therapies to be successfully instituted [bib_ref] Are intra-articular steroid injections useful for the treatment of the osteoarthri tic..., Dieppe [/bib_ref] [bib_ref] A French controlled multicentre study of intra-articular corticosteroids in the treatment of..., Mazieres [/bib_ref]. In spite of fears to the contrary, repeated injections do not appear to be harmful [bib_ref] Intra-articular steroid therapy: repeated use in patients with chronic arthritis, Keagy [/bib_ref]. Other injectable compounds (eg glycosaminoglycan polysulphate, hyaluronate, and orgotein?a superoxide dismutase which inhibits free radical peristence) are still being assessed and are currently unlicensed in the UK. When to refer patients for specialist advice Patients with osteoarthritis present to their general practitioner because of increasing pain, increasing disability, concern about the diagnosis, and the limitation of their activities. General practitioners should make the diagnosis, explain, educate, and advise, and initiate therapy. Referral for specialist advice may be necessary when there is a diagnostic uncertainty or there are persistent and poorly controlled symptoms. Increasing disability or a local complication such as locking of the knee are also reasons for referral. Most patients should be followed up in the community by their general practitioner. Patients need medical review of their osteoarthritis for advice on medication and physiotherapy; to look for complications such as bone collapse, avascular necrosis, instability of the joints, and acute crystal synovitis; and to minimise the risk of side-effects of medication by ensuring their early detection. When to consider surgery Pain is the most important single reason for surgery. When pain becomes intolerable or unmanageable by medical means, operative treatment should be considered. Progressive loss of movement leading to deformity is a strong relative indication for surgery. When deformity exacerbates pain, for example in the varus osteoarthritic knee, correction of the deformity alone, in this example by osteotomy of the varus knee, may be indicated. The main reasons for surgery are given in [fig_ref] Table 4: Reasons for surgery [/fig_ref]. Osteotomy and arthroplasty are the mainstays of surgical treatment. The choice of procedures and implants is outside the scope of these medical guidelines [bib_ref] Hip and knee joint replacements. Drug and Therapeutics, Anonymous [/bib_ref]. Surgical intervention must be weighed against patients' social circumstances and age; it must also take account of potential loss of employment. The general effects of surgery on health status should also be weighed in the balance [bib_ref] How good are knee replacements?, Anonymous [/bib_ref] [bib_ref] Arthroscopic lavage of osteoarthritic knees, Livesley [/bib_ref]. Arthroscopic treatment with surface debridement, washout, and similar procedures is sometimes useful. ## Patients' needs and expectations The first need is for adequate pain relief. The second need is for information and education. This will include explanations about why osteoarthritis has developed, its likely clinical course, the role of contributory factors such as obesity, and whether to rest or use the joints. Useful information in these areas is unfortunately limited. When referral is needed for specialist rheumatological or surgical advice, this should be readily available. As well as specialist medical advice, a rheumatology unit may have nurses and paramedical staff with important roles in the management of patients with osteoarthritis. Direct access to physiotherapy and Increasing deformity Complications such as sudden locking of knee Progressive disability and dependency other paramedical services by general practitioners is common, but uncertainty remains as to whether these approaches are effective, or may be wasted effort. The medical needs of people with osteoarthritis The needs of patients with osteoarthritis are large [fig_ref] Table 5: Facilities and services needed by patients with [/fig_ref]. A survey of self-reported disability in Great Britain by the Office of Population, Censuses and Surveys (OPCS) found that osteoarthritis involves 4% of adults up to 60 years of age, rising to 25% of 60-74 year-olds and 65% aged over 75 years [bib_ref] What do rheumatologists do? A pilot audit study, Bamji [/bib_ref]. Analysis of outpatient attendances in specialist rheumatology clinics in the UK showed that patients with osteoarthritis accounted for 10-45% of new referrals and 5-25% of follow-up patients [bib_ref] The present and future adequacy of rheumatology manpower; a study of healthcare..., Marder [/bib_ref] [bib_ref] Arthroscopic lavage of osteoarthritic knees, Livesley [/bib_ref]. In North America a surveyassumed a prevalence of 3,500 per 100,000 patient years and suggested that 60% of patients with osteoarthritis would require two specialist consultations. Applying these statistics to a UK district of 250,000 would mean 10,500 outpatient visits annually for osteoarthritis. This is a very heavy workload and would require either a substantial increase in the number of rheumatologists or a different approach to the management of the condition. The continued emphasis on the management of osteoarthritis within the primary care setting in the UK, and the contribution towards its management made by general practitioners, may explain the apparent divergence from North American practice. Total hip arthroplasty for osteoarthritis is the most frequent major elective surgical procedure. Over 12 months in 1988/9 about 42,000 hips were replaced in NHS hospitals , 38% of them for osteoarthritis. In that year 36/100,000 were on the waiting list. The number of knee arthroplasties has increased to 15/100,000, 61% of them for osteoarthritis. In some Was a plain joint radiograph taken appropriately? 3. Did the patient receive adequate education and advice? ## 4. Were non-pharmacological treatments considered? ## 5. Were aids and appliances given when needed? ## 6. Was analgesia used when required or access available for other modalities of pain relief? 7. Were non-steroidal anti-inflammatory drugs used judiciously? ## 8- Was intra-articular steroid injection given when needed? ## 9. Was surgical referral considered when needed? 10. Was a follow-up plan made with good communication with general practitioners based on the need for most patients to be reviewed within the community? Progressive damage of major joints 3. Loss of social independence, increasing disability and loss of work (if relevant) [bib_ref] Analysis by age, sex, and distribution of symptomatic joint sites, Cushnaghan [/bib_ref]. Serious drug reactions areas of the UK, especially London, the private sector makes a substantial contribution towards the number of hip and knee arthroplasties undertaken. # Conclusions Osteoarthritis is common and causes considerable persisting pain and disability. It is a frequent cause of consultations in general practice and referral for specialist rheumatological advice. It often necessitates replacement of major joints such as the hip and knee. Despite its frequency, the natural history of osteoarthritis and its overall progression are not well defined; nor are the relative advantages of different types of physical treatment and the persistent use of non-steroidal antiinflammatory drugs fully evaluated. It is necessary to define the effects of current medical and surgical treatments and interventions on the course and outcome of osteoarthritis to establish an appropriate environment in which to provide optimal treatment and help for patients with osteoarthritis. Such endeavours will require fuller epidemiological studies with systematic measures of disease severity, as judged by pain experienced and functional capacity. Suggested measures for audit are given in [fig_ref] Table 6: Suggested audit measures for lower limb Availability of consultant rheumatologists in local... [/fig_ref]. [table] Table 1: Differential diagnosis of osteoarthritis [/table] [table] Table 3: Reasons for specialist referral [/table] [table] Table 4: Reasons for surgery [/table] [table] Table 5: Facilities and services needed by patients with [/table] [table] Table 6: Suggested audit measures for lower limb Availability of consultant rheumatologists in local hospitals 2.Collaboration between GPs and hospital specialists 3.Access to surgery and combined rheumatology and orthopaedic clinics Process 1.Were appropriate clinical assessments made to establish the diagnosis and exclude other causes of joint pain? [/table]	None	None	Osteoarthritis is a frequent medical problem. In general practice, musculoskeletal problems account for one in 10 of new consultations, 18% of them for osteoarthritis [1]. Many patients with osteoarthritis receive all the treatment they need from their general practitioner. Others require specialist rheumatological advice, and a few need joint replacement surgery. Guidelines for the care of this common problem as it affects the lower limbs will assist in the provision of the most appropriate care and help to identify areas where further research is necessary.
a847cf1463f0acc0c71297f0b9afa024510f3a33	pubmed	Difficult Airway Society guidelines for awake tracheal intubation (ATI) in adults	Difficult Airway Society guidelines for awake tracheal intubation (ATI) in adults Awake tracheal intubation has a high success rate and a favourable safety profile but is underused in cases of anticipated difficult airway management. These guidelines are a comprehensive document to support decision making, preparation and practical performance of awake tracheal intubation. We performed a systematic review of the literature seeking all of the available evidence for each element of awake tracheal intubation in order to make recommendations. In the absence of high-quality evidence, expert consensus and a Delphi study were used to formulate recommendations. We highlight key areas of awake tracheal intubation in which specific recommendations were made, which included: indications; procedural setup; checklists; oxygenation; airway topicalisation; sedation; verification of tracheal tube position; complications; management of unsuccessful awake tracheal intubation; post-tracheal intubation management; consent; and training. We recognise that there are a range of techniques and regimens that may be effective and one such example technique is included. Breaking down the key practical elements of awake tracheal intubation into sedation, topicalisation, oxygenation and performance might help practitioners to plan, perform and address complications. These guidelines aim to support clinical practice and help lower the threshold for performing awake tracheal intubation when indicated. ## Recommendations 1 Awake tracheal intubation must be considered in the presence of predictors of difficult airway management. 2 A cognitive aid such as a checklist is recommended before and during performance of awake tracheal intubation. 3 Supplemental oxygen should always be administered during awake tracheal intubation. 4 Effective topicalisation must be established and tested. The maximum dose of lidocaine should not exceed 9 mg.kg À1 lean body weight. Why were these guidelines developed? Awake tracheal intubation (ATI) has a high success rate and a low-risk profile and has been cited as the gold standard in airway management for a predicted difficult airway. However, ATI is reported to be used in as few as 0.2% of all tracheal intubations in the UK [bib_ref] 4th National Audit Project of the Royal College of Anaesthetists and the..., Cook [/bib_ref]. There are barriers preventing broad uptake and use of awake techniques for securing the airway. We aimed to produce generalisable guidelines to improve patient safety by making ATI more accessible to all clinicians, trainers and institutions. Rather than inform expert practice, these guidelines aim to support the use of ATI by more clinicians, with a particular focus on those that do not regularly perform ATI. There remains heterogeneity in clinical practice, underscoring the need for a more consistent approach using the available evidence, which these guidelines aim to deliver. ## What other guidelines exist? Although there are many guidelines on unanticipated difficult airway management [bib_ref] Difficult Airway Society 2015 guidelines for management of unanticipated difficult intubation in..., Frerk [/bib_ref] [bib_ref] Obstetric Anaesthetists' Association and Difficult Airway Society guidelines for the management of..., Mushambi [/bib_ref] [bib_ref] Recommendations for airway control and difficult airway management, Petrini [/bib_ref] [bib_ref] The difficult airway with recommendations for management -Part 1 -Intubation encountered in..., Law [/bib_ref] [bib_ref] Practice guidelines for management of the difficult airway: an updated report by..., Apfelbaum [/bib_ref] [bib_ref] All India Difficult Airway Association 2016 guidelines for the management of unanticipated..., Myatra [/bib_ref] [bib_ref] All India difficult airway association 2016 guidelines for the management of unanticipated..., Ramkumar [/bib_ref] [bib_ref] Difficult intubation and extubation in adult anaesthesia, Langeron [/bib_ref] [bib_ref] Scandinavian SSAI clinical practice guideline on pre-hospital airway management, Rehn [/bib_ref] [bib_ref] S1-Leitlinie Atemwegsmanagement: Leitlinie der Deutschen Gesellschaft f€ ur An€ asthesiologie und Intensivmedizin..., Piepho [/bib_ref] [bib_ref] airway management guideline 2014: to improve the safety of induction of anesthesia, Anon [/bib_ref] , there are few that specifically focus on the anticipated difficult airway. The ASA, Canadian Airway Focus Group, French Society for Anesthesia and Intensive Care and German Society for Anesthesiology and Intensive Care describe clinical decision making in the anticipated difficult airway [bib_ref] The difficult airway with recommendations for management -Part 1 -Intubation encountered in..., Law [/bib_ref] [bib_ref] Practice guidelines for management of the difficult airway: an updated report by..., Apfelbaum [/bib_ref] [bib_ref] Difficult intubation and extubation in adult anaesthesia, Langeron [/bib_ref] [bib_ref] S1-Leitlinie Atemwegsmanagement: Leitlinie der Deutschen Gesellschaft f€ ur An€ asthesiologie und Intensivmedizin..., Piepho [/bib_ref]. How do these guidelines differ from existing guidelines? Introduction A strategy for difficult airway management is necessary when facemask ventilation, supraglottic airway device (SAD) placement or ventilation, tracheal intubation or insertion of a front-of-neck airway (FONA) is predicted to be challenging. The incidence of difficult facemask ventilation is 0.66-2.5% [bib_ref] Diagnostic accuracy of anaesthesiologists' prediction of difficult airway management in daily clinical..., Nørskov [/bib_ref] [bib_ref] Prediction of difficult mask ventilation using a systematic assessment of risk factors..., Nørskov [/bib_ref] [bib_ref] Incidence, predictors, and outcome of difficult mask ventilation combined with difficult laryngoscopy:..., Kheterpal [/bib_ref] [bib_ref] Prediction and outcomes of impossible mask ventilation: a review of 50,000 anesthetics, Kheterpal [/bib_ref] , difficult SAD placement or ventilation 0.5-4.7% [bib_ref] Survey of laryngeal mask airway usage in 11,910 patients: safety and efficacy..., Verghese [/bib_ref] [bib_ref] Incidence of and risk factors for difficult ventilation via a supraglottic airway..., Saito [/bib_ref] [bib_ref] A comparison of the i-gel with the LMA-Unique in non-paralysed anaesthetised adult..., Francksen [/bib_ref] [bib_ref] The airway: problems and predictions in 18,500 patients, Rose [/bib_ref] [bib_ref] A randomised comparison of the Portex Softseal TM laryngeal mask airway with..., Cook [/bib_ref] , difficult tracheal intubation 1.9-10% [bib_ref] Diagnostic accuracy of anaesthesiologists' prediction of difficult airway management in daily clinical..., Nørskov [/bib_ref] [bib_ref] Incidence, predictors, and outcome of difficult mask ventilation combined with difficult laryngoscopy:..., Kheterpal [/bib_ref] [bib_ref] Predicting difficult intubation in apparently normal patients: a meta-analysis of bedside screening..., Shiga [/bib_ref] [bib_ref] A documented previous difficult tracheal intubation as a prognostic test for a..., Lundstrøm [/bib_ref] [bib_ref] Will this patient be difficult to intubate? the rational clinical examination systematic..., Detsky [/bib_ref] and combined difficulty in both facemask and tracheal intubation 0.3-0.4% [bib_ref] Incidence, predictors, and outcome of difficult mask ventilation combined with difficult laryngoscopy:..., Kheterpal [/bib_ref]. As a rescue technique after failed tracheal intubation, one study reported that SADs have a success rate as low as 65% in difficult airway management [bib_ref] Supraglottic airway devices in difficult airway management: a retrospective cohort study of..., Thomsen [/bib_ref]. The reported incidence of requirement for emergency FONA and death due to airway management are 0.002-0.07% (1:50,000-1:1400) [bib_ref] 4th National Audit Project of the Royal College of Anaesthetists and the..., Cook [/bib_ref] [bib_ref] Danish Anaesthesia Database. Emergency surgical airway management in Denmark: a cohort study..., Rosenstock [/bib_ref] [bib_ref] A prospective, cohort evaluation of major and minor airway management complications during..., Huitink [/bib_ref] and 0.0006-0.04% (1:180,000-1:2800), respectively [bib_ref] 4th National Audit Project of the Royal College of Anaesthetists and the..., Cook [/bib_ref] [bib_ref] A prospective, cohort evaluation of major and minor airway management complications during..., Huitink [/bib_ref]. The risk and severity of adverse outcomes during difficult airway management is highlighted by the plethora of guidelines and cognitive aids for airway rescue [bib_ref] Difficult airway management algorithms: a directed review, Edelman [/bib_ref]. Awake tracheal intubation involves placing a tracheal tube in an awake, spontaneously-breathing patient, most commonly with flexible bronchoscopy (ATI:FB) or videolaryngoscopy (ATI:VL, . This allows the airway to be secured before induction of general anaesthesia, avoiding the potential risks and consequences of difficult airway management in an anaesthetised patient [bib_ref] Strategies for the prevention of airway complications -a narrative review, Cook [/bib_ref]. Awake tracheal intubation has a favourable safety profile because both spontaneous ventilation and intrinsic airway tone are maintained until the trachea is intubated [bib_ref] Videolaryngoscopy vs. fibreoptic bronchoscopy for awake tracheal intubation: a systematic review and..., Alhomary [/bib_ref] [bib_ref] A study of flexible fiberoptic bronchoscopy aided tracheal intubation for patients undergoing..., Ajay [/bib_ref] [bib_ref] A prospective cohort study of awake fibreoptic intubation practice at a tertiary..., El-Boghdadly [/bib_ref] [bib_ref] The incidence, success rate, and complications of awake tracheal intubation in 1,554..., Law [/bib_ref] [bib_ref] A retrospective study of success, failure, and time needed to perform awake..., Joseph [/bib_ref]. Awake tracheal intubation can be unsuccessful in 1-2% of cases, but this rarely leads to airway rescue strategies or death [bib_ref] A prospective cohort study of awake fibreoptic intubation practice at a tertiary..., El-Boghdadly [/bib_ref] [bib_ref] The incidence, success rate, and complications of awake tracheal intubation in 1,554..., Law [/bib_ref] [bib_ref] A retrospective study of success, failure, and time needed to perform awake..., Joseph [/bib_ref]. These guidelines aim to increase the use of ATI by providing clear guidance for clinicians to support decision making, preparation and performance of ATI in the setting of a predicted difficult airway. # Methods The development of these guidelines followed the appraisal of guidelines for research and evaluation (AGREE) reporting checklist [bib_ref] The AGREE Reporting Checklist: a tool to improve reporting of clinical practice..., Brouwers [/bib_ref]. To ensure these guidelines are supported by best evidence, a systematic review adhering to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) recommendations [bib_ref] The PRISMA statement for reporting systematic reviews and meta-analyses of studies that..., Liberati [/bib_ref] [62], it is recommended that ECG, non-invasive blood pressure, pulse oximetry and continuous end-tidal carbon dioxide monitoring are used throughout the process of ATI (Grade C). It is acknowledged that end-tidal carbon dioxide monitoring during ATI may be challenging in current practice. Workspace ergonomics have an impact on performance and safety [bib_ref] Safer anaesthetic rooms: human factors/ergonomics analysis of work practices, Davis [/bib_ref] [bib_ref] Human factors and ergonomics as a patient safety practice, Carayon [/bib_ref] , and should be considered before starting the procedure (Grade D; [fig_ref] Figure 1: Grade D [/fig_ref] ; Supporting Information, Appendix S2) [bib_ref] Guidelines for the management of tracheal intubation in critically ill adults, Higgs [/bib_ref]. This includes optimising the position of patient, operator and assistants, as well as location of equipment and monitors, which should be in the direct line of sight of the operator. There is no consensus on the ideal operator or patient position [bib_ref] Airway management in adult patients with deep neck infections: a case series..., Ovassapian [/bib_ref] [bib_ref] Influence of patient posture on oxygen saturation during fibre-optic bronchoscopy, Meghjee [/bib_ref] [bib_ref] Flexible bronchoscopy in supine or sitting position, Van Zwam [/bib_ref] [bib_ref] Posture influences patient cough rate, sedative requirement and comfort during bronchoscopy: an..., Ling [/bib_ref] , but there are physiological and anatomical advantages to having patients sitting up [bib_ref] Preoxygenation in the obese patient: effects of position on tolerance to apnoea, Altermatt [/bib_ref] [bib_ref] Sitting posture decreases collapsibility of the passive pharynx in anesthetized paralyzed patients..., Isono [/bib_ref] [bib_ref] The effects of head and body positioning on upper airway collapsibility in..., Ikeda [/bib_ref]. Complications or unsuccessful ATI, although uncommon, should be prepared for [bib_ref] A prospective cohort study of awake fibreoptic intubation practice at a tertiary..., El-Boghdadly [/bib_ref] [bib_ref] The incidence, success rate, and complications of awake tracheal intubation in 1,554..., Law [/bib_ref] [bib_ref] A retrospective study of success, failure, and time needed to perform awake..., Joseph [/bib_ref] , and immediate access to emergency drugs, staff and equipment is essential (Grade C). A plan for unsuccessful ATI, including possible postponement, FONA or high-risk general anaesthesia, should be discussed explicitly and agreed on by all team members before beginning the procedure ## Checklists In the peri-operative setting the use of cognitive aids, such as checklists, improves inter-professional communication, teamwork and patient outcomes [bib_ref] Simulation-based trial of surgical-crisis checklists, Arriaga [/bib_ref] [bib_ref] Crisis checklists for the operating room: development and pilot testing, Ziewacz [/bib_ref] [bib_ref] Do safety checklists improve teamwork and communication in the operating room? A..., Russ [/bib_ref] [bib_ref] A surgical safety checklist to reduce morbidity and mortality in a global..., Haynes [/bib_ref]. In anaesthetic practice, cognitive aids enhance performance in simulated emergency scenarios [bib_ref] The impact of didactic read-aloud action cards on the performance of cannula..., Harvey [/bib_ref] [bib_ref] The effects of a displayed cognitive aid on non-technical skills in a..., Marshall [/bib_ref] , and their use been recommended in elective airway management [bib_ref] 4th National Audit Project of the Royal College of Anaesthetists and the..., Cook [/bib_ref]. Given the potential benefits, we recommend a cognitive aid such as a checklist before and during performance of ATI (Grade D; Supporting Information, Appendix S2). The key components of ATI are sedation, topicalisation, oxygenation and performance (sTOP; [fig_ref] Figure 2: The Difficult Airway Society awake tracheal intubation [/fig_ref]. The 's' is in lower case to emphasise the optional nature of sedation. ## Oxygenation The reported incidence of desaturation (S p O 2 ≤ 90%) with low-flow (< 30 l.min À1 ) oxygen techniques during ATI ranges between 12% and 16% [bib_ref] Awake fiberoptic or awake video laryngoscopic tracheal intubation in patients with anticipated..., Rosenstock [/bib_ref] [bib_ref] A technique of awake fibreoptic intubation. Experience in patients with cervical spine..., Sidhu [/bib_ref] [bib_ref] Fiberoptic intubation in 327 neurosurgical patients with lesions of the cervical spine, Fuchs [/bib_ref]. When warmed and humidified high-flow nasal oxygen is used, the reported incidence of desaturation is 0-1.5% [bib_ref] A prospective cohort study of awake fibreoptic intubation practice at a tertiary..., El-Boghdadly [/bib_ref] [bib_ref] Optimizing oxygenation and intubation conditions during awake fibreoptic intubation using a high-flow..., Badiger [/bib_ref] ; this was the most common oxygenation strategy used by experts responding to our survey. Although there are no randomised controlled trials comparing air vs. oxygen during ATI, data from bronchoscopy studies demonstrate that there is a significant difference in the incidence and severity of desaturation [bib_ref] Supplemental oxygen during moderate sedation and the occurrence of clinically significant desaturation..., Rozario [/bib_ref] [bib_ref] Pulse oximetry during fibreoptic bronchoscopy in local anaesthesia: frequency of hypoxaemia and..., Milman [/bib_ref]. In patients receiving sedation in a variety of settings, administration of oxygen has been shown to reduce the incidence of desaturation when compared with air [bib_ref] Supplemental oxygen during moderate sedation and the occurrence of clinically significant desaturation..., Rozario [/bib_ref] [bib_ref] Effects of sedation and supplemental oxygen during upper alimentary tract endoscopy, Reed [/bib_ref] [bib_ref] A prospective study evaluating the usefulness of continuous supplemental oxygen in various..., Reshef [/bib_ref] [bib_ref] The utility of high-flow oxygen during emergency department procedural sedation and analgesia..., Deitch [/bib_ref] [bib_ref] The utility of supplemental oxygen during emergency department procedural sedation and analgesia..., Deitch [/bib_ref]. United Kingdom, European and North American recommendations for sedation all suggest the use of supplemental oxygen [bib_ref] European Society of Anaesthesiology and European Board of Anaesthesiology guidelines for procedural..., Hinkelbein [/bib_ref] [bib_ref] Practice guidelines for moderate procedural sedation and analgesia 2018: a Report by..., Surgeons [/bib_ref] [bib_ref] Guidance on the provision of sedation services 2016. In: Royal College of..., Newton [/bib_ref]. Whilst airway topicalisation alone may rarely be associated with desaturation and airway obstruction [bib_ref] Complications of awake fibreoptic intubation without sedation in 200 healthy anaesthetists attending..., Woodall [/bib_ref] [bib_ref] Total airway obstruction during local anesthesia in a non-sedated patient with a..., Ho [/bib_ref] , there is no significant difference in the incidence of desaturation between ATI:FB and ATI:VL techniques, and therefore the recommendations apply to both approaches [bib_ref] Videolaryngoscopy vs. fibreoptic bronchoscopy for awake tracheal intubation: a systematic review and..., Alhomary [/bib_ref]. ## Airway topicalisation The success of ATI depends on effective topical application of local anaesthetic to the airway. Vasoconstriction of the nasal passage reduces the incidence of epistaxis [bib_ref] A comparison of the effects of epinephrine and xylometazoline in decreasing nasal..., Song [/bib_ref] [bib_ref] Epistaxis and nasotracheal intubation-prevention with vasoconstrictor spray, O'hanlon [/bib_ref]. The use of topical nasal vasoconstrictors before nasotracheal intubation is recommended (Grade A). Lidocaine has theoretical safety benefits over other local anaesthetic agents due to a favourable cardiovascular and systemic toxicity risk profile [bib_ref] Local anesthetic systemic toxicity: current perspectives, El-Boghdadly [/bib_ref] ; this is the most commonly used local anaesthetic agent for ATI. Following airway topicalisation, clinical evidence of toxicity or levels exceeding toxic plasma concentrations have been shown with lidocaine doses of 6.0-9.3 mg.kg À1 lean body weight [bib_ref] Serum concentrations of lignocaine and its metabolite monoethylglycinexylidide during fibre-optic bronchoscopy in..., Milman [/bib_ref] [bib_ref] Randomized-controlled trial to study the equivalence of 1% versus 2% lignocaine in..., Hasmoni [/bib_ref] [bib_ref] Absorption of lidocaine during aspiration anesthesia of the airway, Mainland [/bib_ref] [bib_ref] Plasma concentrations of lignocaine during fibreoptic bronchoscopy, Efthimiou [/bib_ref] [bib_ref] Combined nebulization and spray-as-you-go topical local anaesthesia of the airway, Williams [/bib_ref]. The dose of topical lidocaine should not exceed 9 mg.kg À1 lean body weight (Grade C) [bib_ref] Dose adjustment of anaesthetics in the morbidly obese, Ingrande [/bib_ref]. The recommendation of 9 mg.kg À1 rather than 9.3 mg.kg À1 is a pragmatic decision to allow ease of calculation. Practitioners should recognise that this is not a target but a maximum dose, and in practice this is rarely required. The total dose of all local anaesthetics administered, regardless of route (e.g. regional anaesthesia or surgical infiltration), [bib_ref] Intratracheal cocaine induced myocardial infarction: an unusual complication of fibreoptic bronchoscopy, Osula [/bib_ref] [bib_ref] Systematic review of topical vasoconstrictors in endoscopic sinus surgery, Higgins [/bib_ref] [bib_ref] Coronary spasm after the topical use of cocaine in nasal surgery, Lenders [/bib_ref] , while its analgesic efficacy during nasotracheal tube insertion is no better than co-phenylcaine (2.5 ml lidocaine 5%/ phenylephrine 0.5%) [bib_ref] Pain during awake nasal intubation after topical cocaine or phenylephrine/lidocaine spray, Cara [/bib_ref]. Cocaine in this setting is therefore not advised, and phenylephrine in combination with lidocaine is more appropriate (Grade A). Depending on the delivery device used, there is variable local anaesthetic absorption [bib_ref] The pharmacokinetics of atomized lidocaine administered via the trachea: a randomized trial, Takaenoki [/bib_ref] but this should not affect the maximal dose calculation. There is insufficient evidence to recommend any individual topicalisation technique (e.g. mucosal atomisation, spray-as-you-go, transtracheal injection, nebulisation) [bib_ref] Awake fiberoptic intubation protocols in the operating room for anticipated difficult airway:..., Cabrini [/bib_ref]. However, blocks of the glossopharyngeal and superior laryngeal nerves have been associated with higher plasma concentrations of local anaesthetic [bib_ref] A comparison of anesthetic techniques for awake intubation in neurosurgical patients, Reasoner [/bib_ref] , local anaesthetic systemic toxicity [bib_ref] Hypotension and bradycardia following superior laryngeal nerve block, Wiles [/bib_ref] and lower patient comfort [bib_ref] Local anesthetic administration for awake direct laryngoscopy. Are glossopharyngeal nerve blocks superior?, Sitzman [/bib_ref]. Invasive techniques should therefore be reserved for those with expertise in their performance (Grade B). Nebulised lidocaine can be used but absorption is variable [bib_ref] The science of nebulised drug delivery, O'callaghan [/bib_ref] ; consequently higher doses have been used to compensate for this [bib_ref] Complications of awake fibreoptic intubation without sedation in 200 healthy anaesthetists attending..., Woodall [/bib_ref]. Regardless of technique used, the adequacy of topicalisation should be tested in an atraumatic manner before airway instrumentation [bib_ref] Local anaesthesia for awake fibreoptic nasotracheal intubation, Kundra [/bib_ref] (Grade D), for example, with a soft suction catheter or Yankauer sucker. The use of an antisialogogue is not mandatory in the performance of ATI and may be associated with undesirable clinical consequences (Grade D; [fig_ref] Table 3: Characteristics of drugs used commonly during ATI [/fig_ref] [bib_ref] pharmacokinetics and some pharmacodynamics findings, Ali-Melkkila [/bib_ref]. There is limited evidence to support their use in ATI, but in anaesthetised patients the clarity of a visual field through a flexible bronchoscope may be improved [bib_ref] Anticholinergics improve fibreoptic intubating conditions during general anaesthesia, Brookman [/bib_ref]. If used, intramuscular antisialogogues should be injected 40-60 min before performing ATI, for peak mucosal drying effect, but there are few data on the intravenous (i.v.) route in this setting. ## Sedation Awake tracheal intubation may be safely and effectively performed without sedation [bib_ref] A prospective cohort study of awake fibreoptic intubation practice at a tertiary..., El-Boghdadly [/bib_ref] [bib_ref] Complications of awake fibreoptic intubation without sedation in 200 healthy anaesthetists attending..., Woodall [/bib_ref] [bib_ref] Training course in local anaesthesia of the airway and fibreoptic intubation using..., Patil [/bib_ref]. However, its use during ATI can reduce patient anxiety and discomfort and increase procedural tolerance [bib_ref] Conscious sedation for awake fibreoptic intubation: a review of the literature, Johnston [/bib_ref]. Minimal sedation is defined as "a drug-induced state during which the patient responds normally to verbal commands, whilst the airway, spontaneous ventilation and cardiovascular function are unaffected". Sedative drugs can produce a number of effects which may be considered desirable (e.g. amnesia) or detrimental (e.g. over-sedation). The risk of over-sedation and its sequelae, including respiratory depression, airway loss, hypoxia, aspiration and cardiovascular instability, make the presence of an independent anaesthetist delivering, monitoring and titrating sedation desirable [bib_ref] 4th National Audit Project of the Royal College of Anaesthetists and the..., Cook [/bib_ref] (Grade D). In certain patient populations, the risk of over-sedation is particularly hazardous, thus an independent practitioner delivering sedation is strongly recommended (Grade D; [fig_ref] Table 4: Special circumstances that may affect standard performance of ATI with suggested management... [/fig_ref]. If required, we recommend the cautious use of minimal sedation (Grade D). Remifentanil and dexmedetomidine are associated with high levels of patient satisfaction and low risk of oversedation and airway obstruction when used for ATI [bib_ref] Conscious sedation for awake fibreoptic intubation: a review of the literature, Johnston [/bib_ref]. A single-agent strategy is safest for the non-expert, and if used, remifentanil or dexmedetomidine are appropriate (Grade A). As a sole sedative agent, propofol is associated with a greater risk of over-sedation, coughing and airway obstruction than remifentanil [bib_ref] Remifentanil target-controlled infusion vs propofol target-controlled infusion for conscious sedation for awake..., Rai [/bib_ref] [bib_ref] A comparison of propofol and remifentanil target-controlled infusions to facilitate fiberoptic nasotracheal..., Lallo [/bib_ref] [bib_ref] TCI remifentanil vs. TCI propofol for awake fiber-optic intubation with limited topical..., Zhang [/bib_ref] and is therefore not advisable in this setting (Grade A) [bib_ref] Conscious sedation for awake fibreoptic intubation: a review of the literature, Johnston [/bib_ref]. If co-administration of sedative agents is to be performed, remifentanil and midazolam are both reversible and therefore appropriate, recognising the increased risk of over-sedation (Grade D). Sedation should not be used as a substitute for inadequate airway topicalisation (Grade D) [bib_ref] Awake fiberoptic intubation protocols in the operating room for anticipated difficult airway:..., Cabrini [/bib_ref]. A suggested sedation regimen is presented in [fig_ref] Figure 2: The Difficult Airway Society awake tracheal intubation [/fig_ref]. ## Two-point check of tracheal tube placement ## Difficult airway society ati technique An example of a practical approach to the sTOP ATI technique is shown in [fig_ref] Figure 2: The Difficult Airway Society awake tracheal intubation [/fig_ref]. This technique has been specifically considered for simplicity and generalisability. We recognise that there are a range of different techniques and regimens which also address the key sTOP components that will be equally effective. ## Special circumstances Specific patient pathophysiology may dictate modifications to the performance of ATI that must be considered and planned for. As with all other aspects of ATI, these modifications can be categorised based on sTOP. Examples of suggested changes to technique are presented in [fig_ref] Table 4: Special circumstances that may affect standard performance of ATI with suggested management... [/fig_ref]. ## Managing complications The reported overall complication rate in patients undergoing ATI either flexible bronchoscopic or videolaryngoscopic, is up to 18% . Complications during ATI occur due to inadequate sTOP. In the event of a complication, its aetiology should be determined and appropriately managed (Grade D; [fig_ref] Figure 3: Managing procedural complications during awake tracheal intubation [/fig_ref]. We define an unsuccessful attempt at ATI as the If airway management is deemed essential, the preferred option for securing the airway after unsuccessful ATI:VL or ATI:FB should be ATI using FONA (ATI:FONA), ## Post-tracheal intubation management Patients who have had ATI due to predicted difficult airway management are at high risk of complications at tracheal extubation [bib_ref] 4th National Audit Project of the Royal College of Anaesthetists and the..., Cook [/bib_ref] [bib_ref] Difficult Airway Society Guidelines for the management of tracheal extubation, Popat [/bib_ref] , and require an appropriate tracheal extubation strategy. Planning, preparation, performing and post-tracheal extubation care should follow DAS guidelines [bib_ref] Difficult Airway Society Guidelines for the management of tracheal extubation, Popat [/bib_ref] (Grade D). Before tracheal extubation, laryngoscopy, either with a direct laryngoscope or videolaryngoscope, may provide useful information for risk stratification of tracheal extubation and any subsequent airway management. The view at laryngoscopy may be altered by the presence of a tracheal tube [bib_ref] Difficult Airway Society Guidelines for the management of tracheal extubation, Popat [/bib_ref]. Therefore, verification of laryngoscopy grade may rule out, but not rule in, easy subsequent asleep tracheal intubation. Topical lidocaine has a dose-dependent duration of analgesic action of up to 40 min although this may vary with concentration and method of administration [bib_ref] Physiologic effects and serum lidocaine concentrations after inhalation of lidocaine from a..., Kirkpatrick [/bib_ref] [bib_ref] Onset and duration of hypoalgesia of lidocaine spray applied to oral mucosa..., Schønemann [/bib_ref]. However, the time to return of laryngeal reflexes can be longer [bib_ref] Lignocaine topicalization of the pediatric airway, Roberts [/bib_ref]. Given that the terminal elimination half-life of lidocaine is up to 2 h, patients should remain nil by mouth for at least 2 h following airway topicalisation for ATI (Grade D). Documentation of ATI in clinical records is necessary to inform and guide future patient management [bib_ref] 4th National Audit Project of the Royal College of Anaesthetists and the..., Cook [/bib_ref]. This ## Consent Clinicians should adhere to the Association of Anaesthetists' guidelines on consent for anaesthesia [bib_ref] Association of Anaesthetists: consent for anaesthesia 2017, Yentis [/bib_ref] (Grade D). Informed consent must be taken, with patients being given information (ideally including a patient information leafletin a timely manner (Grade D). The risks of ATI and its alternative (induction of general anaesthesia before securing the airway) should be discussed [fig_ref] Table 5: Incidence of complications when asleep or awake tracheal intubation is performed [/fig_ref] ## Training Successful performance of ATI has been shown to be independent of seniority, but related to experience [bib_ref] A prospective cohort study of awake fibreoptic intubation practice at a tertiary..., El-Boghdadly [/bib_ref]. There are many strategies used for training in the technical aspects of ATI, including the use of manikins, simulators, cadavers and patients [bib_ref] Complications of awake fibreoptic intubation without sedation in 200 healthy anaesthetists attending..., Woodall [/bib_ref] [bib_ref] Effective nonanatomical endoscopy training produces clinical airway endoscopy proficiency, Martin [/bib_ref] [bib_ref] Evaluating the ORSIM â simulator for assessment of anaesthetists' skills in flexible..., Baker [/bib_ref] [bib_ref] Development and initial evaluation of a novel, ultraportable, virtual reality bronchoscopy simulator, Casso [/bib_ref] [bib_ref] Comparison of the efficacy and efficiency of the use of virtual reality..., Jiang [/bib_ref] [bib_ref] Proficient manipulation of fibreoptic bronchoscope to carina by novices on first clinical..., Marsland [/bib_ref] [bib_ref] Fiberoptic intubation using anesthetized, paralyzed, apneic patients results of a resident training..., Cole [/bib_ref] [bib_ref] Virtual airway simulation to improve dexterity among novices performing fibreoptic intubation, Oliveira [/bib_ref]. All anaesthetists should seek every opportunity to attain and maintain skills in ATI and all departments should support this [bib_ref] 4th National Audit Project of the Royal College of Anaesthetists and the..., Cook [/bib_ref] (Grade C). Awake tracheal intubation is a skill in the compulsory higher training curriculum of the Royal College of Anaesthetists, but opportunities for training are known to be limited [bib_ref] Perception of training needs and opportunities in advanced airway skills: a survey..., Mcnarry [/bib_ref] [bib_ref] Difficult airway management practice patterns among anesthesiologists practicing in the United States:..., Ezri [/bib_ref] [bib_ref] An audit of fibreoptic intubation training opportunities in a UK teaching hospital, Wiles [/bib_ref] [bib_ref] Fibreoptic intubation skills among anaesthetists in New Zealand, Dawson [/bib_ref] [bib_ref] Airway management practices at German university and university-affiliated teaching hospitals -Equipment, techniques..., Goldmann [/bib_ref]. These guidelines provide a common stem for # Discussion The primary aims of these guidelines are to provide practitioners with a comprehensive document on ATI. These guidelines should support clinical practice and lower the performance threshold thereby increasing the use of ATI when indicated. The quality of evidence supporting many recommendations is limited, with interventions and outcomes being highly heterogeneous. This is likely influenced by the fact that ATI can be successfully performed in a wide range of settings and patients with varying techniques [bib_ref] Awake fiberoptic intubation protocols in the operating room for anticipated difficult airway:..., Cabrini [/bib_ref]. For example, the use of SADs as a conduit to ATI or optical stylets in awake patients have not been well-described but warrant future investigation as their role becomes more defined. Similarly, the lack of previously published specific guidelines means that research in ATI is disparate and inconsistent [bib_ref] From evidence based on practice to evidence-based practice: time for a difficult..., Ahmad [/bib_ref]. However, we have sought and appraised the available evidence in ATI, and in its absence we have incorporated the practical and theoretical experience of international experts. We have involved patients, DAS members and international experts in order to further understand current practice and the need for these guidelines. Formal resource implication analysis has not been conducted; however, the tools to practically perform ATI are available widely, and thus we expect the resource impact to be modest. These guidelines prioritise patient safety and provide recommendations for best clinical practice. It is hoped that they will lead to a paradigm shift in clinical practice and improve the care of patients with predicted difficult airway management in the UK and beyond. C. Rosenstock and L. Lundstrøm for data provided from the Danish Anaesthesia Database in [fig_ref] Table 5: Incidence of complications when asleep or awake tracheal intubation is performed [/fig_ref] [fig] 5: Cautious use of minimal sedation can be beneficial. This should ideally be administered by an independent practitioner. Sedation should not be used as a substitute for inadequate airway topicalisation. 6 The number of attempts should be limited to three, with one further attempt by a more experienced operator (3 + 1). 7 Anaesthesia should only be induced after a two-point check (visual confirmation and capnography) has confirmed correct tracheal tube position. 8 All departments should support anaesthetists to attain competency and maintain skills in awake tracheal intubation. [/fig] [fig] Figure 1: Grade D). It is important to select an appropriate route for tracheal intubation, visualisation device and tracheal tube. The route for tracheal intubation should take into account patient anatomy, surgical access and tracheal extubation plan (Grade D). For example, in patients with limited mouth opening, the nasal approach may be the only option, while in patients having nasal surgery, the oral approach may be the preferred route. There is no evidence or consensus Examples of ergonomics for awake tracheal intubation (ATI). The primary operator should have a direct line of sight of the patient, video monitor and patient monitor, as well as immediate access to infusion pumps, anaesthetic machine, suction and oxygen delivery device. If a second anaesthetist is present, they should be positioned with a direct line of sight of the patient and have immediate access to infusion pumps, as well as be able to access all other equipment. The anaesthetic assistant's primary position should be with immediate access to the airway trolley, and in proximity to the operator. (a) Awake tracheal intubation performed with the operator positioned facing the patient who is in a sitting up position. (b) Awake tracheal intubation performed with the operator positioned behind the supine/semi-recumbent patient. This figure forms part of the Difficult Airway Society guidelines for ATI in adults and should be used in conjunction with the text. ©Difficult Airway Society 2019. [/fig] [fig] Figure 2: The Difficult Airway Society awake tracheal intubation (ATI) technique. This figure forms part of the Difficult Airway Society guidelines for ATI in adults and should be used in conjunction with the text. HFNO, high-flow nasal oxygen; LA, local anaesthetic; FB, flexible bronchoscopy; MAD, mucosal atomising device; TCI, target-controlled infusion; Ce, effect-site concentration; VL, videolaryngoscopy. ©Difficult Airway Society 2019. [/fig] [fig] Figure 3: Managing procedural complications during awake tracheal intubation (ATI). This provides a framework for managing complications, but is not meant to be a comprehensive guide. This figure forms part of the Difficult Airway Society guidelines for ATI in adults and should be used in conjunction with the text. F I O 2 , fractional inspired concentration of oxygen; O 2 , oxygen ©Difficult Airway Society 2019. 520 [/fig] [fig] Figure 4: The Difficult Airway Society management of unsuccessful awake tracheal intubation (ATI) in adults. This algorithm forms part of the Difficult Airway Society guidelines for ATI in adults and should be used in conjunction with the text. HFNO, high-flow nasal oxygen; SAD, supraglottic airway device; FONA, front-of-neck airway; GA, general anaesthesia. ©Difficult Airway Society 2019. attempts; and any complications or notes (Grade D; Supporting Information, Appendix S3). [/fig] [table] Table 2: Grading of recommendations based on the level of evidence available. [/table] [table] Table 3: Characteristics of drugs used commonly during ATI. [/table] [table] Table 4: Special circumstances that may affect standard performance of ATI with suggested management options. [/table]	None	None	Awake tracheal intubation has a high success rate and a favourable safety profile but is underused in cases of anticipated difficult airway management. These guidelines are a comprehensive document to support decision making, preparation and practical performance of awake tracheal intubation. We performed a systematic review of the literature seeking all of the available evidence for each element of awake tracheal intubation in order to make recommendations. In the absence of high‐quality evidence, expert consensus and a Delphi study were used to formulate recommendations. We highlight key areas of awake tracheal intubation in which specific recommendations were made, which included: indications; procedural setup; checklists; oxygenation; airway topicalisation; sedation; verification of tracheal tube position; complications; management of unsuccessful awake tracheal intubation; post‐tracheal intubation management; consent; and training. We recognise that there are a range of techniques and regimens that may be effective and one such example technique is included. Breaking down the key practical elements of awake tracheal intubation into sedation, topicalisation, oxygenation and performance might help practitioners to plan, perform and address complications. These guidelines aim to support clinical practice and help lower the threshold for performing awake tracheal intubation when indicated.
8bf309cc9d35a5ab457f36681c950b7d353ed7e7	pubmed	Allergy: Conventional and Alternative Concepts	Allergy: Conventional and Alternative Concepts # Introduction The RCP booklet on Allergy?conventional and alternative concepts has been written for doctors and patients alike. Its aim is to provide a brief summary of how the common allergic diseases are diagnosed and treated by conventional allergists using scientific and validated techniques and remedies. The approaches of practitioners of alternative allergy have also been appraised. The introductory section lays emphasis on the definition of allergy. Allergy must be regarded as a form of exaggerated sensitivity (hypersensitivity) in which there is a specific alteration of the immune system. However, there is still confusion amongst the general public, and many doctors, as to what constitutes a true allergic disease. For this reason allergy (and its mimics) is divided in the booklet into four broad categories. Category 1 includes the common atopic allergic diseases such as allergic rhinitis (including hayfever), allergic (atopic) asthma, and immediate anaphylactic reaction to foods. These are all IgE-mediated and involve mast cells, histamine and other pharmacological agents. Category 2 contains the non-IgE-mediated hypersensitivity diseases such as contact dermatitis, extrinsic allergic alveolitis (eg farmer's lung, bird fancier's lung) and coeliac disease. Here a variety of other immunological mechanisms are proposed such as T-cell-mediated hypersensitivity and immune complex disease. There is a third group (category 3) in which conditions are attributable to external agents but are non-immunological. Food intolerance is an example (see below). Category 4 consists of conditions such as chronic fatigue syndrome and certain psychological disturbances which have been incorrectly attributed to allergy. Most conventional doctors do not consider that there is an allergic basis to these disorders; but they have attracted the attention of practitioners of 'alternative allergy'. It may be the failure of conventional medicine to classify, diagnose and treat these conditions satisfactorily that has frustrated many patients and led them to take recourse to unproven forms of treatment. Allergic diseases are common, and although training in clinical immunology and allergy has only recently been introduced into the National Health Service, there are facilities for allergy testing at most major hospitals. A comprehensive and regularly updated list of allergy clinics in the NHS can be obtained from the British Society for Allergy and Clinical Immunology (BSACI Secretariat, Conference Associates, Congress House, 55 New Cavendish Street, London W1M 7RE). [Added in proof] Because allergic reactions affect different parts of the body, the BSACI is conducting courses for doctors to improve their knowledge and treatment of these disorders. Courses are designed not only for general practitioners, who in the first instance see most of the people with allergic disorders, but also for specialists whose primary interest is in diseases which often manifest allergic reactions affecting specific organs such as the eyes, nose, lungs, gut and skin. ## Scope of allergic diseases The most common allergic disease is summer hayfever?affecting about 10 to 15 per cent of the population. Although the pollen counts have been steadily falling, for some unknown reason the incidence of hayfever seems to be increasing. Many believe that atmospheric pollution may contribute, especially since the presence of sulphur dioxide in the atmosphere has been shown to potentiate other allergic conditions such as allergic asthma. The diagnosis is usually readily obtained from the clinical history and confirmed by the 'skin prick test'. There is particular concern about the apparent increase in allergy to the house dust mite. Central heating and poor ventilation in modern houses provides the warm moist environment for mites to flourish. Allergy to the house dust mite is the most common cause of chronic allergic rhinitis. It is also associated with worsening of asthma and aggravation of atopic eczema after direct skin contact. Allergy to animals is also an important cause of allergic disease, particularly chronic rhinitis and asthma. Wherever the pet population increases, allergy to domestic animals appears to be more prevalent. Cat allergens seem to be a common cause of asthma in sensitised subjects but dogs, horses, mice, rats, guinea pigs, hamsters and gerbils are all potent sources of allergenic material. Birds can also give rise to allergic disease, including extrinsic allergic alveolitis. The role of allergy in asthma is difficult to define precisely since asthma can be triggered by a variety of agents including allergens, viral infections, exercise, exposure to fumes and other irritants, certain drugs, food and drink, and occasionally food additives. Allergy is a common cause of childhood asthma. The importance of a specific allergen in a single individual is usually suspected from the clinical history. Many mould spores are allergenic but may be difficult to incriminate since other factors may also be involved. The precise contribution of allergy, as opposed to other triggers, is of practical importance, however, where the allergenic substance or substances can be easily identified and avoided. Occupational asthma is triggered by sensitising agents inhaled in the workplace. The important agents are platinum salts, isocyanates, epoxy resins, colophony fumes, proteolytic enzymes, laboratory animals and grain (or flour) dust. Pharmaceutical products, wood dusts and castor bean dust may also be involved. Occupational asthma is an important cause of ill-health and time off work. Allergy to stinging insects (particularly wasps and bees) is a rare but potentially serious problem. A few deaths from general anaphylaxis following wasp and bee stings are still reported in the United Kingdom each year. In proven cases allergen immunotherapy gives effective protection against further stings. Allergy to drugs represents only a small proportion of all adverse reactions to drugs since reactions must be distinguished from drug overdose, side effects, toxicity, intolerance and idiosyncratic reactions. True allergic reactions are relatively common with antibiotics (mainly penicillins and cephalosporins) and muscle relaxants used in anaesthesia. Many other agents such as local anaesthetics and aspirin cause typical hypersensitivity reactions but the precise immunological nature of these remains uncertain. Although swelling, itching and redness are found in many different skin disorders, a clear association between allergy and the skin is often very difficult to establish. Despite a large literature and much debate it appears that allergy plays a role in a minority of cases of chronic urticaria and atopic dermatitis. Atopic eczema is often made worse by food in very young children but this is less common in older children and adults. Contact dermatitis may be due to allergy, irritation, or both. Patch tests are the standard methods for testing for allergic contact sensitivity. Food allergy is one of the most controversial subjects in the practice of allergy because there are no universally agreed definitions and diagnostic criteria for it. Since many adverse reactions to foods do not involve the immune system the more embracing term food intolerance is often preferred. Food allergy, intolerance and aversion have been divided in the RCP report on allergy into five groups. In group 1 there are the undisputed allergies which involve immunoglobulin E. These examples include the immediate, sometimes violent, reactions which occur in susceptible subjects after ingestion of nuts, eggs, milk, fish and shellfish. Group 2 consists of food allergy associated not with IgE but with strong evidence that the immune system is altered. Examples are coeliac disease and cow's milk protein enteropathy. Group 3 includes non-allergic food reactions (food intolerance) to foods affecting certain susceptible individuals. Examples include some types of irritable bowel syndrome, food-induced migraine, reactions to sulphites or nitrites as well as those due to a lack of digestive enzymes (hypolactasia, low aldehyde dehydrogenase) or due to more complex mechanisms (eg tartrazine, red wines and cheeses). Allergen avoidance is sometimes relatively easy for those who are sufficiently motivated (eg avoidance of pets). Avoiding dust mites is more difficult, but regular cleaning can be useful and chemicals which kill mites (acaricides) are under trial. Pollen grains are virtually impossible to avoid. Work-related allergies result from exposure to occupational agents, which good work practices can prevent. Drugs used in hayfever include the new non-sedating antihistamines and corticosteroid nasal drops and sprays. Systemic corticosteroids should only be considered in patients with severe continuous symptoms. Sodium cromoglycate spray can be used as an alternative to corticosteroids. Sodium cromoglycate eye drops are also useful for allergic conjunctivitis. Drugs used in asthma include those for relief, ie symptomatic treatment, the most effective drugs being the P-agonists. P-Agonists are particularly useful for relief of wheeze and are also very effective in protecting against exercise-induced asthma. There has been concern that (3-agonists used without other forms of treatment in moderate to severe asthma might mask Journal of the Royal College of Physicians of London Vol. 26 No.July 1992 the presence of underlying inflammation. Most patients with chronic asthma require preventive treatment in the form of inhaled corticosteroids or, particularly in children and young adults, sodium cromoglycate. In adults intermittent or long-term treatment with corticosteroids has become the mainstay of therapy in all but mild asthma. Immunotherapy (desensitisation or hyposensitisation) has been used for about 70 years and is a form of treatment for selected patients with proven atopic allergy. It aims to provide some protection from the effects of natural exposure by giving increasing doses (usually by injection) of the antigens which induce allergic symptoms. Immunotherapy is not without risk and, while this is so, many allergists believe that it should only be used in (a) patients with severe summer hayfever who have failed to benefit sufficiently from anti-allergic drugs and (b) patients hypersensitive to wasp and bee venom. Because immunotherapy is relatively expensive and requires considerable commitment by both doctor and patient, its use should be carefully assessed in each case. Immunotherapy is not recommended for chronic asthma because it rarely works and may lead to severe reactions. In the United Kingdom allergen injection immunotherapy for the treatment of IgE-mediated disease, including summer hayfever, has generally been discontinued as a result of the recommendations of the Committee on Safety of Medicines (CSM) in October 1986. Concerned about deaths from severe bronchospasm and anaphylaxis, the CSM recommended that injections should only be given where facilities for full cardiorespiratory resuscitation are immediately available and patients are kept under medical observation for at least two hours after treatment. Thus successful immunotherapy depends on: (1) careful selection of patients; (2) the use of standardised vaccines; and (3) a skilled operator, ie a person who has had formal training in this form of treatment and is aware of the potential dangers, particularly anaphylaxis. ## Alternative concepts of allergy The rival claims of mainstream and alternative practitioners of allergy bewilder many patients and doctors. Conventional doctors are worried that many of the claims of alternative practitioners are unsubstantiated. They are disappointed that there are very few properly conducted double-blind placebo-controlled trials and believe that the benefit claimed by many alternative practitioners is the result of suggestion or the placebo response. Before a new form of investigation or treatment can be accepted, the claims made for it should be confirmed on several occasions and should be repeatable by other researchers. According to the RCP document many of the claims made for alternative methods of diagnosing and treating allergy do not stand up to scrutiny. Clinical ecologists believe in the concept of a disease which they describe as 'environmental illness' or 'chemical hypersensitivity syndrome' which is held to be responsible for a wide range of symptoms. When multiple hypersensitivities, hypersensitivity to Candida infection, or food-associated myalgic encephalomyelitis are diagnosed on arbitrary grounds and in patients with very similar symptoms, this itself raises questions about their validity. The main criticism raised against clinical ecology relates to the lack of a clear, critical and objective approach and the frequent use of unproven methods in diagnosis and treatment. The much publicised provocation-neutralisation test (the Miller technique) is subject to particular criticism, especially as its interpretation is often subjective and open to bias. In this procedure test substances are administered at successively higher doses by intradermal or subcutaneous injection until there is an increase in the size of the cutaneous weal where the substance has been injected. Different doses are then given serially until the weal response disappears. When carried out under careful double-blind conditions the responses of patients to active and control injections were indistinguishable. The frequency of so-called positive responses to injected extracts appeared to be the result of suggestion and chance [bib_ref] A double-blind study of symptom provocation to determine food sensitivity, Jewett [/bib_ref]. Clinical ecologists treat some of their patients in environmental control units constructed from inert material. There is no evidence, however, that they confer any clinical benefit apart from filtering the air for removal of certain recognised allergens and avoiding conditions which favour the house dust mite and the effect of passive smoking. Several other diagnostic tests and treatments are used by practitioners of alternative allergy. They include the leukocytotoxic test which involves mixing the patient's leukocytes on a microscope slide with an extract of specific food and inspecting the cells for evidence of damage. This test has been heavily criticised and can be very misleading. The Vega test (an 'electrical' or 'black box' test) is widely used but its value is unproven and there are no controlled trials to substantiate the claims made for its use. Hair analysis is used by practitioners of alternative methods either to identify elevated levels of toxic heavy metals or low levels of selenium, zinc, chromium, manganese and magnesium (where replacement therapy is often advised). There are no scientific data to substantiate these hypotheses. A completely different form of hair analysis is dowsing in which a pendulum is swung over a hair sample. Many commercial laboratories claim to diagnose allergic diseases from samples of hair. Studies have concluded that these are 'unscientific and economically wasteful'. Other unusual methods include applied kinesiology and auriculo-cardiac reflex methods. These have either failed to withstand a double-blind study or are unsupported by any objective data. Enzyme-potentiated desensitisation involves mixing a minute amount of allergen with applying it to the skin in an attempt to desensitise to pollens and food allergens (for ulcerative colitis). Some trials have been published but lack sufficient detail for subjective appraisal. While homoeopathy has been claimed to benefit hayfever sufferers (using a solution of grass pollen diluted to a point where no molecules remained) [bib_ref] Is homoeopathy a placebo response? Controlled trial of homoeopathic potency, with pollen..., Reilly [/bib_ref] , no attempt has been made to compare the effects with those of conventional anti-allergic drugs. Other areas of interest to practitioners of alternative allergy include Candida hypersensitivity syndrome, mercury hypersensitivity from dental fillings, allergy to electricity, and chronic fatigue or postviral syndrome (often called myalgic encephalomyelitis). While the persistence of symptoms after a viral infection can at times cause concern, there is no convincing evidence to suggest that these conditions are allergic disorders ?r that the proposed methods of treating them are valid. There is no case for asking the National Health Service or medical insurance companies to pay for any of the reported procedures. Not all the evidence concerning alternative medical procedures is wholly negative. There are some areas in which valid conclusions cannot be drawn on the available evidence. Hypnosis was popularised as a method of therapy in the late eighteenth century for conditions which can now be recognised as largely psychosomatic. It has been claimed to help some asthmatics and deserves further evaluation. Similar claims have been made in respect of acupuncture. Herbal remedies have also been claimed to be of value for allergies but, in general, there is no evidence that they work. A possible exception is the use of traditional Chinese medicinal plants in the treatment of atopic eczema in childhood. One carefully designed placebo-controlled double-blind trial has reported substantial benefit [bib_ref] A controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic..., Sheehan [/bib_ref]. This study has generated considerable interest and will need to be confirmed. The subject of allergy seems to be particularly suitable for promoting unorthodox treatments. Why do patients seek out such therapy? Is this because of a failure of orthodox medicine to recognise and respond to their needs and anxieties? In part this must be true. In comparing the conventional and the unorthodox approaches we should however also be concerned about the reliability of the alternative diagnostic tests in use and the validity of the diagnoses made and treatment given. Some of the test methods, in particular, can be seriously misleading [bib_ref] How reliable are commercial allergy tests?, Sethi [/bib_ref] [bib_ref] Commercial hair analysis, Barrett [/bib_ref]. Diagnosis and treatment are also important. Medical practitioners are very familiar with patients who express psychological illness as physical symptoms and who are then convinced that they have a physical disease. The number of patients in a doctor's surgery with anxiety symptoms can rise sharply when there is intense media interest in a currently fashionable disease. The misdiagnosis of such patients as having an allergic disease can be unfortunate, especially in those who are depressed. Such errors can also delay the diagnosis of conditions which may become fatal if neglected, including cancers which can begin with relatively non-specific symptoms [bib_ref] Adverse consequences arising from misdiagnosis of food allergy, Robertson [/bib_ref]. By recommending unhealthy diets, reinforcing obsessional behaviour or encouraging social isolation further damage is caused. Vulnerable people should be aware that there are some laboratories and practitioners who rely on controversial and unproven procedures such as leukocytotoxic testing, provocation and neutralisation injections, and sublingual provocation tests which are not considered by independent observerseither to be effective or to have a scientific basis. Better evidence of efficacy is needed before these procedures can be accepted as valid. Allergy is an exaggerated response of the immune system to external substances. It plays a role in a wide range of diseases. In some, such as summer hayfever, the symptoms are entirely due to allergy. In other conditions, particularly asthma, eczema and urticaria, allergy plays a part in some patients but not all. In these situations, allergy may either have a major role or provide just one of many triggers. In an individual patient's illness, the importance of allergy may change with time. The most common allergens (substances causing allergy) are grass and tree pollens, the house dust mite, products from pets and other animals, agents encountered in industry, wasp and bee venom, drugs, and certain foods. Food allergy presents a particularly difficult problem. Some individuals who react to food suffer from true food allergy but in others there is no evidence of an alteration in the immune system. Here value. There have, however, been many false and misleading claims and serious harm may be caused by misdiagnosis or delays in appropriate treatment. The public should be warned against costly methods of diagnosis and treatment which have not been validated. It is clear that many patients improve as a result of suggestion or the 'placebo response'. The placebo response can be very powerful and for this reason it requires further scientifically based research since a better understanding of the interplay between the brain and allergy associated symptoms might result in improved forms of therapy. On the other hand, the placebo response must be clearly distinguished from the effects claimed for a particular form of treatment. Allergic diseases are common and the cause of much ill health. Improvements in diagnosis and treatment of allergy, like other branches of medicine, can only be made by rigorous clinical scientific studies.	None	None	Allergy is an exaggerated response of the immune system to external substances. It plays a role in a wide range of diseases. In some, such as summer hayfever, the symptoms are entirely due to allergy. In other conditions, particularly asthma, eczema and urticaria, allergy plays a part in some patients but not all. In these situations, allergy may either have a major role or provide just one of many triggers. In an individual patient's illness, the importance of allergy may change with time. The most common allergens (substances causing allergy) are grass and tree pollens, the house dust mite, products from pets and other animals, agents encountered in industry, wasp and bee venom, drugs, and certain foods. Food allergy presents a particularly difficult problem. Some individuals who react to food suffer from true food allergy but in others there is no evidence of an alteration in the immune system. Here the term 'food intolerance' is preferable. Conventional doctors treat allergy by allergen avoidance--where this is possible--and drugs that relieve symptoms. In a few selected cases, in which other methods have failed, immunotherapy (desensitisation or hyposensitisation) is recommended. Patients who consult practitioners of alternative allergy often do so because they are dissatisfied with the conventional approach to diagnosis and treatment, and sometimes because they have conditions which conventional doctors do not accept as having an allergic basis. There is a very wide range of alternative approaches to allergy, including the methods used by clinical ecologists, acupuncturists and homoeopathists. Hypnosis may have a small role to play in asthma, and similar claims for acupuncture need to be evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)
3234130c7c35b10577be25140c0cc22695f6759e	pubmed	SEOM clinical guideline for treatment of kidney cancer (2017)	SEOM clinical guideline for treatment of kidney cancer (2017) The goal of this article is to provide recommendations about the management of kidney cancer. Based on pathologic and molecular features, several kidney cancer variants were described. Nephron-sparing techniques are the gold standard of localized disease. After a randomized trial, sunitinib could be considered in adjuvant treatment in high-risk patients. Patients with advanced disease constitute a heterogeneous population. Prognostic classification should be considered. Both sunitinib and pazopanib are the standard options for first-line systemic therapy in advanced renal cell carcinoma. Based on the results of two randomized trials, both nivolumab and cabozantinib should be considered the standard for second and further lines of therapy. Response evaluation for present therapies is a challenge. Introduction [bib_ref] Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN..., Ferlay [/bib_ref]. This means the 8th most frequent tumor among men and the 14th among women. In addition, a number of 144,000 deaths due to kidney cancer occurred worldwide. In Spain, the estimated incidence in 2015 was 3590 cases, with an ASR of 15.8 cases per 100,000-person-year [bib_ref] Cancer incidence in Spain, Galceran [/bib_ref]. Comparing to former statistics, kidney cancer incidence is progressively stabilizing or decreasing. Differences have been observed among geographic areas, with the highest incidence rates in developed regions. Most renal cancers (75%) are diagnosed over the age of 60. No differences among races seem apparent. There are several well-established epidemiologic risk factors: smoking, obesity, hypertension, and familial cancer syndromes [bib_ref] Epidemiology and risk factors for kidney cancer, Chow [/bib_ref]. Approximately, 2-3% of kidney cancer cases are related to a hereditary autosomal dominant syndrome, the most frequent of whom is von Hippel-Lindau syndrome associated with clear-cell renal cell carcinoma. Several other factors have been related, such as end-stage renal disease, parity in women, and toxic exposure like trichloroethylene. # Methodology The SEOM guidelines have been developed with the consensus of ten genitourinary cancer oncologists from SEOM (Spanish Society of Medical Oncology) and SOGUG (Spanish Oncology Genitourinary Group). To assign a level of levels of evidence and grades of recommendation, we have used [fig_ref] Table 1: Levels of evidence/grades of recommendation Levels of evidence I Evidence from at... [/fig_ref] [bib_ref] Infectious Diseases Society of America, American Society of Blood and Marrow Transplantation...., Dykewicz [/bib_ref]. Statements without grading were considered justified standard clinical practice by the SEOM/SOGUG faculty and experts. ## Diagnosis and staging More than 50% of renal cell carcinomas (RCC) are detected incidentally. The classic triad of flank pain, visible haematuria, and palpable abdominal mass is rare (6-10%) and correlates with aggressive histology and advanced disease. Paraneoplastic syndromes are found in approximately 30% of patients with symptomatic RCC. Some symptomatic patients present with symptoms caused by metastatic disease, such as bone pain or persistent cough. Abdominal computed tomography (CT) scan represents the gold standard in the staging of RCC. Enhancement in renal masses is determined by comparing Hounsfield units (HU) before and after contrast administration; a change of 15 or more HU suggests malignancy [bib_ref] Pitfalls in renal mass evaluation and how to avoid them, Israel [/bib_ref]. Abdominal CT provides information for staging: function and morphology of the contralateral kidney; primary tumor extension; venous involvement; locoregional lymph nodes status; adrenal glands; and other solid organs involvement [bib_ref] Stage T3a renal cell carcinoma: staging accuracy of CT for sinus fat,..., Sokhi [/bib_ref]. Contrast-enhanced CT angiography is useful in selected cases for detailed information on renal vascular supply. Abdominal magnetic resonance imaging (MRI) is not performed routinely, but may provide additional information on venous involvement [bib_ref] Imaging of advanced renal cell carcinoma, Mueller-Lisse [/bib_ref]. MRI is indicated in patients allergic to intravenous CT contrast medium and in pregnancy without renal failure [bib_ref] Improved assessment of renal lesions in pregnancy with magnetic resonance imaging, Putra [/bib_ref]. Despite a high accuracy of both CT and MRI in RCC diagnosis, these tests are not able to reliably distinguish oncocytoma and fat-free angiomyolipoma from RCC [bib_ref] Renal oncocytoma: CT features cannot reliably distinguish oncocytoma from other renal neoplasms, Choudhary [/bib_ref]. For evaluation of advanced disease, chest CT is accurate for chest staging [bib_ref] Computerized tomography in the preoperative staging for pulmonary metastases in patients with..., Lim [/bib_ref]. Since most bone metastases are symptomatic at diagnosis, routine bone imaging is not [bib_ref] Renal oncocytoma: CT features cannot reliably distinguish oncocytoma from other renal neoplasms, Choudhary [/bib_ref] Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain [bib_ref] The diagnostic value of bone scan in patients with renal cell carcinoma, Koga [/bib_ref]. However, bone scan and brain CT or MRI should be used if specific clinical or laboratory signs and symptoms are present. In patients with impaired renal function, an isotope renogram and total renal function evaluation should be considered. In general, positronemission tomography (PET) is not recommended [bib_ref] Significance of 18F-fluorodeoxyglucose positronemission tomography/computed tomography for the postoperative surveillance of advanced..., Park [/bib_ref]. The staging of RCC is done according to the eighth TNM classification system (2017) that is used for all histologic variants of renal carcinoma. This system is supported by both the American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC). The TNM system is shown in [fig_ref] Table 2: Kidney cancer TNM staging AJCC UICC 2017 [/fig_ref]. Stage grouping for RCC based on AJCC TNM 2017 is shown in. ## Recommendations - Abdominal CT scan is the gold standard for staging of RCC and provides information on primary, regional, and metastatic involvement. Level of evidence: III. Grade of recommendation: A. - Abdominal MRI is an alternative in several circumstances. Chest CT is recommended for thorax staging. Bone scan and brain studies are not routinely recommended. Level of evidence: III. Grade of recommendation: B. ## Pathological and molecular classification Among kidney cancers, completely different entities can be found from both the histology and molecular perspective. It is estimated that around 85% of kidney tumors are RCC being the clear cell (ccRCC) histology the most frequent one, accounting for up to 75-80% of all RCC [bib_ref] Morphologic, molecular, and taxonomic evolution of renal cell carcinoma: a conceptual perspective..., Udager [/bib_ref]. The genomic study defined by the Cancer Genome Atlas (TCGA) of more than 400 ccRCC samples revealed the importance of mutations of genes related to angiogenesis, mainly the von Hippel Lindau (VHL) gene, together with mutations altering the chromatin remodelling complexes (PBRM1, ARID1A, and SMARCA4) and other epigenetic regulators such as SETD2 and BAP1. It was also observed that 28% of the samples are harbouring mutations affecting the PI3K/Akt pathway that directly affect metabolic intracellular routes. Among patients with non-clear cell histology (nccRCC), papillary RCC (pRCC) is the most frequent one and comprises around 10-15% of RCC cases. Papillary tumors include two main subtypes (type I and type II), which differ in their molecular drivers and prognosis. Type I pRCC is mostly associated with mutations in the MET oncogene and exerts a more favorable prognosis, while type II patients use to harbour aberrations in the Krebs cycle gene fumarate hydratase (FH) that confer a very poor prognosis in most cases [bib_ref] Comprehensive molecular characterization of papillary renal-cell carcinoma, Linehan [/bib_ref]. Sarcomatoid features are present in 1-8% of RCC tumors mostly seen in patients with predominant clear cells areas. Other non-ccRCC subtypes include chromophobe (chRCC) tumors with an incidence rate of * 5%, collecting duct tumors (\ 1%) and more rare cases like Xp11 translocation (tRCC) or medullary subtypes that exert a poor clinical outcome despite of systemic treatment [bib_ref] The somatic genomic landscape of chromophobe renal cell carcinoma, Davis [/bib_ref]. In addition, there are around 4-5% of tumors that remain unclassified. The distinct histology tumor subtypes are conditioning different sensitivity to the broad range of systemic available therapies for metastatic RCC (mRCC). Beyond the pathological subtype, the TCGA of ccRCC identified four stable subsets in both mRNA (m1-m4) and miRNA (mi1-mi4) expression data sets. What it seems to be more important is that there could be a relationship between these molecular subgroups and the sensitivity to tyrosine kinase inhibitors (TKI). In this regard, sunitinib might not work in those patients with ccrcc-1 and -4 subgroups (c-myc and immune-like profiles, respectively) that it does in ccrcc-2 and -3 (normal-like, and classical subtypes, respectively) as shown in a retrospective analysis conducted in 53 patients with metastatic ccRCC [bib_ref] Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib..., Beuselinck [/bib_ref]. More recently, it has been shown that molecular profiling could also help to identify not only patients that are sensitive to be treated with antiangiogenics but also those that are most likely to respond to novel immuno-oncology agents. ## Local and locoregional disease Surgery is the treatment of choice for localized renal cell cancer. Partial nephrectomy (nephron-sparing surgery) is indicated in tumors smaller than 7 cm if technically feasible. This approach is associated with better long-term preservation of renal function and similar oncological outcomes than radical surgery. However, this procedure is not always technically feasible, mainly due to anatomical or surgical factors. In these cases, laparoscopic radical nephrectomy is an alternative. Partial nephrectomy is also the preferred approach for patients with bilateral tumors or a single functional kidney. Radical nephrectomy is indicated in T2-4 tumors. Laparoscopic approach is preferred to open radical nephrectomy in T2 and selected T3a tumors, because it is associated with less surgical-related complications. In T3b and T4 tumors, open radical nephrectomy is the approach of choice. When a tumor thrombus is present, it has to be completely excised. Extended lymphadenectomy and adrenalectomy have not shown added survival benefit and should not be routinely performed unless there is evidence of involvement. Radiofrequency and cryotherapy are local ablative techniques in development that constitute a therapeutic alternative in elderly or high-risk patients with small renal cancers, as well as in hereditary RCC syndromes, bilateral tumors, or single functional kidney. Initial active surveillance is also an acceptable alternative in elderly or highrisk patients with small renal masses. Patients should be followed with repeated abdominal imaging and surgery performed in those cases that show clinical progression during the follow-up. Several different classifications have been proposed to assess the risk of recurrence in patients with localized renal cell cancer treated with nephrectomy [bib_ref] Risk group assessment and clinical outcome algorithm to predict the natural history..., Zisman [/bib_ref]. Regarding the role of systemic therapies in patients with high risk of relapse a recent study has shown a significant improvement in disease-free survival (DFS) in patients who received adjuvant sunitinib for 1 year [bib_ref] Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy, Ravaud [/bib_ref]. This benefit seems to be especially apparent in the group of patients with higher risk features. Unfortunately, mature overall survival (OS) data are not available yet. Moreover, toxicity of sunitinib was considerable in this population. On the other hand, another study comparing 1-year treatment with sunitinib, sorafenib or placebo showed no differences in terms of DFS between arms [bib_ref] Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a..., Haas [/bib_ref]. However, differences in population prognostic features and dose intensity of therapy between both studies are remarkable. At this moment, 1-year adjuvant therapy with sunitinib could be a non-approved individualized alternative to consider in selected high-risk patients. Neoadjuvant therapy for localized renal cell cancer has been studied in several small clinical trials. Their results suggest that this approach is feasible, and might be especially useful in large unresectable masses, high-level venous tumor thrombus involvement, and patients with large masses and imperative indications for nephron sparing surgery. Nevertheless, at present, this approach still remains investigational. [bib_ref] Interferon-alfa as a comparative treatment for clinical trials of new therapies against..., Motzer [/bib_ref]. The MSKCC risk system classifies patients with mRCC into three categories: poor, intermediate, and favorable risks. Multivariate analysis showed five variables as independent adverse prognostic factors: Karnofsky performance status (KPS) less than 80%, interval from diagnosis to treatment of less than 1 year, serum hemoglobin level less than the lower limit of normality (LLN), serum lactate dehydrogenase (LDH) greater than 1.5 times the upper limit of normality (ULN) and corrected serum calcium greater than the ULN. Those patients with none of these factors were classified as low risk (good prognosis), those with 1 or 2 factors were considered intermediate risk, and patients with 3 or more factors were considered poor risk. Trials with patients treated with contemporary VEGFtargeted therapies have been analyzed to outline a newer prognosis classification. The International Metastatic Database Consortium (IMDC) retrospectively assessed 645 patients with mRCC treated with sorafenib, sunitinib or bevacizumab-IFNa and identified six variables to classify cases into favorable, intermediate and poor prognosis groups [bib_ref] Prognostic factors for overall survival in patients with metastatic renal cell carcinoma..., Heng [/bib_ref] : KPS less than 80%, time from nephrectomy less than 1 year, hemoglobin less than LLN, serum corrected calcium greater than ULN, platelets greater than ULN and absolute neutrophil count greater than ULN. Data from these patients were used to generate a similar model that can be used to predict survival in second-line therapy after progression to VEGF-targeted agents [bib_ref] The international Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic..., Ko [/bib_ref] and also in patients with non-clear mRCC [bib_ref] Metastatic non-clear cell renal cell carcinoma treated with targeted agents: characterization of..., Kroeger [/bib_ref]. [fig_ref] Table 4: MSKCC and IMDC risk criteria for poor overall survival [/fig_ref] summarizes MSKCC (Motzer) and IMDC (Heng) risk criteria. ## Recommendations ## Recommendation - Prognostic classifications, such as MSKCC and IMDC, should be used for management of mRCC patients. Level of evidence: II. Grade of recommendation: B. ## Role of surgery Two prospective clinical trials assessed the role of debulking or cytoreductive nephrectomy in patients with mRCC treated with IFNa. Both studies randomized patients to receive IFNa alone or nephrectomy followed by IFNa, finding a significant improvement in terms of survival favoring the nephrectomy approach [bib_ref] Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis, Flanigan [/bib_ref]. However, the mechanism responsible for this beneficial effect remains unclear and patients should be carefully selected. Patients most likely to benefit from nephrectomy include those with resectable primary tumor, good performance status, adequate organ function, and no significant comorbidities or involvement of central nervous system [bib_ref] The evolving role of surgery for advanced renal cell carcinoma in the..., Rini [/bib_ref]. Recommendations and level of evidence are provided in [fig_ref] Table 5: SEOM guideline recommendations for kidney cancer [/fig_ref]. The role of cytoreductive nephrectomy in patients who receive subsequent targeted therapy is currently under evaluation in three prospective trials investigating sunitinib or pazopanib with or without nephrectomy in patients with mRCC. Retrospective evidence from the IMDC with data of 1658 patients showed significantly longer OS in the group of cytoreductive nephrectomy in patients with favorable and intermediate prognosis, nevertheless in patients with poor prognosis debulking nephrectomy did not provide any benefit [bib_ref] Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results..., Heng [/bib_ref]. Metastasectomy may be considered in mRCC patients with favorable prognostic features: good performance status (PS), limited metastatic disease, prolonged time between initial diagnosis, and development of metastases and the possibility for a complete resection [bib_ref] Resection of metastatic renal cell carcinoma, Kavolius [/bib_ref]. ## First-line systemic treatment The current standard of care in the first-line setting focuses on the inhibition of angiogenesis. In this scenario, either sunitinib, bevacizumab plus IFNa, or pazopanib improved progression-free survival (PFS) compared with IFNa or placebo in patients with good or intermediate prognosis, with PFS of 8.5-11 months [bib_ref] Sunitinib versus interferon alfa in metastatic renal-cell carcinoma, Motzer [/bib_ref] [bib_ref] Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a..., Escudier [/bib_ref] [bib_ref] Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with..., Rini [/bib_ref] [bib_ref] Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a..., Sternberg [/bib_ref]. Although similar benefit was seen with bevacizumab plus IFNa, sunitinib and pazopanib, oral VEGFR tyrosine kinase inhibitors (TKI), have become the standard of care in this situation. Both sunitinib and pazopanib were compared in the noninferiority phase III COMPARZ trial, which demonstrated no difference in outcomes with the two agents [bib_ref] Pazopanib versus sunitinib in metastatic renal-cell carcinoma, Motzer [/bib_ref]. Nevertheless, no predictors of response to targeted therapy are available; thereby, the choice of therapy is usually based on the patient's prognostic profile, patient and physician Abdominal CT scan is the gold standard for staging of RCC and provides information on primary, regional and metastatic involvement. preference and experience, and drug efficacy and toxicity profiles. In patients with poor-risk features, the mTOR inhibitor temsirolimus has been shown to improve OS compared with IFNa alone and represents the only option supported with level I evidence [bib_ref] Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, Hudes [/bib_ref]. Other alternatives include sunitinib, pazopanib, and bevacizumab combined with IFNa, based on the minimal inclusion of poor-risk patients in pivotal trials and expanded-access studies of these drugs. Immunotherapy with high-dose interleukin-2 (HD-IL2) remains a viable therapeutic option in centers with experience for patients with good prognosis mRCC clear-cell histology and low-volume disease. The full potential of checkpoint inhibitors in the front-line setting is under investigation. ## Recommendations ## Second line and sequence Current options for treatment of advanced ccRCC in second line and beyond include immunotherapy with PD-1 blockade and TKI. Nivolumab, an antibody against PD-1, and cabozantinib, an oral TKI targeting VEGFR, MET and AXL, were compared with everolimus, an mTOR inhibitor previously approved in second line of treatment of mRCC, in two different randomized phase III trial including 821 and 658 patients with mRCC patients previously treated with at least one prior antiangiogenic therapy one prior antiangiogenic therapy [bib_ref] Nivolumab versus everolimus in advanced renal-cell carcinoma, Motzer [/bib_ref] [bib_ref] Cabozantinib versus everolimus in advanced renal-cell carcinoma, Choueiri [/bib_ref] Both cabozantinib and nivolumab increased OS (figures of 21.4 and 25.0 months, respectively) and response rate (RR), while PFS was significantly better for the former and no differences were observed for the latter. However, toxicity profiles were different, with less grade 3-4 adverse events and treatment discontinuations for nivolumab compared to everolimus. On the other hand, 60% of patients treated with cabozantinib required dose reductions due to toxicity. Based on this data, both nivolumab and cabozantinib has been granted approval for this indication by regulatory agencies [IA, A]. The combination of lenvatinib, another oral TKI of VEGFR1-3, FGFR1-4, PDGFRa, RET, and KIT, and everolimus was compared in a randomized phase II study with either everolimus or lenvatinib alone in patients with mRCC treated with one previous VEGF-targeted therapy [bib_ref] Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma:..., Motzer [/bib_ref]. Significant differences for OS, PFS, and RR were described for lenvatinib plus everolimus compared to everolimus alone. Dose reductions due to toxicity and treatment discontinuation because of adverse events in patients allocated to lenvatinib plus everolimus were required, respectively, in 71 and 24% of cases, respectively. Based on this data, the FDA approved lenvatinib in combination with everolimus in this setting . No direct comparisons have been performed between any PD-1 blocking therapy and the TKI that increase OS in these patients, and no valid biomarkers exist to select the most appropriate treatment for each patient. Therefore, decisions to use these options should be guided by clinical characteristics (e.g., contraindications for immunotherapy (e.g., autoimmune diseases, organ transplant) or to TKI (e.g., uncontrollable hypertension, intolerance) and by the toxicity expected for each agent . Other TKI, such as axitinib [bib_ref] Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS):..., Rini [/bib_ref] and sorafenib [bib_ref] Sorafenib in advanced clear-cell renal-cell carcinoma, Escudier [/bib_ref] and mTOR inhibitors, such as everolimus [bib_ref] Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled..., Motzer [/bib_ref] have not shown increased OS after prior antiangiogenic therapy and should not be used before the previous agents. Axitinib against sorafenib, and everolimus, against placebo, demonstrated PFS benefit in phase III trials. Yet, they may remain acceptable options afterwards, although randomized trials in this setting are unavailable [IV, D]. ## Recommendations - Nivolumab and cabozantinib have shown increased OS in patients with advanced ccRCC previously treated with antiangiogenics, and are the recommended treatments for these patients. Level of evidence: I. Grade of recommendation: A. - Decisions to use either agent may be based on the expected toxicity and on contraindications for each drug, as randomized data is lacking. Level of evidence: IV. Grade of recommendation: D. - Lenvatinib in combination with everolimus has shown increased OS in patients with advanced ccRCC in a randomized phase II trial, and is another valid alternative for these patients. Level of evidence: II. Grade of recommendation: B. - Axitinib and everolimus have not shown increased OS after prior antiangiogenic therapy and should not be used before the previous agents. Nevertheless, they may remain acceptable options following such agents, although they have not been tested in randomized trials in this setting. Level of evidence: II. Grade of recommendation: B. ## Non clear-cell renal cell carcinoma While non-clear cell histologies constitute a minority of cases of RCC, they pose a significant therapeutic challenge. Non-ccRCC are characterized by morphology, growth pattern, cell of origin, and by the histochemical and biologic bases that underlie the different types of tumors. The general approach to treatment of non-ccRCC mirrors that for ccRCC. A meta-analysis of targeted therapy clinical trials suggests that VEGF-targeting agents may have activity in patients with both non-clear cell or clear cell histologies with sarcomatoid features [bib_ref] Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and..., Vera-Badillo [/bib_ref]. Another meta-analysis comparing effectiveness and adverse effects of different systemic treatments for non-ccRCCs described that single studies showed a trend towards favoring sunitinib in terms of OS and PFS (HR 1.41, 80% confidence interval) [bib_ref] A systematic review and meta-analysis comparing the effectiveness and adverse effects of..., Fernández-Pello [/bib_ref]. These tumors do not respond to immunotherapy with IL-2, although dramatic responses have been reported with anti-PD-1 [bib_ref] Anti-programmed cell death protein 1 (PD-1) antibody nivolumab leads to a dramatic..., Geynisman [/bib_ref]. Besides the identification of genomic basis, results from some phase II, randomized trials are of interest for these RCC subtypes. The ESPN [bib_ref] Everolimus versus sunitinib prospective evaluation in metastatic non clear cell renal carcinoma..., Tannir [/bib_ref] and ASPEN [bib_ref] Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma..., Armstrong [/bib_ref] studies compared sunitinib and everolimus in patients with metastatic non-ccRCC (or ccRCC with [ 20% sarcomatoid features in ESPN). Primary endpoint was PFS in first-line therapy for both trials. Results were obtained from 68 and 108 patients, respectively. For both trials, although not statistically significant, sunitinib was superior overall compared with everolimus at delaying disease progression. However, it was also associated with a higher rate of severe toxicity. Interestingly, sunitinib was found to be more effective for papillary-type kidney cancers and for better prognosis patients. On the other hand, patients with chromophobe and poor-risk tumors treated with everolimus had a longer median PFS. In summary, the evidence base concerning the treatment of this group of patients is relatively small. Although activity with VEGFR TKI or mTOR inhibitors has been observed, shorter survival times and lower response rates compared to ccRCC patients highlight continuing medical need for new treatment approaches in this patient population. ## Recommendation - VEGFR inhibitors, such as sunitinib, are the preferred option for papillary RCC. Level of evidence: II. Grade of recommendation: B. ## Response evaluation and follow-up For patients with advanced renal cell carcinoma on systemic treatment, response evaluation is generally performed every 2-3 months with a CT scan of the thorax and abdomen. Response Evaluation Criteria in Solid Tumors (RECIST) is still the standard method to assess drug response or resistance, although caution is needed to avoid false interpretations of progression of the disease. In this setting, other evaluation methods could better correlate treatment with TKI or immunotherapies with clinical outcome, but its use in the daily clinical practice is not available yet [bib_ref] Revised Choi imaging criteria correlate with clinical outcomes in patients with metastatic..., Thian [/bib_ref] [bib_ref] iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics, Seymour [/bib_ref]. There is no standard protocol for the follow-up after a definitive treatment for a localized renal cell carcinoma. The higher risk of recurrence following surgical resection is in the first 3 years being 1-2 years the median time to relapse. For this reason, the follow-up must be more intensive on this period. However, there is no clear recommendation about the timing and number of tests to perform. The most extended imaging test is the CT scan of the chest and abdomen. Several surveillance protocols use a risk-stratified approach and are useful to define the best follow-up strategy for each patient [bib_ref] Follow-up for clinically localized renal neoplasms: AUA guideline, Donat [/bib_ref]. These protocols take many variables into account such us TNM stage, Fuhrman grade or type of local treatment (partial versus radical nephrectomy). For patients with a high or intermediate risk of relapse, a closer follow-up is recommended, especially for the first 2-3 years (CT scan every 3-6 months), while a less frequent follow-up is needed for patients with a low risk of relapse and after 3 years of surveillance. Moreover, the optimal duration of surveillance is not clear either. Due to the presence of late relapses, further follow-up after 5 years is performed in some institutions, especially for patients with intermediate or high risk. ## Recommendation - After a definitive treatment for a localized renal cell carcinoma, a follow-up should be planned. Level of evidence: V. Grade of recommendation: B. Recommendations and level of evidence are provided in [fig_ref] Table 5: SEOM guideline recommendations for kidney cancer [/fig_ref] Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://crea tivecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. [fig] •: Debulking or cytoreductive nephrectomy is the standard of care for selected mRCC patients with good or intermediate prognosis; however, this procedure should be avoided in the majority of patients with poor-risk features. Level of evidence: III. Grade of recommendation: B. Metastasectomy can be considered in selected patients with limited number of metastases with long [/fig] [table] Table 1: Levels of evidence/grades of recommendation Levels of evidence I Evidence from at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomized trials without heterogeneity II Small randomized trials or large randomized trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity [/table] [table] Table 2: Kidney cancer TNM staging AJCC UICC 2017 [/table] [table] Table 4: MSKCC and IMDC risk criteria for poor overall survival [/table] [table] Table 5: SEOM guideline recommendations for kidney cancer [/table]	None	https://link.springer.com/content/pdf/10.1007/s12094-017-1765-4.pdf	None
82f5aeb9bd143220dd4adfaefbc27dd5cf032373	pubmed	Evaluation of New Anti-Infective Drugs for the Treatment of Respiratory Tract Infections	Evaluation of New Anti-Infective Drugs for the Treatment of Respiratory Tract Infections These guidelines deal with the evaluation of anti-infective drugs for the treatment of respiratory tract infections. Five clinical entities are described: streptococcal pharyngitis and tonsillitis, otitis media, sinusitis, bronchitis, and pneumonia. A wide variety of microorganisms are potentially pathogenetic in these diseases; these guidelines focus on the bacterial infections. Inclusion of a patient in a trial of a new drug is based on the clinical entity, with the requirement that a reasonable attempt will be made to establish a specific microbial etiology. Microbiologicevaluation of efficacy requires isolation of the pathogen and testing for in vitro susceptibility. Alternatively, surrogate markers may be used to identify the etiologic agent. The efficacy of new drugs is evaluated with reference to anticipated response rates. Establishment of the microbial etiology of respiratory tract infections is hampered by the presence of "normal flora" of the nose, mouth, and pharynx, which may include asymptomatic carriage of potential pathogens. This issue is addressed for each category of infection described. For example, it is suggested that for initial phase 2 trials of acute otitis media and acute sinusitis tympanocentesis or direct sinus puncture be used to collectexudate for culture. Acute exacerbationsof chronic bronchitis also present difficulties in the establishment of microbial etiology. These guidelines suggest that clinical trials employ an active control drug but leave open the possibility of a placebo-controlled trial. For pneumonia, the guidelines suggest the identification and enrollment of patients by the clinical type of pneumonia, e.g., atypical pneumonia or acute bacterial pneumonia, rather than by etiologic organism or according to whether it was community or hospital acquired. For each respiratory infection, the clinical response is judged as cure, failure, or indeterminate. Clinical improvement is not acceptable unless quantitative response measures can be applied. These guidelines deal with the evaluation of anti-infective drugs for the treatment of respiratory tract infections. Five clinical entities are described: streptococcal pharyngitis and tonsillitis, otitis media, sinusitis, bronchitis, and pneumonia. A wide variety of microorganisms are potentially pathogenetic in these diseases; these guidelines focus on the bacterial infections. Inclusion of a patient in a trial of a new drug is based on the clinical entity, with the requirement that a reasonable attempt will be made to establish a specific microbial etiology. Microbiologicevaluation of efficacy requires isolation of the pathogen and testing for in vitro susceptibility. Alternatively, surrogate markers may be used to identify the etiologic agent. The efficacy of new drugs is evaluated with reference to anticipated response rates. Establishment of the microbial etiology of respiratory tract infections is hampered by the presence of "normal flora" of the nose, mouth, and pharynx, which may include asymptomatic carriage of potential pathogens. This issue is addressed for each category of infection described. For example, it is suggested that for initial phase 2 trials of acute otitis media and acute sinusitis tympanocentesis or direct sinus puncture be used to collectexudate for culture. Acute exacerbationsof chronic bronchitis also present difficulties in the establishment of microbial etiology. These guidelines suggest that clinical trials employ an active control drug but leave open the possibility of a placebo-controlled trial. For pneumonia, the guidelines suggest the identification and enrollment of patients by the clinical type of pneumonia, e.g., atypical pneumonia or acute bacterial pneumonia, rather than by etiologic organism or according to whether it was community or hospital acquired. For each respiratory infection, the clinical response is judged as cure, failure, or indeterminate. Clinical improvement is not acceptable unless quantitative response measures can be applied. This is one of a series of disease-specific guidelines that have been prepared to assist sponsors and investigators in the development, conduct, and analysis of studies of new antiinfective drugs. These guidelines deal with the conduct of phase 1 through phase 4 clinical trials and are subsets of the General Guidelines for the Clinical Evaluation of Anti-Infective Drug Products, which should be consulted for prerequisites to conducting studies in humans. ## A. overview and scope of guidelines These guidelines for the evaluation of drugs for the treatment of respiratory tract infections include acute streptococcal pharyngitis and tonsillitis, acute otitis media, acute and chronic sinusitis, acute exacerbations of chronic bronchitis, and acute infectious pneumonia (table 1). The focus is primarily on infections of bacterial etiology, especially those due to respiratory pathogens such as Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus irfiuenzae, and Moraxella (Branhamella) catarrhalis and respiratory anaerobes (e.g., Bacteroides species, Fusobacterium nucleatum, and Peptostreptococcus species). Readers should consult the specific guidelines for the evaluation of new anti-infective drugs for mycobacterial and fungal infections. The guidelines for clinical microbiology provide important background information and should be used in concert with the current guidelines. ## B. general principles of care for patients with respiratory tract infections The respiratory tract infections considered in these guidelines are among the most frequent disease entities encountered in both children and adults. They are associated with potentially serious morbidity if unattended or treated subop-timally. They also are infections in which evaluation of specific anti-infective therapy may be difficult. The reasons for the difficulties include: (1) routine noninvasive collection of specimens and culture techniques are often inadequate, and specimens are regularly contaminated by the indigenous microflora of the oropharynx and the upper airways; (2) the microbial etiology is often complex and polymicrobial; and (3) newly recognized etiologic agents continue to emerge (e.g. , Legionella species, Chlamydia pneumoniae, and Coxiella burnettii). Even with the use of sophisticated sampling and microbiologic techniques, the causative agents can be identified only for a small proportion (60%-80% at best) of patients. Furthermore, good clinical practice requires empiric initiation of anti-infective therapy for these conditions (with the possible exception of group A streptococcal pharyngitis) on the basis of a presumptive initial diagnosis before confirmatory microbiologic data are available. Frequently, the microbiologic response to therapy cannot be definitively evaluated, even when the etiologic agent has been identified. This is often the case in otitis media, sinusitis, and pneumonia, when the use of invasive procedures such as tympanocentesis, sinus puncture, or transtracheal aspiration to confirm microbial eradication in the patient who is improving clinically generally is considered unjustified. Thus, whereas microbiologic failure can be documented by repeat cultures, microbiologic eradication can only be assessed presumptively on the basis of clinical response. The current standards of anti-infective therapy for the respiratory tract infections encompassed in these guidelines are summarized in table 1. ## C. controversies and future trends In addition to the changing trends in microbial etiology, several controversial areas exist: (1) the clinical significance of ,B-Iactamaseproduction among respiratory pathogens and The respiratory tract infections under study should be categorized according to the ageof the patient, chronicity of the disease, and anyunderlying or concomitant disease(s) in the patient. ## B. preclinical studies Theinvestigational drugshould have in vitroactivity against the specific respiratory tract pathogen to be evaluated in a pathogen-specific studyandactivity against the vastmajority ofstrains ofthemost likely encountered pathogens in a diseasespecific study. Evaluation oftheinfluence ofcombination therapy is desirable, as is assessment of the emergence of resistance in vitro. Information obtained from studies in animals maybe of assistancein identifying preliminary dosage schedules for humans. Evaluations of efficacy in standardized animalmodels of infection may be performed. Determination of drug levels in respiratorytract secretions (suchas sinus, middle-ear, or endotracheal aspirates) or in tissue (such as pulmonary parenchyma) is not required because at present the clinical significance of these concentrations is uncertain. ## Institutions Institutions should be capable of performing the following studies relevant to the management of respiratorytract infections when appropriate to a specific protocol: nucleic acid probeanalysis foridentification ofselected respiratory pathogens, radiography andcomputerized tomography (CT) and/or magnetic resonance imaging of the head and neck, sinuses, and chest; arterialblood gasdeterminations; tympanocente-sis; sinus puncture; thoracentesis; and bronchoscopy. These studies should be done in addition to routine diagnostic microbiologic testing. Alternatively, special studies may be performed at a reference laboratory skilled in these procedures and approved by the appropriate authorities. ## E. study design and implementation The preferred design is the randomassignment of patients to the investigational-drug and active-control-drug groups. Therandomization schedule shouldbe maintained bya study monitor. Patients should be stratified according to age, severity of infection, presence of underlying disease, and concomitant non-antibacterial therapy. Blinding of both subjects and investigators to treatment group(double-blind design) is encouraged whenever feasible. In all cases, the inclusion and exclusion criteria should be clearly identified prior to initiation of the study. All patients enrolled in the study should be assessed on the basis of "intention to treat." A uniform approach to clinical and microbiologic assessment duringand after therapy shouldbe implemented. Endpointsforbothclinicaland microbiologic evaluation should be clearly stated, and whenever possible a quantitative scoring system should be devised. Patient compliance shouldbe verified (e.g., by pill counts or by appropriate assays of drug concentrations in serum or other body fluids). The clinical entity addressed in this guideline is group A j3-hemolytic streptococcalpharyngitis and tonsillitis. Not included are clinical cases of pharyngitis due to other agents or cases in which streptococcihavebeen isolated in cultures of throatspecimens but have notbeen documented to be group A j3-hemolytic streptococci. [bib_ref] Disparate cultures of middle ear fluids, Pelton [/bib_ref] GroupA j3-hemolytic streptococcal pharyngitis remains one of the most frequentacute infections seen in ambulatory patients, especially school children between 5 and 8 years of age [bib_ref] Comprehensive review of morbidity and mortality trends for rheumatic fever, streptococcal disease,..., Quinn [/bib_ref] [bib_ref] Streptococcal disease world-wide: present studies and prospects, Rotta [/bib_ref] [bib_ref] Streptococcal pharyngitis, Tanz [/bib_ref] [bib_ref] Streptococcal pharyngitis in the 1980s, Dillon [/bib_ref]. Antibiotic therapy for streptococcalpharyngitis is aimed not only at symptomatic improvement of the acute infection [bib_ref] Effect of penicillin and aureomycin on the natural course of streptococcal tonsillitis..., Brink [/bib_ref] [bib_ref] Comparative effects ofpenicillin, aureomycinand terramycin on streptococcal tonsillitis and pharyngitis, Denny [/bib_ref] [bib_ref] Effect of treatment on streptococcal pharyngitis: is the issue really settled, Denny [/bib_ref] [bib_ref] Does penicillin make Johnny's strep throat better?, Hall [/bib_ref] [bib_ref] Streptococcal pharyngitis: placebo controlled double-blind evaluation of clinical response to penicillin therapy, Krober [/bib_ref] [bib_ref] The effect of penicillin therapy on the symptoms and signs of streptococcal..., Nelson [/bib_ref] and the prevention of suppurative complications but also, and most importantly, at the prevention of the subsequent occurrenceof acute rheumatic fever [bib_ref] Comprehensive review of morbidity and mortality trends for rheumatic fever, streptococcal disease,..., Quinn [/bib_ref] [bib_ref] Prevention of rheumatic fever, Dajani [/bib_ref]. The incidence of acute rheumatic fever in the United States has declined dramatically overthe past severaldecades, suchthat by the 1980sit wasa rare sequelaof streptococcal pharyngitis [bib_ref] Comprehensive review of morbidity and mortality trends for rheumatic fever, streptococcal disease,..., Quinn [/bib_ref] [bib_ref] Streptococcal pharyngitis in the 1980s, Dillon [/bib_ref]. However, between1984and 1986fourmajor outbreaks of acute rheumatic fever in three states resulted in a heightened concern for optimal treatment of streptococcal pharyngitis [bib_ref] Acute rheumatic fever: the come-back of a disappearing disease, Ferrieri [/bib_ref] [bib_ref] The fall and rise of rheumatic fever in the United States, Kaplan [/bib_ref] [bib_ref] Resurgence of rheumatic fever in the intermountain area of the United States, Veasy [/bib_ref]. Penicillin, given orally or intramuscularly, has generally beenconsidered the drug of choiceand the drugagainst which other regimens havemost often been judged. A full 10 days of oral therapy or a single injection of benzathine penicillin is required [bib_ref] Streptococcal pharyngitis, Tanz [/bib_ref] [bib_ref] Streptococcal pharyngitis in the 1980s, Dillon [/bib_ref]. Shortening a course of penicillin by even a few days has been shown to resultin an appreciable increase in the rate of treatment failure. However, even withthe recommended 10 days of oral therapy, the failure rate may still be high [bib_ref] Streptococcal pharyngitis, Tanz [/bib_ref] [bib_ref] Streptococcal pharyngitis in the 1980s, Dillon [/bib_ref]. In recent studies, penicillintherapy, givenorally or intramuscularly, has been associated withratesof microbiologic failure as high as 20%-30%, in contrast to the rates of5%-10% seen 20 years ago. The reasons for this increase are not clear,although the presenceof j3-lactamase-producing organisms in the throat flora and an increasein the tolerance of streptococci to penicillin havebeen suggested as contributing causes. Resistanceto erythromycin, a frequently used al- Group A j3-hemolytic streptococcalpharyngitiscan not be diagnosed accuratelyon clinical grounds alone because it is frequently difficult to differentiate this entity from pharyngitis caused by other organisms. Therefore, diagnosis requires a positiveculture for group A j3-hemolytic streptococcifrom a throatswab specimen in a patientwith symptomatic pharyngitis. Alternatively, the diagnosismaybe made by use of one of therapiddiagnostic kitsthatcandetectgroupA j3-hemolytic streptococcal antigen directly from a throat swab specimen [bib_ref] Suitability of throat culture procedures for detection of group A streptococci as..., Kellogg [/bib_ref] [bib_ref] Specificity study of kits for detection of group A streptococci directly from..., Facklam [/bib_ref] [bib_ref] Identification of streptococcal pharyngitis in office laboratory: reassessment of new technology, Radetsky [/bib_ref] [bib_ref] Rapid strep tests: making sense of a crowded market. Contemporary, White [/bib_ref]. For the purposeof the evaluation of newdrugs, however, the diagnosis shouldbe confirmedwith a throat culture, since the sensitivity (37%-100%, most 60%-95%) and specificity (70%-100%, most >90%) of the rapid detection kits are quite variable [bib_ref] Suitability of throat culture procedures for detection of group A streptococci as..., Kellogg [/bib_ref] [bib_ref] Specificity study of kits for detection of group A streptococci directly from..., Facklam [/bib_ref] [bib_ref] Identification of streptococcal pharyngitis in office laboratory: reassessment of new technology, Radetsky [/bib_ref] [bib_ref] Rapid strep tests: making sense of a crowded market. Contemporary, White [/bib_ref]. Drugsused for the treatmentof group A j3-hemolytic streptococcalpharyngitis shouldhavebeen shown to havebactericidal activity against group A j3-hemolytic streptococci and to haveundergone relevant phase 1 studiesprior to the initiation of clinical investigations. The drug under consideration shouldhave a lowindex of toxicity in bothchildrenandadults, sincea numberof otheragents existthat offer acceptabletherapyfor group A j3-hemolytic streptococciand since streptococcal pharyngitis is usually a minor disease. Furthermore, the drug shouldresult in clinical improvement within 24-48 hoursoftheinitiation oftherapy, withresolution offever within 48 hours in uncomplicated streptococcalpharyngitis, as can be expected withpenicillin andother antimicrobial agents currentlyapproved for treatmentof streptococcalpharyngitis [bib_ref] Effect of penicillin and aureomycin on the natural course of streptococcal tonsillitis..., Brink [/bib_ref] [bib_ref] Comparative effects ofpenicillin, aureomycinand terramycin on streptococcal tonsillitis and pharyngitis, Denny [/bib_ref] [bib_ref] Effect of treatment on streptococcal pharyngitis: is the issue really settled, Denny [/bib_ref] [bib_ref] Does penicillin make Johnny's strep throat better?, Hall [/bib_ref] [bib_ref] Streptococcal pharyngitis: placebo controlled double-blind evaluation of clinical response to penicillin therapy, Krober [/bib_ref] [bib_ref] The effect of penicillin therapy on the symptoms and signs of streptococcal..., Nelson [/bib_ref]. The drug under considerationalso should provide an acceptably low rate of microbiologic failure associated with recurrence or persistent carriage and a rate no greater than that associatedwith current standard therapy with penicillin (10 %-20 %) [bib_ref] Streptococcal pharyngitis, Tanz [/bib_ref] [bib_ref] Streptococcal pharyngitis in the 1980s, Dillon [/bib_ref]. The drug shouldbe capableof preventing the suppurative complications of group A streptococcal pharyngitis and, ideally, of preventing rheumatic fever. It would be desirable to have data indicating that the drug is capable ofpreventing rheumatic fever, but it is recognized that this goal may not be achievable. ## (c) future trends A current concern in the treatment of acute streptococcal pharyngitis is whether the failure rate for penicillin therapy will continue to climb and whether penicillin should still be considered the standard therapy. In addition, there is controversy about when antimicrobial therapy should be initiated. Clinical differentiation of group A streptococcal pharyngitis from other causes of sore throat is not alwayspossible, a problem that raises the question of whether antibiotic therapy should be initiated before bacteriologic confirmation is available. Furthermore, prompt treatment of group A (3-hemolytic streptococcal pharyngitis has been shown to interfere with the antibody response and possibly to result in a higher rate of recurrence than that seen in patients whose therapy is delayed for a few days [bib_ref] Adverse and beneficial effectsof immediate treatment of group A beta-hemolytic streptococcal pharyngitis..., Pichichero [/bib_ref]. Last, controversy exists concerning whether post-treatment cultures should be obtained to detect bacteriologic failures and whether asymptomatic carriage necessitates treatment [bib_ref] The group A streptococcal carrier state. A reexamination, Gerber [/bib_ref]. ## Clinical definitions of the disease Patients eligible for study entrance are children or adults with symptomatic pharyngitis or tonsillitis of acute onset clinically consistent with infection with group A I3-hemolytic streptococci and from whom group A (3-hemolytic streptococci have been isolated in cultures of throat -swab specimen or for whom a rapid screening test has indicated the presence of streptococci. To be evaluable for efficacy, the screening test results must be confirmed by culture. The guideline generally applies to ambulatory patients. ## (a) clinical criteria Signs and symptoms of acute pharyngitis or tonsillitis of acute onset include sore throat and evidence on physical examination of inflammation of the uvula and pharynx or tonsils, including erythema, often with edema of the tissues, with or without exudate. Fever mayor may not be present. ## (b) microbiologic criteria A single culture specimen should be obtained from the posterior pharynx prior to initiation of anti-infective therapy. At least 10 colonies of group A I3-hemolytic streptococci should be present on the culture plate. A throat specimen for culture is obtained with use of a throat swab that is passed over both sides of the posterior pharynx and the uvula. The preferred culture medium is sheep's-blood agar. All cultures negative at 24 hours should be reincubated for another 24 hours. Reduced oxygen tension may enhance identification of group A (3-hemolytic streptococci. Such a reduction may be achieved in a simple manner by stabbing the agar after the sample is streaked or by using a coverglass pressed onto the primary zone of inoculation [bib_ref] Suitability of throat culture procedures for detection of group A streptococci as..., Kellogg [/bib_ref]. Group A streptococci are identified by the bacitracin method or by an-other method of at least equal sensitivity and specificity [bib_ref] Suitability of throat culture procedures for detection of group A streptococci as..., Kellogg [/bib_ref] [bib_ref] Identification of streptococcal pharyngitis in office laboratory: reassessment of new technology, Radetsky [/bib_ref]. If a rapid diagnostic test is used for identification of group A streptococci, the findings must be confirmed by culture [bib_ref] Specificity study of kits for detection of group A streptococci directly from..., Facklam [/bib_ref] [bib_ref] Identification of streptococcal pharyngitis in office laboratory: reassessment of new technology, Radetsky [/bib_ref] [bib_ref] Rapid strep tests: making sense of a crowded market. Contemporary, White [/bib_ref]. The streptococci obtained on culture should be saved for subsequent typing when possible. ## Information needed before conducting clinical trials in humans The drug under consideration should be active in vitro against group A (3-hemolytic streptococci. ## Special qualifications of investigators and institutions The institution or the investigator should have access to a clinical microbiology laboratory where the following tests can be performed: culture of throat swabs on sheep's-blood agar and identification of group A (3-hemolytic streptococci. Alternatively, a single laboratory may process samples referred from participating centers. ## Design and implementation of phase 1, 2, and 3 clinical trials ## (a) demographic characteristics of the study population Clinical studies should include patients of different age groups, since the clinical manifestations of group A streptococcal pharyngitis and tonsillitis may vary with age of the patient. Streptococcal pharyngitis is uncommon in children <3 years of age. Classic exudative pharyngitis is most frequently observed in school-aged children. Group A streptococcal pharyngitis in teenagers and adults is often atypical. ## (b) inclusion and exclusion criteria Children, adolescents, and adults of both sexes should be included. For other considerations, see General Guidelines, section IX. ## (c) selection of the comparison drug It is not considered ethical to use a placebo control. An active control drug should be used. The control agent should be selected on the basis of previous experience demonstrating that it is among the most effective agents for the treatment of group A (3-hemolytic streptococcal pharyngitis at standardized and well-tolerated doses. ## (d) study design The study should compare the trial drug with the active control drug. The treatment regimens should be randomized and of a double-blind design whenever possible. ## (e) administration of the study drug Phase 1 studies shouldprovide adequateinformation concerning dose, dosage interval, andotherpharmacokinetic characteristics. The usefulness of monitoring concentrations in serumor other bodyfluids or tissuesshouldhave been determined. The form of the drug (liquid, tablet, capsule)should be acceptable for patients of any age included in the study and should be an accurate dose (e.g., no cutting of tablets required). Theusualtreatment coursewithstandard regimens (e.g., penicillin or erythromycin) is 10days. The optimalduration of therapy with the study drug maybe determined by additional studies. The initiation of therapy should be standardized, i.e., at the time of clinical diagnosis or at the time of culture confirmation. ## (j) modifications during conduct of the study Ifit proves necessary to add a seconddrug or to substitute a newantimicrobial drug, treatment is considered to have failed clinically. In the eventof allergy to or failure of either drug being evaluated, the patient shouldbe treated with an alternative, standard active drug. ## (g) evaluability Response should be evaluated by both clinical and bacteriologic assessment. Clinical assessment should include history andphysical examination. Documentation of the clinical response with regard to symptoms and signs, including fever, shouldbe obtainedat 3-5 days after initiation of therapy and at weekly intervals (±2 days) thereafteruntil the patient is asymptomatic. The 3-to 5-day assessment may take the form of a telephone call. Patients should be observed posttherapy for a sufficient time to permit detection ofrelapse of disease and/orpost-streptococcal nephritisor carditis. The periodof post-treatment evaluation will varywithknowledge of the durationof anti-infective activitysubsequent to terminationof administration of the test drugs. Asa generalguide, patients shouldbe followed-up for 2-4 weeks after termination of therapy. Evaluation of thebacteriologic response requires a repeated throatcultureat the firstfollow-up visit, within4-7 days after the end of therapy, and at any time clinical symptoms recur. Additional posttreatment throatculturesmaybe necessary for patients treatedwith drugs known to remain in serum or tissue for intervals beyond the initial4-to 7-day evaluation. All organisms recovered should be saved for typing if possible. GroupA streptococci recovered duringtherapy or at the time of the follow-up visit should be evaluated for their in vitro susceptibility to the study drug. Theserologic response to groupA~hemolytic streptococci may be evaluated in acute-and convalescent-phase sera for titersofantibody to streptolysin-O (ASO) or otherstreptococcal antigens. Serologic evaluation, however, is not required for evaluation of drug efficacy. Compliance shouldbe evaluated by the return of all medicationcontainers andof anyremaining drugat the endoftherapy. Documentation of drug in the urine or blood may also be used to assess compliance. (1) Definition ofclincial response. Clinical cureis defined as complete disappearance of signs and symptoms without recurrence; clinical cure with recurrence is defined as the development of symptomatic pharyngitis documented to be causedbygroupA~hemolytic streptococci beforeor during follow-up in patients who were asymptomatic at the initial follow-up assessment; and clinical failure is defined as lack of any response to therapy. (2) Definition of microbiologic response. Microbiologic eradication is defined as eradication of group A ,8-hemolytic streptococci at the initialand subsequent follow-up examinations; microbiologicpersistence is defined as failure to eradicate group A ,8-hemolytic streptococci at the time of initial follow-up; andmicrobiologic relapse is defined as initialsuppression of groupA~hemolytic streptococci withsubsequent positive cultures for group A ,8-hemolytic streptococci. Thefinal assessment of efficacy maybe categorized according to both clinical and microbiologic criteria as in table 3. Otitis media is the most frequent diagnosis recorded for infants and children who visit physicians because of illness. Before 3 years of age more than two-thirds of children have had one or more episodes of acute otitis media (AOM) and more than one-third have had three or more episodes [bib_ref] Greater Boston Otitis Media Study Group. Epidemiology of otitis media during the..., Teele [/bib_ref]. The highest incidence of AOM is in children 6-24 months of age. The incidence declines with age except for a limited reversal of the downward trend at the time of entry into day care or school. Although middle-ear infection is considered uncommon in adults, a recent survey identified almost 4 million visits to physicians by adults each year for this problem [bib_ref] Middle ear disease in samples from the general population. II. History of..., Rudin [/bib_ref]. Males have a significantly increased risk for AOM, and Native Americans and Canadian and Alaskan Eskimos have high rates and severe disease. Incomplete data suggest that American blacks have fewer episodes of ear infection than do members of other racial groups in the United States. Early occurrence of the first episode of AOM, sibling history of recurrent AOM, not being breast fed, and attendance in day care are all associated with increased risk for recurrent AOM [bib_ref] Greater Boston Otitis Media Study Group. Epidemiology of otitis media during the..., Teele [/bib_ref] [bib_ref] Frequency and severity of infection in day care, Wald [/bib_ref]. Since AOM and secretory otitis media (SOM) are defined by the presence of middle-ear effusion (MEE), techniques to determine the presence of air or fluid in the middle ear are critical to diagnosis. Three methods are available: the standard technique of pneumatic otoscopy, typanometry, and acoustic reflectrometry. Tympanometry uses an electroacoustic impedance bridge to record compliance of the tympanic membrane (TM) and provides objective evidence of the status of the middle ear and the presence or absence of fluid. Technical difficulties limit the use of tympanometry in children during the first 6 months of life. The acoustic otoscope or reflectometer is a hand-held instrument that utilizes principles of reflected sound waves to diagnose the presence of air or fluid in the middle ear. The microbiology of AOM has been documented by appropriate cultures of MEE obtained by needle aspiration. Many studies have been performed in the United States, Scandinavia, and Japan. The bacteriologic results are consistent in demonstrating the importance of S. pneumoniae, H. influenzae (90 % nontypable, 10% type b), and M. catarrhalis. S. pneumoniae is the most important bacterial cause of otitis media and is defined in MEE of about one-third of children with AOM. Otitis media due to H. irfiuenzae has been associated with 20%-30% of cases of AOM, and rv20%-30% ofthese strains produce J3-lactamase. M. catarrhalis has been isolated from MEE in 7%-20% of cases of AOM, and a majority of these strains produce J3-lactamase. Virologic and epidemiologic data suggest that viral infection frequently is associated with AOM. Mycoplasma pneumoniae does not appear to playa role in AOM, although some patients with lower respiratory tract disease due to M. pneumoniae may have con-comitantAOM. C. trachomatis is a cause of AOM but almost exclusively in infants <6 months of age. The microbiologic diagnosis of AOM can be made only by aspiration of MEE. This procedure should be done only by persons skilled in the technique. Cultures of throat and nasopharyngeal swab specimens are of no value because they are neither sensitive nor specific when compared with culturs of isolates from the middle ear. The results of cultures of middle-ear fluids from the two ears are disparate in rv20 % of cases of AOM (e.g., effusion from one ear may be sterile while the effusion from the other yields a bacterial pathogen, or different bacterial pathogens are isolated from the two ears). Therefore, for evaluation of new drugs or vaccines, it is important that each diseased ear be aspirated for a complete microbiologic assessment and that outcome for each ear be evaluated separately [bib_ref] Disparate cultures of middle ear fluids, Pelton [/bib_ref]. Suppurative sequelae such as mastoiditis and other infratemporal and intracranial complications occur but are uncommon in developed countries. Hearing loss is the most important complication of AOM and MEE. Patients with MEE suffer from hearing loss of variable severity. On average, a patient with fluid in the middle ear has a 25-decibel hearing loss. Since intellectual development is dynamic during infancy, when the incidence of AOM is highest, there is concern that any impediment to reception or interpretation of auditory stimuli might have an adverse effecton development of speech, language, and cognitive abilities. Some studies suggest that children with histories of recurrent AOM have lower scores in tests of linguistic and cognitive abilities than do their diseasefree peers [bib_ref] the Greater Boston Otitis Media Study Group. Otitis media in infancy and..., Teele [/bib_ref]. ## (a) scope of guideline The clinical entity discussed in this guideline is limited to AOM (synonyms include acute suppurative OM and acute purulent OM). The microorganisms considered are S. pneumoniae, H. infiuenzae, and M. catarrhalis. Not included in this guideline are secretory otitis media and chronic suppurative otitis media. SOM is defined as the presence of MEE behind an intact TM without acute signs or symptoms (synonyms include chronic OM with effusion, persistent MEE, OM with effusion, and serous OM). Chronic suppurative OM is defined as chronic discharge from the middle ear through a perforation of the TM (synonym includes chronic OM). ## (b) general principles of care for patients with acute otitis media Tympanocentesis and culture of MEE is required for microbiologic diagnosis of AOM. Nose and throat cultures are of no value. Tympanocentesis is a safe procedure when performed by skilled and experienced persons. The procedure provides not only specific microbiologic diagnosis but also symptomatic relief of acute pain by decompressing the em 1992;15 (Suppl 1) middle-earabscess. There is transientpain during the few seconds of the procedure. Rare untoward events may occur, including bleeding, tearing of the tympanic membrane, and ossicular dislocation. Approximately one-third of children with AOM caused by a bacterial pathogen improve without treatment with antibacterial drugs. Clinical resolution may occur because the contents of the middle ear are spontaneously discharged, either through the eustachian tube or by means of a spontaneous perforation of the TM. With appropriate antimicrobial therapy, however, signs and symptoms of AOMimprovewithin48-72 hours. MEE maypersist (even though sterile) for weeks to months after onset of AOM. The goals of antimicrobial therapy for AOM are the rapid resolution of signs and symptoms of disease; sterilization of the MEE; prevention of suppurative sequelae; reduction of the occurrence of relapse and recurrences; and decrease in time spent with MEE. The preferredantimicrobialagent for the patient with AOM must be active againstS. pneumoniae, H. irfluenzae, and M. catarrhalis. Group A streptococci, Staphylococcus aureus, gram-negative enteric bacilli, and anaerobic bacteria are infrequent causes of AOMand need not be considered in initial therapeutic decisions. Amoxicillin or an equivalenthas been the standard regimenfor AOMsinceit is effective againstmost strains of the three major pathogens and is well tolerated, producing limited adverse effects. However, since at present 20%-30% of H. irfluenzae strainsand 50%-70% of M. catarrhalis strains in the United States produce~-lactamase, ã -lactamase-stable agent (such as amoxicillinplus a~-lacta mase inhibitor, a second-or third-generation cephalosporin) or a combination such as trimethoprim-sulfamethoxazole or erythromycin/sulfisoxazole may also be used. Clinical trials with these agents indicate that all regimens are of approximately equal clinical efficacy when the bacterial pathogens are susceptible. The control drug chosen for a clinical trial should be among the most effective and safe agentsavailable for treatment. It is expected that an effective agent will sterilize the middle-ear fluid of bacterial pathogens in >80% of infected ears within 72 hours. A second aspiration of middle-earfluidshouldbe consideredfor anypatientfor whom the outcome at 72 hours is clinical failure. Chemoprophylaxis has been shown to be of value in the prevention of acute illness in children who have had recurrent AOM [bib_ref] Sulfisoxazole as chemoprophylaxis for recurrent otitis media -a double-blind crossover study in..., Perrin [/bib_ref]. More than 10 studies in which a penicillin, a sulfonamide, or erythromycinwas used haveidentifiedprotective efficacy against new episodes of AOM in 60%-90% of cases in comparisons with a placebo control group. ## (c) future trends The changing susceptibilitypatterns of bacterial pathogens associatedwith AOMwarrant considerationof new and effectivedrugs with activityagainstall major pathogens. Newdrugs should have advantages over currently available agents, including (1) ease of administration to ensure compliance and greater conveniencefor the patient (e.g., once-a-day dosing, drug stabilityat room temperature, prolongeddrug shelf-life); (2) reduced incidence of relapse and recurrence; and (3) reduced duration of MEE after resolution of acute signs and symptoms. Newdiagnostic instrumentswith improvedcapacity for examinationof the middle ear (of most importance is diagnosis of the presence of fluid in the middle ear) also are needed. Even the most experienced otoscopists are accurate in diagnosing the presence of MEE in only rv80% of cases. Tympanometryand acoustic reflectometry are of value in assisting the otoscopist but are insufficiently sensitive and specific to assure accuracy of diagnosis for all children enrolled in clinical trials. A noninvasive technique for determining the organisms present in MEE is needed for the facilitation of appropriate microbiologic diagnosis and optimal use of approved drugs. Currently, only needle aspiration of the fluid from both middle ears assures definition of the etiologicagentsof AOM. ## Clinical definitions of the disease ## (a) general definition Patients eligible for inclusion in studies will be children or adults with symptomsand signs clinicallycompatiblewith AOM. [bib_ref] Comprehensive review of morbidity and mortality trends for rheumatic fever, streptococcal disease,..., Quinn [/bib_ref] Clinical criteria. AOM is defined as inflammation of the middle ear evidencedby the presence of fluid and accompanied by specific signs or symptoms such as ear pain, ear drainage, hearing loss, or nonspecific findings such as fever, lethargy, irritability, anorexia, vomiting, or diarrhea. Thepresence ofMEE is definedby pneumatic otoscopy with or without use of tympanometry or acoustic reflectometry. ## (b) minimal diagnostic criteria permitting inclusion in trials (2) Microbiologic criteria. Specific microbiologic diagnoses of AOM can be determinedonly by aspirationof MEE. Both ears should be aspirated when the patient has bilateral AOM. Tympanocentesis is a standard procedure and is described in various texts on otolaryngology [bib_ref] Otitis media in infants and children: tympanocentesis, Bluestone [/bib_ref]. The procedure should be performed only by qualified personnel with previous experience. Nose and throat cultures are of no value in the microbiologic diagnosis of AOM since they are neither sensitive nor specific for predicting bacteria present in MEE. Specimens for such cultures may be obtained from selected patients for monitoring change in susceptibility patterns of nasopharyngeal or oropharyngeal isolates during the course of antimicrobial therapy. ## Information needed before conducting clinical trials in humans The drug under consideration should have proven in vitro activity against S. pneumoniae, H. injluenzae, and M. catarrhalis. Group A streptococci, S. aureus, gram-negative enteric bacilli, and anaerobic bacteria are infrequent causes of ADM and need not be considered in initial therapeutic decisions. In vivo evidence of sterilization of bacterial pathogens should be obtained with use of an appropriate dosage schedule in an animal model of ADM. The chinchilla has been used most frequently in assessments of pathogenesis and therapy and should be considered for such in vivo studies. ## Special qualifications of investigators and institutions The investigator or the institution should have access to a clinical microbiologic laboratory where personnel can perform the following tests: culture of MEE for the isolation and identification of common pathogens in ADM and in vitro susceptibility testing, including tests for ,B-Iactamase production. The institution should have appropriate facilities and investigators experienced in middle-ear examination and aspiration of MEE. ## Design and implementation of phase 1, 2, and 3 clinical trials ## (a) demographic characteristics of the study population Clinical studies should be conducted with patients of different age groups and racial backgrounds. In newborns and infants up to 6 weeks of age, the bacterial pathogens in ADM differ from those in older children and include organisms acquired during delivery. In addition, pharmacologic considerations are different for older infants and children. The incidence of ADM is highest between the ages of 6 and 24 months. The risk for ADM is significantly increased in males, Native Americans, and Canadian and Alaskan Eskimos, and the risk may be lower for black Americans than for white Americans. ## (b) inclusion and exclusion criteria Children, adolescents, and adults of both sexes should be included in studies. Phase 1 evaluations may include singledose administration before tympanocentesis to assess the penetration of drug into middle-ear fluids. Initial clinical studies should not include children with focal anatomic, physiologic, or systemic immune defects; children who had received a systemic antimicrobial agent within the past 7 days for treatment of an illness other than ADM; and neonates or infants <12 weeks of age. ## (c) selection of the comparison drug The control agent should be selected on the basis of expected patterns of in vitro susceptibility of the most common pathogens (S. pneumoniae, H. injluenzae, and M. catarrhalis) in the community. ## (d) study design and stratification Because of the difficulties in obtaining reliable cultural information in ADM even under protocol conditions, it may be appropriate to adopt a sequential study strategy: (1) A small (r'-JI00 patients) phase 2 trial can be conducted in which MEE aspiration and culture is performed for all patients to document the unique microbiology of the population to be studied. In vitro antimicrobial susceptibility testing should be performed for all MEE isolates, and both clinical and presumed microbiologic outcome should be assessed (see definitions below). Repeat aspiration ofMEE is required only if there is evidence of clinical failure. In the phase 2 trial, an "open" uncontrolled study may be conducted. Because the number of centers that perform tympanocenteses is presently limited and a second aspiration of MEE cannot be recommended for children who are clinically cured or improved, the microbiologic response is correctly termed presumptive eradication. Clinical and presumed microbiologic efficacyfor a minimum of 60 patients with documented ADM, with 20 cases each due to the three major bacterial pathogens (S. pneumoniae, H. injiuenzae, and M. catarrhalis, respectively) should be sufficient to determine whether the drug is effective on an organism-specific basis. Both organism-specific and disease-specific responses should be evaluated. For the purpose of organism-specific evaluation, a minimum of 20 isolates from~20 patients is required for evaluation. (2) If the preliminary assessment is favorable (i.e., a clinical and presumed microbiologic response rate of~80 %), a larger, comparative phase 3 trial with an active control should be conducted. A double-blind study design is desirable whenever feasible; in any event, the evaluator should be blinded. Aspiration of MEE for microbiologic diagnosis before treatment is desirable but not required, but aspirates from those patients who fail to respond clinically are required. ## (e) administration of the study drug All drugs will be provided to the patient by the investigator or his or her designee. For young children unable to swallow tablets or for those with a small body mass, the use of a suspension or other acceptable formulation is necessary for accurate dosing. ## (j) modifications during conduct of the study It is not anticipated that addition of a new antimicrobial agent will be required. If there is clinical failure (see definition below) after 72 hours of therapy, tympanocentesis should be performed; modification of antimicrobial therapy will be based on the data obtained from culture and from susceptibility testing. ## (g) evaluability Both clinical and presumed microbiologic responses should be assessed. After enrollment, observations should be made 3-5 daysafter initiation of therapy and at least 2 and 4-6 weeks later. The precise period of posttreatment evaluation will vary according to knowledge of the anticipated duration of antiinfective activity subsequent to termination of administration of the test drugs. At each visit an interval medical history should be obtained and otoscopic examination, including tympanometry or acoustic reflectometry, should be performed to determine the status of the middle ear. During reexaminations, children should be assessed for other foci of infection and for adverse effects of the test drug. The treatment outcomes for the study and control groups should be compared according to the proportion of patients in the following outcome categories: (1) clinical cure with presumed microbiologic eradication; (2) clinical failure with microbiologic persistence; and (3) clinical relapse or recurrence. (1) Definition of clinical response. Clincal cureis defined as resolution of signs and symptoms (e.g., pain, fever, vomiting), exclusive of MEE, within 72 hours in a child who remains well throughout the course of therapy and follow-up. Clinical failure is defined as lack of resolution of signs and symptoms, exclusive of MEE, within 72 hours of onset of therapy. Relapse is defined as reappearance of signs and symptoms of ADM after initial response during or within 4 days of conclusion of therapy. Recurrence is defined as reappearance of signs and symptoms of ADM~5 days after the conclusion of therapy. (2) Definition ofmicrobiologic response. It is recognized that whereas the microbiologic response can be accurately assessedonly by repeat aspirationsof MEE during or after com-pletion of antimicrobial therapy, repeat tympanocentesis in a patient who is clinically improving is generally not warranted. All patients for whom outcome is classified as clinical failure, relapse, or recurrence should undergo repeated aspiration of MEE before their antimicrobial regimens are toms of acute sinusitis are often difficult to distinguish from those of the common cold or from allergic (vasomotor) rhinitis. The most common complaints are cough (80 %) and nasal discharge (75 %). Parents often notice a malodorous breath among preschoolers (50% of cases) who have neither signs of pharyngitis nor poor dental hygiene [bib_ref] The diagnosis and management of sinusitis in children: proceedings of a closed..., Epidemiology [/bib_ref] [bib_ref] Acute maxillary sinusitis in children, Wald [/bib_ref]. In adults, postnatal purulent discharge and facial pain over the affected sinus that worsens with movement or percussion are the cardinal symptoms [bib_ref] Sinus infections, Vortel [/bib_ref] [bib_ref] Etiology and antimicrobial therapy of acute maxillary sinusitis, Hamory [/bib_ref]. Fever occurs in <50% of cases. Hyposmia, jaw pain with mastication, nasal congestion, and a history of recent upper respiratory infection are other manifestations. In patients with nosocomial sinusitis secondary to prolonged nasotracheal intubation, the clinical features, except for unexplained fever, may be relatively silent. Symptoms associated with chronic sinusitis are usually less intense but more protracted than those in acute sinusitis. Fever is uncommon. Fatigue, general malaise, and an ill-defined feeling of unwellness and irritability can be more prominent than local symptoms of nasal congestion, facial pain, or postnasal drip [bib_ref] Chronic maxillary sinusitis. Definition, diagnosis and relation to dental infections and nasal..., Melen [/bib_ref]. The precise microbial etiology of sinusitis can be determined only by direct aspiration of the sinus, since nasopharyngeal secretions are regularly contaminated by the indigenous flora and culture results correlate poorly with results for sinus aspirates [bib_ref] Sinus infections, Vortel [/bib_ref] [bib_ref] Etiology and antimicrobial treatment of acute sinusitis, Gwaltney [/bib_ref]. This difficulty may limit the ability to make a definitive assessment of the microbiologic response to anti-infective therapy. S. pneumoniae and unencapsulated H. influenzae are responsible for >50% of cases of acute sinusitis in adults, while M. catarrhalis in addition to S. pneumoniae and H. influenzae account for two-thirds of cases in children [bib_ref] The diagnosis and management of sinusitis in children: proceedings of a closed..., Epidemiology [/bib_ref] [bib_ref] Etiology and antimicrobial treatment of acute sinusitis, Gwaltney [/bib_ref] [bib_ref] Bacteriologic findings of acute maxillary sinusitis in young adults, Hr [/bib_ref] [fig_ref] Table 4: Microbial causes of acute maxillary sinusitis [/fig_ref]. S. aureus is a common nasal contaminant and an infrequent cause of acute sinusitis. Obligate anaerobes are uncommonly isolated in acute sinusitis. In contrast, the microbiology of chronic sinusitis is usually logic persistence, emergence of resistance, or superinfection and optional determinations of drug concentrations in MEE for such patients; (3) repeated hematologic, hepatic, and renal function studies as appropriate; (4) monitoring of change in susceptibility patterns of bacterial isolates in nasoor oropharyngeal culture specimens for selected patients; and (5) recording of allergic or toxic reactions or important adverse effects, which will be grounds for terminating the use of either the study drug or the standard drug. ## (c) assessment after completion of therapy and follow-up Patients should be followed up clinically and by otoscopy biweekly until MEE has completely resolved. Repeated aspiration of MEE should be performed for patients with clinical relapse or recurrence. The time to resolution of MEE should be recorded. Laboratory studies to monitor resolution of infection and adverse reactions should be repeated according to the protocol. c. Sinusitis # Background Sinusitis is a common disorder both in children and adults. Approximately 0.5 % of upper respiratory infections in children are complicated by acute sinusitis, and 0.02 % of adults have chronic sinusitis. Because of the location and rich vascular supply of the sinuses, these infections are potentially life-threatening in that intracranial suppurative complications may result, including epidural or subdural empyema, brain abscess, or cavernous sinus thrombosis. Early diagnosis and effective antimicrobial therapy are critical for the prevention of such complications as well as chronic sequelae. The paranasal sinuses are lined with ciliated pseudo-columnar epithelium and are connected to each other through small tubular openings, the sinus ostia, which drain into various regions of the nasal cavity. The paranasal sinuses are generally considered to be sterile, although transient colonization by the resident upper respiratory flora does occur [bib_ref] Bacteriology of the maxillary sinuses in patients with cystic fibrosis, Shapiro [/bib_ref]. Conditions that affect the patency of the sinus ostia, .the normal mucociliary function of the sinus epithelium, or immune defenses of the upper airways or events that facilitate direct introduction of microorganisms into the paranasal sinuses are the key predisposing factors to sinus infection [bib_ref] The diagnosis and management of sinusitis in children: proceedings of a closed..., Epidemiology [/bib_ref]. Such conditions include viral upper respiratory tract infections, respiratory allergies, alterations in mucus (e.g., cystic fibrosis), and selective deficiencies in immunoglobulins. Dental extraction or periapical infections of the maxillary molar teeth are a particularly important cause of maxillary and chronic sinusitis. The clinical manifestations of sinusitis vary greatly depending on the duration of infection (i.e., acute or chronic) and the age of the patient (i.e., child or adult). In children, symp- [bib_ref] Bacteriological study in chronic maxillary sinusitis, Su [/bib_ref] [bib_ref] Anaerobic infection of the paranasal sinuses, Frederick [/bib_ref]. Viridans streptococci and nonencapsulated H. infiuenzae are the major aerobic isolates. Nosocomially acquired sinusitis secondary to head trauma or prolonged nasotrachea1 intubation is commonly causedbypolymicrobial gram-negative bacilli and S. aureus as well as by anaerobes [bib_ref] Clinical characteristics of nosocomial sinusitis, Humphrey [/bib_ref]. Fungal sinusitis is rare, but Aspergillus, Mucor, Candida, Pseudoallescheria boydii (Scedosporium spiospermum) and other saprophytic fungi can cause invasive diseaseusually in the debilitated host. Although antecedent viral upper respiratory infection is an important cause of acute sinusitis, viruses (e.g., rhinovirus, influenza, parainfluenza, and adenovirus) are isolated only in 15%of antralaspirates [bib_ref] Etiology and antimicrobial treatment of acute sinusitis, Gwaltney [/bib_ref]. ## (a) scope of guideline The clinical entities included in this guideline are acute sinusitis (symptoms present for~4 weeks) and chronic sinusitis (symptoms present for~3 months). Not included in this guideline are subacute cases (symptoms lasting 1-3 months), whichhave a variable naturalhistory and in which the bacterial etiology is poorly defined. ## (b) general principles of care for patients with acute and chronic sinusitis The goals of antimicrobial therapy for acute sinusitis are [bib_ref] Comprehensive review of morbidity and mortality trends for rheumatic fever, streptococcal disease,..., Quinn [/bib_ref] the eradication of the causative pathogens; (2) the provision of symptomatic relief; (3) the restoration and improvementof sinusfunction; and (4) the prevention of intracranial complications and chronic sequelae. Although many management options are available, antimicrobial agents are the mainstay of therapy for acute sinusitis. The therapeutic efficacy of anti-infective agents for acute sinusitis hasbeenestablished by placebo-controlled clinical trials [bib_ref] Comparative effectiveness of amoxicillin and amoxicillin-elavulanatepotassium in acute paranasal sinus infections in..., Wald [/bib_ref] and in studies that employed sinus aspiration before and after treatment [bib_ref] Etiology and antimicrobial treatment of acute sinusitis, Gwaltney [/bib_ref] [bib_ref] Treatment of acute maxillary sinusitis in childhood-a comparative study of amoxicillin and..., Wald [/bib_ref]. Standardtherapy is usuallyselected on anempiricbasisanddirected against themost likely pathogens, including H. infiuenzae, S. pneumoniae, and M. catarrhalis (see [fig_ref] Table 4: Microbial causes of acute maxillary sinusitis [/fig_ref]. Oral therapy with a J3-lactam agent suchas ampicillin for 10-14 days is generally prescribed and is considered the standardregimenfor acute sinusitis in bothchildren and adults. A favorable rate ofclinical response of70%-80% canbe expected withthisregimen. In penicillinallergic patients, a second-generation cephalosporin (e.g., cefaclor), a macrolide/sulfonamide (e.g., erythromycin/sulfisoxazole) or trimethoprim/sulfonamide (such as trimethoprimsulfamethoxazole) combinations have yielded comparable results. Penicillins (such as amoxicillin plus a J3-lactamase inhibitor) or cephalosporins thathavea more-extended spectrum have not yielded superior results in controlled trials [bib_ref] Comparative effectiveness of amoxicillin and amoxicillin-elavulanatepotassium in acute paranasal sinus infections in..., Wald [/bib_ref] [bib_ref] Treatment of acute maxillary sinusitis in childhood-a comparative study of amoxicillin and..., Wald [/bib_ref] [bib_ref] Treatment of acute maxillary sinusitis -amoxicillin, azidocillin, phenylpropanolamine and pivampicillin, Axelsson [/bib_ref] even though theprevalence ofJ3-lactamase-producing strains among respiratory pathogens appears to be increasing(upto 20% ofH. influenzae strains, 50%-70% ofM. catarrhalis strains,and20%-30% of respiratoryanaerobes) [bib_ref] Beta-lactamase producing bacteria in head and neck infection, Brook [/bib_ref]. In 'patients with chronic sinusitis, surgical procedures to facilitate sinus drainage through the creationof an artificial ostium and submucosal resection of diseased tissue appear to be the mainstays of treatment. The role of anti-infective agents in chronic sinusitis is not as clear as that in acute sinusitis. Conservative therapy with anti-infective agents or sinusirrigationwithout surgical intervention is successful in onlyone-thirdof cases [bib_ref] Sinus infections, Vortel [/bib_ref] [bib_ref] Short and long-term treatment results in chronic maxillary sinusitis, Melen [/bib_ref]. Withcombined medicaland surgical treatment, the curerate forchronicmaxillary sinusitis is >60% after 3 years of follow-up [bib_ref] Short and long-term treatment results in chronic maxillary sinusitis, Melen [/bib_ref]. Anti-infective agents useful forchronic sinusitis should have broad-spectrum activity against respiratory anaerobes as well as against viridansstreptococci, S. pneumoniae, H. influenzae, and M. catarrhalis. ## (c) future trends Several issuesin the management of acute and chronic sinusitis remain controversial. These include: [bib_ref] Comprehensive review of morbidity and mortality trends for rheumatic fever, streptococcal disease,..., Quinn [/bib_ref] the optimal duration of therapy for acute and chronic sinusitis; (2) the clinicalrelevance of the increasing prevalence of in vitro resistanceto J3-lactam agents among upper respiratorypathogens; (3)the roleofrespiratory allergy in recurrent or chronic sinusitis; (4) the value of adjunctive measures such as oral or topical decongestants, antihistamines, and intranasal steroids in the treatment of acuteand chronic sinusitis (such measures must be standardized in both study and control groups during initialassessment of new antibiotic regimens for both acute and chronic sinusitis); (5) the optimal mode of surgical management in chronic sinusitis (i.e., preservation of sinus epithelium vs. radical mucosal resection); (6) avoidance of the need for sinus puncture by the use of endoscopic sinoscopy for performing quantitative cultures. ## Clinical definitions of the disease ## (a) general definition Patients eligible for study will be children or adults with symptoms and signs clinically compatible with acute or chronic sinusitis. ## (b) minimum diagnostic criteria permitting inclusion in trials (I) Clinical criteria. Acute sinusitis is defined as inflammation of the sinuses associated with symptoms lasting~4 weeks. Clinical findings suchas fever, headache, malartenderness, andnasal discharge (which are often nonspecific) should be supported by objective localizing studies such as radiography, ultrasonography, or CT. Transillumination of the S75 sinuseshas a relatively low sensitively (74%) and specificity (47%) for acute sinusitis [bib_ref] Etiology and antimicrobial treatment of acute sinusitis, Gwaltney [/bib_ref] and should not be used as the solediagnostic criterion. Transillumination is alsoless informativein children<6 years of age (40% concordanceand 20% discordance compared with radiographic findings) because of either poor cooperationof the child in performingthe test or thedevelopmental variations of the sinuses in this agegroup [bib_ref] The diagnosis and management of sinusitis in children: proceedings of a closed..., Epidemiology [/bib_ref]. Anterior rhinoscopy mayrevealhyperemicand edematous nasal turbinates, often with purulent dischargefrom the middle meatus where the orifices of the maxillary, frontal, andanteriorethmoidal sinusesenterthe intranasal cavity [bib_ref] Endoscopic paranasal sinus surgery, Schaefer [/bib_ref]. Imaging studies (roentgenography, ultrasonography, or CT) should be performed in all cases. Other laboratory studies suchas neutrophil count, erythrocyte sedimentation rate, and C-reactive protein should also be performed. Chronic sinusitis is definedas inflammation of the sinuses associated with symptoms lasting >3 months that are compatiblewithradiographic abnormalities (determined byroentgenography, ultrasonography, or CT). If possible, chronic sinusitis should be confirmedby endoscopic sinoscopy with direct visualization of the sinusmucosa, appropriatemicrobiologic sampling, and histopathologic evaluation [bib_ref] Endoscopic paranasal sinus surgery, Schaefer [/bib_ref] [bib_ref] Headaches and sinus disease. The endoscopic approach, Stammberger [/bib_ref]. (2) Microbiologic criteria. The precise microbial etiology of sinusitis can be determined only by direct aspiration or injection wash of the sinus cavity. Cultures of the surface of the nasal vestibule or the nasopharynx are unreliable becauseof their regularcontamination bythe residentmicroflora and should not be used for assessment of microbiologic efficacy of study regimens. Access to the maxillary sinus can be obtainedintranasally througha puncturebelow the inferior turbinate and to the frontal sinus through a puncture below the infraorbital rim oftheeye. Thorough cleansing of thepuncture site with an appropriate antiseptic is important to minimize contamination of the specimen with surface bacteria. If no fluid is obtained, 1 mL of sterile normal saline without bactericidalpreservativeshouldbe instilledand the washings reaspirated. Specimens should be sent to the laboratory for leukocytecounting, gram staining, and culture for aerobes, anaerobes, fungi, and mycobacteria. Viral cultures are of investigational interest. Withthe appropriate technique, >76% of such specimenswill yield positivecultures in acute maxillary sinusitis [bib_ref] Bacteriologic findings of acute maxillary sinusitis in young adults, Hr [/bib_ref]. Furthermore, if organisms are seen on gram-stained preparations of antral secretions, a presumptive diagnosis can be made by assessing the bacterial morphotype in up to 90% of cases [bib_ref] Macroscopic purulence, leukocyte counts and bacterial morphotypes in relation to culture findings..., Hr [/bib_ref]. Quantitative cultures (~103 cfu/mL of aspirate) are usefulin distinguishing true infection from colonization or contamination [bib_ref] Etiology and antimicrobial treatment of acute sinusitis, Gwaltney [/bib_ref] [bib_ref] Sinusitis of the maxillary antrum, Evans [/bib_ref] , but such studies are labor-intensive and are not required for microbiologic diagnosis in clinical trials. In chronic sinusitis, microbiologic diagnosis can be confirmedby cultureof diseasedmucosaobtainedby biopsyduring endoscopicsinoscopy or surgery. In such cases, the culture results should be correlated with the histopathologic findings to exclude the possibility of specimen contamination. ## Information needed before conducting clinical trials in humans For a pathogen-specific evaluation, the drug under consideration should haveprovenin vitro activity against the specific bacteriaprevalent in sinusitis, and for a disease-specific evaluation (i.e., acute vs. chronic, pediatric vs. adult), the drug should havea broad range of activity against the most prevalent pathogens. ## Special qualifications of investigators and institutions The investigator or subinvestigator should have the necessary skillsto perform sinuspuncturefor microbiologic evaluationsof acuteandchronicsinusitis and endoscopic sinoscopy for studies of chronic sinusitis. The institution should have the facilities and personnel with expertise to perform and interpret radiographs, ultrasonography, or CT and microbiologic studies of the paranasal sinuses. ## Design and implementation of phase 1, 2, and 3 clinical trials ## (a) demographic characteristics of the study population Clinical evaluation of new treatment regimens should be conducted with patients grouped by specified age, underlying disease, duration of symptoms, and presence or absence of respiratory allergy. Since these factors appear important both in predictingthe microbial etiologyand in overallprognosis,their contribution to treatmentoutcomeshouldbe carefully controlledby appropriate randomizationduring patient enrollment or by stratification eitherprospectively or posthoc during analysis of results. ## (b) inclusion and exclusion criteria Children, adolescents, and adults of both sexesare eligible for inclusion. Patientswho havereceivedother antimicrobial therapy within the preceding 2 weeks, patients with hypersensitivity reactions to drugs of a similar class, and patients with other concurrent, acute infectious illnesses should be excluded. ## (c) selection of the comparison drug In acute sinusitis, an active control regimen with proven efficacy againstS. pneumoniae, H. injluenzae, and M. catarrhalis shouldbe used. In chronicsinusitis, a placebo-controlled trial is consideredjustified since the role of antimicrobial therapy for this condition remains unclear at this time. ## (d) study design and stratification Because of the difficulties in obtaining reliable cultural information about sinusitis even under protocol conditions, it may be appropriate to adopt the following sequential study strategy. (1) Conduct a small (rvlOO patients) phase 2 trial in which sinus puncture and culture is performed for all patients to document the unique microbiology of the intended study population, with at least 20 cases of each of three major bacterial pathogens implicated (S. pneumoniae, H. irfiuenzae, M. catarrhalis). In vitro antimicrobial susceptibility testing of all sinus isolates should be performed. Both clinical and presumed microbiologic outcomes are assessed (see definitions below). Repeated aspiration of the sinus is required only if there is evidence of clinical failure. In the phase 2 trial, an "open" uncontrolled study may be conducted, although a randomized comparative double-blind trial with an active control is still desirable despite the clearly inadequate size of the sample for meaningful comparisons of clinical response rates. A conrolled comparison provides additional information regardmg the expected response rate in a particular community. Both organism-specific and disease-specific responses should be evaluated. For purposes of organism-specific evaluation a minimum of 20 isolates from~20 patients is required for evaluation. (2) If the preliminary assessment is favorable (i.e., a clinial and presumed microbiologic response rate of~70 %), it IS reasonable to conduct a larger, comparative phase 3 trial with at1 active control. Sinus puncture for microbiologic diagnosis and sinus radiography before treatment are desirable but not required, but examination of aspirates and sinus radiographs is necessary for those patients who fail to respond clinically. In vitro antimicrobial susceptibility testing should be performed for all isolates from cultures. Use of adjunctive medications such as oral or nasal decongestants, antihistamines, or intranasal steroids should be standardized such that hey~re used either in both the study and control groups or in neither of the groups. Similarly, in studies of chronic sinusitis, the mode of concomitant surgical therapy (i.e., endoscopic sinuscopy with limited mucosal curettage vs. a more conventional approach of radial mucosal resections) should also be standardized or stratified. The projected sample size must include consideration of the expected difference in efficacy of the study and control regimens, the expected proportion of cases due to each of the major bacterial pathogens (and that one-fourth of all cases of acute sinusitis are due to nonbacterial causes that would not be affected by either antibacterial agent), and an anticipated rate of spontaneous clinical cure of rv30 %among children with acute sinusitis [bib_ref] The diagnosis and management of sinusitis in children: proceedings of a closed..., Epidemiology [/bib_ref]. ## (e) administration of study drug The treatment course is usually 10-14days for acute sinus-itis. Si.nce the opt~mal duration of therapy has not been clearly estabhshed for either acute or chronic sinusitis, this could be the mainfocus of evaluationin phase 4 trials. Patients should be assigned randomly to the test or "control" group, and if p~e~reatment cultures of the sinuses are not performed, the chmcal and presumed microbiologic response should be evaluated by a blinded observer. For children unable to swallow tablets or whose body mass is small, either a suspension or an acceptable alternative formulation of the study drug or the control drug is necessary for precise dosing. ## If) modifications during conduct of the study Modification of the study by the addition of a new antimicrobial agent may be necessary if the clinical response after 3-5 days of therapy is suboptimal. In such instances sinus aspiration for documentation of the microbiologic response is required before the therapeutic regimen is modified. Addition of a new antimicrobial agent constitutes a clinical failure of the initial treatment regimen. ## (g) evaluability Both clinical and presumed microbiologic responses should be~s~:ss.ed. Clinical evaluation should be made 3-5 days after imuation of therapy and weekly or biweekly thereafter until the resolution of all symptoms and signs. Use of a scoring system, pa:ticularly a binomial (yes/no) objective scoring system, for SIgns and symptoms such as fever, pain, headache, tenderness, nasal discharge, and purulence is strongly encouraged. Imaging studies (roentgenography, ultrasonography, or CT) should be repeated at least at the completion of antimicrobial therapy. Patients with chronic sinusitis should be further assessed by repeated endoscopic sinoscopy before or after completion of therapy. Information about concentrations ?f dru~in sinus aspirates or mucosal biopsies may be of value III studies of chronic sinusitis, but they are not critical to studies of efficacyin acute sinusitis and are not required for final evaluation. Since a repeat of sinus puncture is generally not justified in patients who have responded clinically to therapy, the microbiologic response in such patients can only be judged presumptively. Comparisons of treatment outcomes in the study and control groups should be made according to the proportion of patients in the following outcome categories: (1) clinical cure with presumed microbiologic eradication; (2) clinical failure with microbiologic persistence; (3) clinical and/or microbiologic relapse and recurrence; and (4) indeterminate. (1) Definition ofclinical response. Clinical cure is defined as complete resolution of signs and symptoms at the conclu-sio~of antimicrobial therapy and at follow-up. Clinical failure IS defined as lack of improvement in signs and symptoms within a defined period of therapy (72 hours for acute sinusi-sn tis and 2 weeksfor chronic sinusitis). Earlyrelapse is defined as reappearane of signsand symptoms or newclinicalfindings of sinusitis within 14daysafter the conclusionof therapy. Late relapse is definedas the reapearrance of signs and symptoms or new clinical findings of sinus infection after 14 days but within 1 month after the conclusion of therapy. (2) Definition of microbiologic reaponse. Presumed microbiologic eradication is definedas cases in whichpretreatment cultures of sinus aspirates were positive, clinical signs and symptoms resolvecompletely, and posttreatmentculturesare not performed because clinical response is complete. Confirmed microbiologic response is defined as cases in which the causativeorganismcannot be isolated in cultures of sinus aspirates performed after 72 hours of antimicrobial therapy. Such repeated cultures of sinus aspirates are likely to be performed only in the setting of clinical failure. A statement as to microbiologic eradication is not possible because of the influence ofconcomitantantimicrobial therapy. Microbiologic persistence is defined as a positive culture of sinus aspirates after at least 72 hours of antimicrobial therapy. If a pretreatment culture of sinus aspirate was performed and was positive, the isolation of the same organism after~72 hours of therapy is considered confirmed microbiologic persistence. If no pretreatment culture of sinus aspirates was performed, isolation of a pathogen after~72 hours of treatment is considered presumptive microbiologic persistence. Superinfectionis defined as the emergenceof new or resistant organisms in cultures of sinus aspirates after~72 hours of antimicrobial therapy. ## Summary of guideline ## (a) baseline assessment should include the following procedures: (1) Initial clinical evaluation and imaging (roentgenography, ultrasonography, or CT) of the paranasal sinuses; (2) hematologic, hepatic, and renal function studies; (3) sinus puncture and microbiologicstudies for phase 2 trials and optionallyfor phase 3 trials; and (4) endoscopic sinoscopy, bacterial cultures,andoptionaltissuebiopsyfor studiesof chronic sinusitis. (b) Assessment During the Course of Therapy Should Include: [bib_ref] Comprehensive review of morbidity and mortality trends for rheumatic fever, streptococcal disease,..., Quinn [/bib_ref] Clinical evaluation at 2-3 and 5-7 days after initiation of antimicrobial therapy, and weekly or biweekly thereafter until resolution of all symptoms and signs; (2) aspiration of sinuses for microbiologic studies for patients who fail to respond clinically after at least 72 hours of antimicrobial therapy to define microbiologic persistence, emergence of resistance, or superinfection; and (3) repeated imaging, hematologic. hepatic, and renal function studies as appropriate. ## (c) assessment after completion of therapy and follow-up Patients should be followed up clinically and with imaging for at least 2 weeksafter completionof antimicrobial therapy to assess relapse or recurrence, clinical complications, and adverseeffects of the antimicrobialregimen. Sinus aspiration should be performed for those patients with clinical relapse or recurrence. ## D. acute exacerbations of chronic bronchitis 1. background Bronchitis is an inflammatory conditionof the tracheobronchial tree. It is both acute and chronic and is caused by a variety of irritants and infectiousagents. Productive cough is the commondenominator of this condition, and the sputum produced ranges from mucoid to frankly purulent. Acute bronchitis is generally an infectious process. It occurs in all age groups and is most common in the winter months, when acuterespiratory infections are prevalent. Most cases are thought to be due to respiratory viruses, including those associatedwith the common cold and other respiratory viruses involved in infections of the lower respiratory tract (e.g., adenovirus, rhinovirus, coronavirus, influenza, parainfluenza, respiratory syncytial virus, coxsackievirus). M. pneumoniae, C. pneumoniae, and Legionella specieshave also been implicated in some cases. The frequency of infection due to these pathogens is not certain. Chronic bronchitis generally is defined as a condition characterized by cough and excessive secretion of mucus in patients who have coughed up sputum on most days during 3 consecutive months for >2 successive years. This disease is caused by prolonged exposure to pulmonary irritants, the mostprominentof whichis cigarette smoke.Atmospheric pollution also playssome role, as do recurrent episodes of infection. Chronic bronchitis results in widely ranging degrees of respiratoryembarrassment. In its most severe forms, obstructive pulmonary disease, emphysema, and respiratory failure occur. Patientswith chronic bronchitis frequently experienceepisodes of acute disease superimposedon the chronic process. These exacerbationsare characterized by some combination of increasing cough, sputum volume and purulence, and respiratory distress. The role of infectionin these episodes has been difficult to define. The bacterial speciesmost oftenmentioned as potential etiologic pathogens include S. pneumoniae, typable(especially typeB)and nontypable H. irfiuenzae, and M. catarrhalis. However, the same organisms, particularly Haemophilus species, can be isolated from the respiratory secretionsof patientswith chronic bronchitiswho do not present with evidence of acute exacerbation [bib_ref] Management of acute and chronic respiratory tract infections, Ellner [/bib_ref]. Gump et al. did report an association between purulence of sputum and an increase in the number of pneumococciin the sputum em 1992;15 (Suppl 1) of patients with acute exacerbations [bib_ref] Role of infection in chronic bronchitis, Gump [/bib_ref]. Haemophilus parainfluenzae, viridans streptococci, and strains of Enterobacteriaceae also are isolated from patients with acute exacerbations of bronchitis, but their pathogenic role is even less welldefined. Viruses, M. pneumoniae, C. pneumoniae, andperhapsLegionella speciesplayan etiologic role in some cases of acute exacerbations. ## (a) scope of guideline The only clinical entity included in this guidelineis acute exacerbation of chronic bronchitis. ## (b) standards of care for acute exacerbations of chronic bronchitis Considerable controversy surrounds the use of antibacterial agents for patientswith acute exacerbations of chronic bronchitis [bib_ref] Erythromycin in the treatment of acute bronchitis in a community practice, Brickfield [/bib_ref] [bib_ref] A placebo-controlled, double-blind trial of erythromycin in adults with acute bronchitis, Dunlay [/bib_ref]. Tager and Speizer [bib_ref] Role of infection in chronic bronchitis, Tager [/bib_ref] reviewed the existing studies in 1975 and concluded that the role of antimicrobial agentsin the management of these patients needed reassessment and that respiratory infections appeared to contribute to worsening of episodesof coughand productionof sputum. A recent double-blind randomizedplacebo-controlled study by Anthonisen et al. [bib_ref] Antibiotictherapy in exacerbations of chronic obstructive pulmonary disease, Anthonisen [/bib_ref] showed a significant clinicalbenefit in association withantibacterial therapy. The recovery of peak air flow wasmore rapid and the rate of clinicaldeteriorations requiring therapeutic intervention was lower in antibiotictreatedpatients. Response to treatment wasevidenced by the trilogy of decreased dyspnea, sputum volume, and sputum purulence. Treatment success wasdefined as resolution within 21 days of all symptoms that accompanied the exacerbation. No attempt at microbiologic confirmation wasperformed in this study. Antibacterial agentsutilizedin thetreatmentgroup included trimethoprim-sulfamethoxazole, amoxicillin, and doxycycline. Althoughcontroversy aboutpossiblemicrobialpathogenesis persists, most clinicianselect to treat the acute exacerbations as infectious events and direct that therapy at S. pneumoniae andH. influenzae and, morerecently, at M. catarrhalis. The duration of therapy is generally 7-10 days. It should be recognized that up to 25%of strains of H. influenzae and 50%-70% of M. catarrhalis strains produce (3-lactamase. ## (c) future trends The etiologicrole of viruses, M. pneumoniae, C. pneumoniae, and Legionella in acute exacerbations of chronic bronchitis needs clarification. Determination of their role will be facilitated by the application of more sensitive and specific microbiologic diagnostic techniques (e.g., nucleic acidprobes, polymerase chain reactions, antigen detection). ## Clinical definitions of the disease ## (a) general definition Patients eligible for study will primarily be adults with symptoms and signscompatible with acute exacerbations of chronic bronchitis. ## (b)minimal diagnostic criteria permitting inclusion in trials (1) Clinical criteria. Patients must (a) havehad a chronic cough and sputumproduction for >2 consecutive years and on mostdaysfor 3 consecutive monthsand (b) haveevidence of acute exacerbation as indicated by some combination of increasedcough and/or dyspnea, increased sputumvolume, or increased sputum purulence. (2) Microbiologic and other laboratory criteria. These criteria include (a) negative chest roentgenogram to rule out pneumonia; (b) productionof purulent sputumas defined by the presence on a gram-stainedpreparation of >25 polymorphonuclear leukocytes and <10 squamous epithelial cells per low-power magnification (X 10) field(thepresenceofpredominant bacterialmorphology maybe noted); (c) documentation of the presence or absence of potential bacterial pathogens and monitoringof emergenceof resistant isolates during antimicrobial therapyby sputumcultureand susceptibility tests. ## Information needed before conducting clinical trials in humans The drug under consideration should have provenin vitro activityagainstS. pneumoniae, H. influenzae, and M. catarrhalis. Dosage ofthe studydrugmustbe determined by means of pharmacokinetic and in vitro studies. ## Special qualifications of investigators and institutions The investigator or subinvestigator shouldhavethe necessary skills to assesspulmonary functionand interpret radiographicstudies. The institution shouldhave adequate facilities for performance of laboratorystudies, including hematologic, hepatic, andrenalfunction testsandstudies ofpulmonary function, especially arterial blood gas analysis, forced vital capacity, FEV! (forcedexpiratory volumein 1 sec), total lung capacity, and peak flow spirometry.. Design and Implementation of Phase 1, 2, and 3 Clinical Trials ## (a) demographic characteristics of the study population Onlyadultpatients(~18 years)with stablechronicpulmonary disease should be included. ## (b) inclusion and exclusion criteria Patients who are experiencing an acute exacerbation of chronic bronchitis are eligible. Patients with cystic fibrosis, patients unable to give informed consent, and patients with a known history of hypersensitivity to the study or control drug should be excluded. Steroid use is not necessarily a criterion for exclusion. ## (c) selection of the comparison drug Even though the use of antibacterial agents for treatment of acute exacerbations of chronic bronchitis is controversial, the presence of S. pneumoniaeand other potential pathogens in some patients and the concomitant need for corticosteroids in some patients suggest the need for an active control drug. Both control and study drugs should be active in vitro against S. pneumoniae, H. influenzae type b, and M. catarrhalis. Placebo-controlled trials may be conducted. ## (d) study design and stratification In phase 1 studies, human pharmacologic and pharmacokinetic studies should demonstrate sufficient absorption and achievement of peak serum concentrations that exceed the MIC90 for the major respiratory pathogens. In phase 2 and 3 trials, study patients should be stratified according to major host factors (e.g., history and duration of smoking). Whenever feasible, studies should be prospective, randomized, and of double-blind design. No additional antimicrobial agent is permitted. Concurrent medications (e.g., bronchodilators) should be administered in the same manner to study and control groups. The study patients may be stratified according to the use of concomitant steroid therapy. Another strategy might be to design a four-arm randomized comparison: (1) study drug with steroids; (2) control drug with steroids; (3) study drug with no steroids; and (4) control drug with no steroids. In projecting a sample size, consideration must be given to the expected difference in efficacy of the study and control regimens and the desirability of undertaking poststudy subset analysis of pertinent patient variables. Variables include (1) the presence or absence of adjunctive treatment; (2) the presence or absence of fever; (3) status of pulmonary function; and (4) characteristics of sputum. ## (e) administration of the study drug Duration oftreatment is generally 7-10 days. However, the optimal duration of therapy could be a main focus of evaluation. In comparative studies, patients should be assigned randomly to the test or "control" group, and insofar as possible, the study should be blinded. ## (j) modification during conduct of the study For patients who do not demonstrate clinical improvement (i.e., decreased dyspnea, cough, and volume and purulence of sputum production) or whose clinical conditions worsen after 3-5 days of treatment, clinical failure will be declared and such patients will be removed from the study. The addition of an antimicrobial agent that is not a study drug will also result in a designation of clinical failure. ## (g) evaluability Clinical response and results of pulmonary function tests and/or arterial blood gas analyses can be used to assess efficacy. The effect of treatment on sputum microbiology will be monitored. Failure to eradicate a potential pathogen in a patient with a complete clinical response is common in this disease. The bronchial secretions of many patients remain "colonized" after the acute episode resolves. All patients entered into the study should be assessed on the basis of intent to treat. The clinical response in both the study and control group will be classified as (1) clinical cure, (2) clinical improvement (which requires measurement of an objective end point, e.g., volume and/or purulence of sputum), (3) clinical failure, and (4) indeterminate. Patients will be evaluated at 3-5 days after initiation of treatment, and weekly thereafter. (1) Definitions ofclinical response. Clinical cureis the resolution of acute symptoms and signs to a baseline level of dyspnea, cough, sputum production, and, if elevated at enrollment, resolution of fever. Clinical improvement is the subjective improvement in dyspnea, with reduction in cough, a quantified reduction in 24-hour volume or purulence of sputum, and a return of the temperature to normal if the patient is initially febrile. Clinicalfailure is the lack of any resolution in the magnitude of the dyspnea, sputum purulence, or fever (if present) that prompted enrollment of the patient in the study. Clinical response indeterminate should be substantitated by stated reasons. The clinical response definition may be supported by improvement or lack of improvement in sequential measurements of the patient's white blood cell count, oxygen saturation, and/or pulmonary function tests. (2) Definitions ofmicrobiologic response. The categories of microbiologic response commonly encountered include eradication, persistence, relapse, reinfection, and superinfection Consult General Guidelines, section XIII.C, for detailed definitions. ## Summary of guidelines ## (a) baseline assessment (1) Initial history and physical examination should be performed just before enrollment. (2) Chest radiography should be performed to rule out pneumonia. (3) Hematologic, hepatic, renal, pulmonary function, and arterial blood gas studies (with room air) should be performed. (4) Gram stain and ern 1992;15 (Suppl 1) culture of sputum plus determintion of 24-hour sputum volume should be performed; nucleic acid probes and culture for Mycoplasma and Legionella may be included. ## (b) assessment during course of therapy (1) At a minimum, patients should undergo clinical evaluation 3-5 days after initiation oftherapy and weekly thereafter until completion of therapy. (2) For febrile patients the body temperature should be determined a minimum of four times daily. (3) Quantitation of the volume of sputum produced daily and/or daily assessments of the degree of sputum purulence may assist in assessment of the patient's clinical response. [bib_ref] Streptococcal pharyngitis, Tanz [/bib_ref] It is helpful to monitor patient's arterial blood gases and/or expiratory flow rates at periodic intervals. The precise frequency depends on the individual protocol (e.g., every 3-5 days for hospitalized patients and perhaps once during therapy for outpatients). (5) Repeated chest radiographic, hematologic, hepatic, and renal studies are appropriate at 3-5 days after treatment has begun and within 48 hours after the end of treatment. (6) A sputum culture during therapy is indicated if there is evidence of clinical failure. In individual patients, such cultural data may be useful in identifying the emergence of bacterial resistance or in documenting failure to eradicate a potential bacterial pathogen (e.g., S. pneumoniae). ## (c) assessment after completion of therapy and follow-up Patients should undergo clinical and microbiologic assessment within 48 hours, 7-14 days, and 21-28 days after completion of therapy. The clinical assessment should include assessment of cough, dyspnea, sputum volume, and sputum purulence. Oximetry to determine oxygen saturation and spirometry should be performed. A chest radiograph is not required unless clinically indicated, since the presence of a pulmonary infiltrate precludes enrollment. Sputum should be submitted for gram staining, culture, and sensitivity testing, or-in the case of mycoplasma or legionella infections -for nucleic acid probe tests. ## E. infectious pneumonia # Background Lower respiratory tract infections include bronchitis, bronchiolitis, and pneumonia and its complications. The relative frequency of isolation of various etiologic agents that cause community-acquired pneumonia differ according to age group, socioeconomic status, underlying disease, time of year, and possible concomitant viral illnesses. Prospective studies of the causes of community-acquired pneumonia are often difficultto interpret because of imprecise methods of microbio-logic diagnosis, such as reliance on sputum culture and/or serologic testing. However, it is generally accepted that in North America viral agents (e.g., respiratory syncytial virus and parainfluenza virus type 3) are most important for children <5 years of age. The inability to obtain sputum from infants and children is a major deterrent to microbiologic diagnosis of pneumonia in this population. M. pneumoniae is considered to be a major cause of community-acquired pneumonias in North Americans 5-25 years of age. In older individuals, mycoplasmas and viruses are less common causes, while bacterial agents are more prevalent. A majority (50%-90%) of cases of pyogenic pneumonia with acute onset in middle-aged or older adults are due to S. pneumoniae [bib_ref] Prospective study of the aetiology and outcome of pneumonia in the community, Woodhead [/bib_ref]. Pneumonias due to H. injtuenzae (either ampicillin-susceptible or ampicillin-resistant), S. aureus, mixed aerobicanaerobic bacteria, and aerobic facultative gram-negative bacilli such as Klebsiella pneumoniae, in rank order, are less common. Legionella species, (determined primarily on the basis of serologic studies) account for a variable proportion of cases of community-acquired pneumonia in adults (e.g., in 1% of patients not requiring hospitalization and in 5 %-20 % of those hospitalized). Legionella species probably account for 10%-15 % of cases of so-called atypical pneumonia [bib_ref] Howcommonis legionnaire's disease?, Anonymous [/bib_ref]. Other agents that cause nonpyogenic, or atypical, pneumonia include M. pneumoniae, C. bumetii, C. pneumoniae, and, rarely, Chlamydia psittaci. In classic pneumonias, the isolation of certain pathogens can often be linked to certain specific conditions of the host (e.g., infection with group A ,6-hemolytic S. pyogenes, S. aureus, H. irfiuenzae, or S. pneumoniae following influenza). Both typable and nontypable strains of H. influenzae are pathogenic primarily among smokers, patients with chronic obstructive pulmonary disease (COPD), and some patients with lymphoma or other malignancies. Aspiration pneumonia in the community is believed to involve mostly the normal oropharyngeal aerobic and anaerobic flora. In the nursing home or nosocomial setting, infections with aerobic gramnegative bacilli and S. aureus are additional considerations in aspiration pneumonia. Data for nosocomial pneumonias prior to 1988 from the Centers for Disease Control (CDC) may not be completely reliable because they appear to be based primarily on results of sputum cultures and cultures of endotracheal suction specimens. Nonetheless, the rank order of pathogens in the last reported CDC survey of nosocomial infections is Pseudomonas aeruginosa (16.9%), S. aureus (12.9%), Klebsiella species (11.6%), and Enterobacter species (9.4%), followed by Escherichia coli, Serratia marcescens, and Proteus species [bib_ref] NationalNosocomial Infection Studyreport. Annual summary, Diseasecontrol [/bib_ref] [bib_ref] Hospital-acquired pneumonia, Pennington [/bib_ref]. Data based on the results of transtracheal aspiration performed on members of a high-risk population of elderly men in a Veterans Administration hospital and nursing home in the 1970s give a different perspective on nosocomial pneumonia. Bartlettet al. [bib_ref] Bacteriology of hospital-acquired pneumonia, Bartlettjg [/bib_ref] relied only on isolates from blood cultures, pleural fluid, andtranstracheal aspirates. They found gram-negative bacilliin about one-halfof 159 patients studied, anaerobes (Peptostreptococcus species were the most common isolates) in about one-third, and S. pneumoniae in about one-fourth. Klebsiella species were the most commonly isolated gram-negative aerobic bacilli. The isolates were polymicrobial in about one-half of the patients. Gram-negative bacilli are morelikely to be involved in nosocomial pneumonia in high-risk populations, such as those in intensive care units, than in other patients. Outbreaks of nosocomial pneumonia dueto someorganisms, including aerobic gram-negative bacilli and organisms not usually appreciated as nosocomial pathogens, may present particular problems. Thelattergroupincludes S. pneumoniae, ampicillin-resistant H. infiuenzae, and M. catarrhalis [bib_ref] A nosocomial outbreak of ampicillinresistant Haemophilus influenzae type b in a geriatric..., Pattersonje [/bib_ref] [bib_ref] A nosocomial outbreak of Branhamella catarrhalis confirmed by restriction endonuclease analysis, Pattersontf [/bib_ref]. The timely use of appropriate systemic antibacterial therapyshould eradicatethe pathogen in a largenumberof cases of pneumonia and lead to a reduction in morbidity as well as mortality. Efficacy ofnewagents should at leastequalthose of established regimens when evaluated in prospective, randomized, controlled trials (active treatmentconcurrentcontrol) [bib_ref] Theclinicalevaluation of antibacterial drugs, Britishsocietyof Antimicrobial [/bib_ref] [bib_ref] Guidelines for evaluating new antimicrobial agents, Gilbert [/bib_ref]. If l3-lactamase-producing pathogens are suspected (e.g., H. influenzae), both the study and control drugs should have in vitro activity against such pathogens. Theefficacy ratesfora newdrug for etiologic agents andclinicalsyndromes in which thereis noestablished therapy should at least equal those in recent historical controls. Data from open studies may be useful in these instances. Dataobtained frompartsoftheworldotherthanthe United States may be considered supporting evidence of efficacy. However, possible regional differences in resistance patterns mustbe notedandmay preclude directcomparison (e.g., appreciably higher resistance to penicillin G among S. pneumoniae strainsisolated in South Africa and to erythromycin in Spain than in North American isolates). The local antimicrobial susceptibility patterns will clearlybe the predominant influence on the choice of concurrentactive treatment control regimens. ## (a) scope of guideline (1) Clinical entities to be included are common communityacquired or nosocomial bacterial pneumonias. Clinical entities not included are bronchitis, bronchiolitis, lowerrespiratory tract infections in patients withcystic fibrosis, lowerrespiratory tract infections caused by infrequent and/or difficultto-diagnose entities (e.g., infections withanaerobic bacteria; psittacosis, Qfever, tularemia, andplague; andinfections with mycobacteria, viruses, or fungi). (2) Microorganisms included in the guideline are S. pneumoniae (prototype), H. injluenzae, S. aureus, facultative aerobic gram-negative bacilli, Pseudomonas species, M. pneumoniae, and Legionella species. ## (b) general principles of care for patients with infectious pneumonia The diagnosis of infectious pneumonia combines clinical, laboratory, andmicrobiologic data. A compatible clinical picture (fever, cough, and/orauscultatoryfindings such as rales and/or evidence of pulmonary consolidation) together with confirmatory chestradiographic findings and isolationof the causative pathogen(s) from suitable respiratory specimens (e.g., expectorated sputum, transtracheal aspirate,bronchial washings or lavage, pleuralfluid) or bloodestablishes the diagnosis of bacterialpneumonia. Pneumonia due to M. pneumoniae is identified by culture or nucleic acid probe and/or by documentation of a fourfold or greater rise in titer of complement-fixing antibody. Detection of cold agglutinins does not establishthe diagnosis. The diagnosis of legionella pneumonia requires isolation of the organism from sputum, a bronchoalveolar lavage specimen, pleural fluid, or blood. Alternatively, Legionella antigen may be detected by immunofluorescence in respiratory secretions or byradioimmunoassay in urine. Also, Legionella maybe detected in respiratorysecretions withnucleic acidprobes. Testing forantibody in acute-and convalescent-phase sera, except for antibody to L. pneumophila serogroup 1, is not specific enough for reliablediagnosis oflegionellosis, especially in areas of lowdisease prevalence. Diagnostic methods for detection of C. pneumoniae are under development. The bacterialpathogens isolated shouldbe tested for susceptibility to antimicrobial agents by standardized methods. Determinations of MBCs, postantibiotic effect, or effect of subinhibitory concentrations of antibiotics are notdone routinely andare notgenerally required forassessment of efficacy. When Mycoplasma or Legionella is isolated, antimicrobial susceptibility testing is not done routinely. Selection of empiricantimicrobial therapy is based on the suspected pathogens and their anticipated susceptibility in vitro. Penicillin G remainsthe drug of choice for almostall S. pneumoniae infections in the UnitedStates. Ampicillin or a cogeneris the drug of choice for pneumonia due to non-Sdactamase-producing H. injluenzae. Aspiration pneumonia acquired in the community is treated with penicillin G, usually without the benefit of culture results. A lincosamide or a combination of a penicillin and a 13-lactamase inhibitor are alternatives. A macrolide (e.g., erythromycin) or tetracycline is preferred forpneumonia dueto M. pneumoniae or C. pneumoniae, and erythromycin is the choice for legionella infections [bib_ref] Acute pneumonia, Donowitz [/bib_ref]. A semisynthetic penicillinaseresistantpenicillin is the treatment of choicefor pneumonia dueto methicillin-sensitive S. aureus. A combination ofa suitable cephalosporin or penicillin and an aminoglycoside is frequently employed for infections due to facultative gramnegative rods or to Pseudomonas. In most other instances of community-acquired pneumonia, combination therapy is usually not required. Oral preparations of the aforementioned parenteral compounds or oral drugs with comp~able in vi.tro activity can be used in milder cases. The optimal duration of therapy varies, but uncomplicated S. pneumoniae pneumonia is usually treated for 7-10 days. For treatment of nosocomial pneumonias (e.g., associatew ith ventilator use), combination therapy with an extendedspectrum penicillin or cephalosporin and an aminoglycoside is commonly employed. Initial therapy must be directed at the suspected pathogens in a given hospital and their known susceptibility profile. Determination of the concentration of antimicrobial agent(s) in serum, other bodily fluids, or tissues is not done routinely. Most often, cure is defined by clinical criteria alone. With resolution of the inflammatory process, the patient is unable to provide secretions from the lower airway for documentation of eradication of the causative pathogen. Patients requiring tracheostomy or endotrachĩ ntubation may have persistent, presumably tracheal, colomzation with an etiologic organism after the criteria for clinical cure of pneumonia are met. Relief of endobronchial obstruction and/or drainage of empyema fluid remains a mainstay of therapy for lower respiratory tract infections. The probability of cure for S. pneumoniae pneumonia is variable and ranges from 95 % in uncomplicated infection to (\)50%-80% with bacteremic disease. Relapse is not a significant problem with S. pneumoniae. ## (c) future trends Newer methods for more precise microbiologic diagnosis of pneumonia, such as the use of semiquantitative cultures of protected endoscopic brushings or bronchoalveolar lavage specimens, are promising.· The practice of changing parenteral therapy to therapy with an oral agent such as a fluoroquinolone after 5-7 days is gaining increasing acceptance, as is the use of intravenous antimicrobial therapy in the home for follow-up management. It is likely that the number and precision of diagnostic techniques that rely on antigen detection or nucleic acid detection will increase. ## Clinical definitions of the disease ## (a) general definition Patients eligible for study are adults and children of both sexes with confirmed or presumptive diagnosis of communityacquired or nosocomial pneumonia. These guidelines may be adapted to treatment of patients in either a hospitalized or ambulatory setting or for patients that progress from hospital to an outpatient setting. ## (b) minimal diagnostic criteria permitting inclusion in trials (1) Clinical criteria. Patients must have signs and symptoms consistent with bacterial pneumonia (chest pain, cough, and/or ausculatory findings such as rales and/or evidence of pulmonary consolidation) with or without fever (oral temperature >38°C [100.4OF]) or leukocytosis (blood leukocyte count >10,000/mm 3 or >15% band forms), and there must be radiographic or other laboratory evidence that supports the diagnosis (see below). (2) Microbiologic and otheretiologic (noncultural) criteria. Specimens obtained by expectoration or by endotracheal aspiration should be screened microscopically for suitability of culture (presence of >25 polymorphonuclear leukocytes and <10 squamous epithelial cells/low-magnification field [x 10]). Suitable specimens should be cultured aerobically in appropriate media. Blood specimens should be cultured for all patients, and pleural fluid, if present, should be aspirated, examined by microscopy, and cultured for both aerobes and anaerobes. The microbiologic diagnosis of infectious pneumonia is confirmed by the following criteria: (a) Purulent expectorated sputum-identification of a predominant suspected pathogen by culture and/or microscopy (e.g., with S. pneumoniae by finding an average of >10 lancetshaped diplococci/oil-immersion field [X 1,000] for 10 fields examined) (material from endotracheal suctioning may also be used, and slides should be saved and made available as part of the case record) or (b) transtracheal aspirate, bronchial brushings, or biopsy material (obtained under direct visualizationwith a fiberopticbronchoscope, preferablydoublesheathed) -gram stain reveals neutrophils and a predominant pathogen is suspected by smear or culture; quantitative cultures of endobronchial brushes from potentially infected ventilator-dependent patients may be of value; (c) pleuralfluid or direct lungaspirateidentification of a predominant pathogen on gram stain or by culture; (d) positiveblood cultureyields a pathogen in a patient with a compatible clinical syndrome of bacterial pneumonia in the absence of another source of bacteremia. Ifan organism is isolated, it should be susceptible to both the study and the control drug. Clinical improvement or stabilization must be documented by 72 hours to permit retention in the study. (e) Surrogate markersdetection of antigen or specific nucleic acid by non-culture methods may be used as a surrogate marker of infection. Culture or other non-cultural methods for confirmation ofthe diagnosis of pneumonia must follow within 24-72 hours of starting therapy to retain the patient in the study. Isolation by culture is not required for the diagnosis of pneumonia due to M. pneumoniae, Legionella, or C. ## Information needed before conducting clinical trials in humans ## (a) in vitro studies See General Guidelines, section II.D. ## (b) in vivo studies Use of accepted animal models for pneumoniacaused by specific pathogens is desirablefor evaluations of dosage, duration of therapy, achievable serum concentrations, and comparisons with other agents for efficacy and relative toxicity, as described in General Guidelines, section II.E. Determinations of levels of antimicrobial agents in respiratory tract secretions and tissue are optionalsince there is a lack of accepted interpretation of results ## Special qualifications of investigators and institutions Physicians should be available who are competent in the following procedures: bronchoscopy, endobronchial protectedbrush sampling, bronchoalveolar lavage, and thoracentesis. In addition to standard clinical microbiology, the laboratory should have access to nucleic acid probes for detection of Legionella and Mycoplasma, detectionof Legionella species antigen, and determination of titers of specific antibody to Mycoplasma and Legionella. ## Design and implementation of phase 1, 2, and 3 clinical trials ## (a) demographic characteristics of study population For most studies, adults (18-65 years of age) and elderly patients (~65 years of age) will be the prototype groups to be studied. Additional potential study populations are neonates, infants, children, and immunosuppressed patients. ## (b) inclusion and exclusion criteria Male andfemale patients willbe included. Pregnantor lactating women will be excluded. Patientswith severeunderlying diseases (e.g., AIDS, metastatic tumor, shock) will be excluded. Patients are excluded if they have received prior therapy witha potentially effective anti-infective agentfor~24 hours. See GeneralGuidelines, sectionIX, for additional details. ## (c) selection of the comparison drug It is notconsidered ethical to usea placebo control in studies evaluating the efficacy of a new anti-infective drug for treatment of pneumonia. Active or historical controls are needed to assess the relative value ofthenewdrug. Thehistoricalcure rate of uncomplicated (nonbacteremic) pneumonia due to S. pneumoniae in healthy hosts is 1'\J95 %. Whenever feasible, the use of a control drug is desirable. The control anti-infective agent should be a drug, or one of several drugs, approved for pneumonia and still recognized by authoritative publications as "standard" treatment. Other considerations are discussedin the General Guidelines, section X. ## (d) study design Whenever possible, the study design shouldbe randomized, prospective, and double-blind. See General Guidelines, sections X and XI, for details. ## (e) patient selection and stratification The spectrumof organisms that causepneumoniais the result of the interplay of multiplehost factors and environmental factors. Only somedeterminant factors in the host-parasite relationship are understood, e.g., the presenceor absence of oropharyngeal binding sites for microorganisms, patientage, immune status prior to infection, aspiration of oropharyngeal secretions, concomitant chronic diseases and/or organ failure, or damageto nonspecific or specific portions of the host defenses against microbial invasion. In a given patient, one or more factors may apply. (1) Community-acquired vs. hospital-acquired pneumonia. Thetraditional distinction between community-acquired and hospital-acquired pneumonia has blurred. Traditional community-acquired pathogens, such as S. pneumoniae or L. pneumophila, are now recognized as causes of hospitalacquired pneumonia. Patients with chronic diseases, e.g., lung, heart, renal, and/or hepatic failure, are cared for with increasing frequency outside of the hospital. These disease statesincrease the likelihood of colonization ofthe oropharyngeal secretions with facultative gram-negative bacilli and, hence, increase the risk of pneumonia due to this class of organisms traditionally associated withnosocomial pneumonia. (2) Patient selection based on clinical category. Because of this blurring between community-and hospital-acquired pneumonia, it is reasonable to select patients as trial candidateson thebasisofthe clinical picture. The greaterthehomogeneity of the randomized population of patients with pneumonia, the greaterthe likelihood thetrial results willhave clinicalimport. Somepatientsmay fit in more than one category. Suggested categories for patients with pneumoniaare presented in table 5. By necessity, the categories are arbitrary and will requireperiodic revision as new insights into pathogenesisemerge. In clinicaltrials ofpatientswhopresent with signsand symptoms of atypical pneumonia, mostpatients enrolled will be ambulatory. In trials of acute bacterial pneumonia, mostpatients willbehospitalized. Atthetimeofpatient For statistical considerations, it is strongly recommended that patients be stratified into no more than three clinical categories of pneumonia. For example, in a comparative trial of two parenteral drugs with an appropriate spectrum of activity, patients could be categorized in one of three categories, i.e., acute bacterial pneumonia, aspiration pneumonia, or respirator-associated pneumonia, and then randomized. Subsequent to the end of the study, patient response can be analyzed by type of infecting organism, presence of organ failure, severity of pneumonia, and other factors. Alternatively, a trial may be designed to study the response of only those patients who meet the clinical criteria for atypical pneumonia. In this example, no stratification would occur prior to randomization. (3) Compromised host. Pneumonia, and other infections in the compromised host, is discussed in detail in the guide-lines on infections in the febrile, neutropenic patient. The compromised host mayor may not be neutropenic, have inadequate immunoglobulins, or exhibit abnormal lymphocyte function. A wide variety of opportunistic pathogens cause pulmonary infection in the compromised patient. Development of a pulmonary infiltrate in a patient with a hematologic malignancy (e.g., leukemia or lymphoma) is a grave prognostic sign and requires an urgent, aggressive, and carefully planned approach to diagnosis and management. For example, local signs of infection in patients who are neutropenic often are fewer and less severe than those in the non-neutropenic person. Frequently, neutropenic patients have distant sites of infection from which organisms may have disseminated to the lungs. No symptoms, signs, or roentgenographic features are specific for a given opportunistic infection in the compromised patient. Noninfectious pulmonary pathologic conditions are common in this population and may mimic infection. These include radiation pneumonitis, drug toxicity, involvement by the underlying malignancy, pulmonary hemorrhage, pulmo-nary infarction, and congestive heart failure. Concurrentand sequential infections of the lung are commonin this population, making the relationship of disease manifestations to a single pathogen difficult to ascertain. Early diagnosis is often critical for these patients. Guidelines used for diagnosis by examination of pulmonary infiltrates in healthy patients maynot be applicable for diagnosisin patients whoare compromised. For example, severely neutropenic patients may not have neutrophils in their sputum despite having significant bacterial or fungal pneumonia, and for some pathogens the sputum culture may be negative despitethe presenceof invasive lung infection (e.g., aspergillus pneumonia) ..The diagnosis of pulmonary infection in the compromised host may require the performance of an invasive procedure, e.g., percutaneous needle aspirationof the lung, transtracheal aspiration, bronchial lavage and brushingfor quantitative bacteriology, transbronchial biopsy, or open lung biopsy. Pneumonia in the compromised patient may be rapidly fatal-hence, the need for empiric antimicrobial therapy. In addition, it is oftennecessaryto reduce the dosageof the immunosuppressive therapeuticagent. Thus, the combinedexpertise of all involved physicians is desirable. ## (f) administration of the study drugs The duration of treatmentvaries with the clinical category of pneumonia, with the results of blood cultures, and with the status of host defenses. For acute bacterial pneumoniain noncompromised hosts, it maybe desirable to treat until the patient's temperature has returnedto and remained in the normal range for a specific period, e.g., 3-5 days. The possible routesof administration and conversion fromone routeof administration to another are discussed in the General Guideline, section XII. ## (g) modifications during conduct of the study See General Guidelines, section XII.F. ## (h) conduct of study Clinical evaluation is based on resolutionor improvement of clinicaland laboratory signsof infectionsuch as fever and leukocytosis, purulent sputumproduction, and radiographic lung infiltrates. Hospitalized patients will be assessed every day during treatment and within 5-7 days after completion of treatment. Bodytemperaturewill be measuredat least every 8 hours during treatment, and the peak temperature for eachdaywillbe recorded. Measurements ofvital signs(blood pressure, heart, and respiratory rates) will be obtained before enrollment and on each day at approximately the same time. The character of the sputum (color, consistency, volume, and number of neutrophils per low-magnification field [x 10D will be recorded when the patient enters the study and at regular intervals thereafter. Arterial blood gas determinations will be performed as clinicallyindicated. A chest radiographwill be obtained 3 days after initiationof therapy, within 72 hours of completion of therapy, and at any other time the investigator deems necessary. The location and extent of pneumonic involvement (e.g., segmental, lobar) and the presenceof pleural effusion must be notedand recorded. Whenever possible, the same radiologist (or a panel of radiologists) from the sameinstitutionshould interpret all radiographs. Other special radiographic studies (e.g., CT scan) will be obtained as clinically indicated. Repeated culturesof respiratory tract secretions,if obtainable, will be performed at48-72hoursafterinitiation oftherapy, within 72 hours of the completion of therapy, and whenever clinically indicated. Standardized susceptibility testing (disk diffusion or broth dilution) will be performed on all isolates considered potentially significant. Blood cultures will be repeatedif initially positiveor if the patient fails to respond to treatment. Collectionof specimens that require the use of semi-invasive techniques (e.g., collection of pleural fluid, transtracheal aspiration, bronchoscopy) should be repeated onlyif the clinicalresponseis suboptimal. Tests for surrogate markers will be repeatedif these were originally used for diagnosis. For all patients a posttherapy evaluation is necessary for collecting information that will assist in makinga precise assessmentof the patient's clinical and microbiologic response to therapy. Patients who have received at least 5 days of therapy and at least 80% or more of prescribed medicationwill have an assessment of clinical response. (1) Clinical cure is defined as complete resolution of all signs and symptoms of pneumonia and improvement or lack of progression of all abnormalities on the chest radiograph. [bib_ref] Streptococcal disease world-wide: present studies and prospects, Rotta [/bib_ref] Clinical failure is defined as anyof the following conditions: persistence or progression of all signs and symptoms after 3-5 days of therapy; development of new pulmonary or extrapulmonary clinical findings consistent with active infection; persistence or progression ofradiographic abnormalities; deathdue to pneumonia; or an inability to complete the study because of adverse effects. (3) Indeterminate indicates that extenuating circumstances preclude classification as cure or failure. (2) Definition of microbiologic response (1) Microbiologic eradication is defined as elimination of the original causative organism(s) from the same site (e.g., expectoratedsputumor normally sterile body fluids such as pleural fluidor blood)during or upon completion of therapy. (2) Presumed microbiologic eradication is defined as absence of appropriate material for culture (e.g., sputum or pleural fluid) for evaluation because the patient has improved clinically and does not produce sputum or because repeated aspiration of pleural fluid is not clinically justified. (3)Microbiologic persistence is defined as failure to eradicate the original causative organism(s) from sites previously listed, whether or not signs or inflammation are present. (4) Microbiologic relapse is defined as recurrence of pulmonary infection with the same organism(s) within 5 days after discontinuation of treatment or during treatment after two consecutive cultures have been negative. (5)Superinfection is defined as development of a new lower respiratory tract infection (documented by fever, chest radiograph, and/or auscultatory findings) during treatment or within 3 days after treatment has been completed that is due to a new or resistant pathogen not recognized as the original causative organism(s). (6) Colonization is defined as the development of a positive sputum culture that yields a bacterial strain other than the primary causative isolate that appears >48 hours after initiation of therapy, persists in at least two repeated cultures, and is not associated with fever, leukocytosis, persistence or progression of pneumonia, or evidence of infection at a distant site. (7) Eradication and reinfection is defined as elimination of the initial infecting pathogen followed by its replacement with a new species or with a new serotype or biotype of the same organism in sputum, pleural fluid, or blood in the presence of signs or symptoms of infection after completion of therapy. ## (8) presumed microbiologic persistence is defined as need for new or additional antimicrobial therapy because of continued infection at the original site in the absence of microbiologic data. (9) Indeterminate is defined as circumstances in which it is not possible to categorize the microbiologic response because of death and the lack of opportunity to perform further cultures, the withdrawal of the subject from the study before follow-up cultures can be obtained, incomplete microbiologic data, or concurrent treatment of the patient with a potentially effective anti-infective agent that is not part of the study protocol. The name of the agent and the dose and duration of this therapy must be recorded. The duration of therapy will affect decisions about patient evaluability and outcome. (10) Otherconsiderations-when more than one pathogen is present, a separate analysis must be made for each organism. ## Summary of guideline (a) Baseline Assessment [bib_ref] Comprehensive review of morbidity and mortality trends for rheumatic fever, streptococcal disease,..., Quinn [/bib_ref] Blood for initial cultures, respiratory tract secretions (sputum), and/or pleural fluid, and/or surrogate markers of infection will be obtained. A complete history and physical examination will be performed. (2) Tests of hematologic, re-nal, hepatic, and pulmonary function will be performed.Radiographic studies such as chest radiography or CT scanning will be performed. Arterial blood gas determinations and other tests, such as a diagnostic bronchoscopy, will be done if clinically indicated. ## (b) assessment during course of therapy (1) Culture of sputum will be repeated at 48-72 hours if available; blood cultures will be repeated at 48-72 hours if initially positive. Semi-invasive tests will be repeated only if there is a suboptimal clinical response. (2) Hematologic, renal, hepatic, and pulmonary function tests will be repeated on days 3-5 of therapy and at least every 5-7 days during therapy.Antimicrobial concentrations in blood will be determined if possible, but pharmacokinetic studies of respiratory secretions and other body fluids are optional. ## (c) assessment after completion of therapy and follow-up (1) If sputum is available, follow-up cultures should be done within 72 hours after completion of therapy. (2) Hematologic, renal, hepatic, and pulmonary function tests will be repeated at 72 hours after completion of therapy. (3) Chest radiography will be performed within 72 hours of completion of therapy, but other imaging (e.g., CT) and semi-invasive studies (e.g., bronchoscopy) will be performed only if the clinical response is suboptimal. ## (d) overall assessment Response to therapy will be judged by a combination of clinical and microbiologic criteria and analyzed by intention to treat. Clinical response is paramount. [fig] Financial: and Scope of Guidelines. . . . . . . . . . . . S64 B. General Principles of Care for Patients with Respiratory Tract Infections . . . . . . . . . . . . . . . .. S64 C. Controversies and Future Trends . . . . . . . . . . . . . S64 TI. GENERAL CONSIDERATIONS S65 A. Disease Definition . . . . . . . . . . . . . . . . . . . . . . . . . . S65 B. Preclinical Studies. . . . . . . . . . . . . . . . . . . . . . . . .. S65 C. Clinical Studies (Phases 1, 2, 3, and 4) . . . . . . .. S65 D. Qualifications of Investigators and Institutions . support: This work was supported by a contract to the Infectious Diseases Society of America from the Food and Drug Administration (no. HHS 223-88-1301). [/fig] [fig] S70 2: Clinical Definitions of the Disease. . . . . . . . . . . . . . .. S70 (a) General definition 570 (b) Minimal diagnostic criteria permitting inclusion in trials. . . . . . . . . . . . . . . . . . . . . . . . . .. S70 (l) Clinical criteria S70 (2) Microbiologic criteria. . . . . . . . . . . . . . . . . . .. S70 3. Information Needed Before Conducting Clinical Trials in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. S7 1 (a) Demographic charcteristics of the study population S71 (b) Inclusion and exclusion criteria. . . . . . . . . . . . . .. S71 (c) Selection of the comparison drug S71 (d) Study design and stratification S71 (e) Administration of the study drug [/fig] [fig] b: Standards of Care for Patients with Group A j3-Hemolytic Streptococcal Pharyngitis [/fig]	None	https://academic.oup.com/cid/article-pdf/15/Supplement_1/S62/20901064/15-Supplement_1-S62.pdf	Abstract These guidelines deal with the evaluation of anti-infective drugs for the treatment of respiratory tract infections. Five clinical entities are described: streptococcal pharyngitis and tonsillitis, otitis media, sinusitis, bronchitis, and pneumonia. A wide variety of microorganisms are potentially pathogenetic in these diseases; these guidelines focus on the bacterial infections. Inclusion of a patient in a trial of a new drug is based on the clinical entity, with the requirement that a reasonable attempt will be made to establish a specific microbial etiology. Microbiologic evaluation of efficacy requires isolation of the pathogen and testing for in vitro susceptibility. Alternatively, surrogate markers may be used to identify the etiologic agent. The efficacy of new drugs is evaluated with reference to anticipated response rates. Establishment of the microbial etiology of respiratory tract infections is hampered by the presence of “normal flora” of the nose, mouth, and pharynx, which may include asymptomatic carriage of potential pathogens. This issue is addressed for each category of infection described. For example, it is suggested that for initial phase 2 trials of acute otitis media and acute sinusitis tympanocentesis or direct sinus puncture be used to collect exudate for culture. Acute exacerbations of chronic bronchitis also present difficulties in the establishment of microbial etiology. These guidelines suggest that clinical trials employ an active control drug but leave open the possibility of a placebo-controlled trial. For pneumonia, the guidelines suggest the identification and enrollment of patients by the clinical type of pneumonia, e.g., atypical pneumonia or acute bacterial pneumonia, rather than by etiologic organism or according to whether it was community or hospital acquired. For each respiratory infection, the clinical response is judged as cure, failure, or indeterminate. Clinical improvement is not acceptable unless quantitative response measures can be applied.
07d9ffd208bb732386a21cad63061c3290e505f0	pubmed	World Federation for Ultrasound in Medicine and Biology Position Statement: How to Perform a Safe Ultrasound Examination and Clean Equipment in the Context of COVID-19	World Federation for Ultrasound in Medicine and Biology Position Statement: How to Perform a Safe Ultrasound Examination and Clean Equipment in the Context of COVID-19 # Introduction On March 11, 2020, the World Health Organization formally declared the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (also known as COVID-19) a pandemic. This has impacted the way health care facilities operate globally to ensure patient and practitioner safety and to minimize all risks associated with infection transmission. Ultrasound is a safe and essential tool for the diagnosis of a variety of medical conditions and for patient care. Bedside lung ultrasound has been invaluable in the treatment of the critically ill [bib_ref] Lung ultrasound in the critically ill, Lichtenstein [/bib_ref] [bib_ref] Is there a role for lung ultrasound during the COVID-19 pandemic?, Soldati [/bib_ref] and, specifically, for diagnosis of pneumonia in COVID-19 patients [bib_ref] Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The..., Gorbalenya [/bib_ref]. Ultrasound is increasingly used within the point of care setting, as chest computed tomography is often not available in emergency departments [bib_ref] Society and College of Radiographers; British Medical Ultrasound Society. Guidelines For professional..., Poggiali [/bib_ref]. Ultrasound may also be used for longitudinal monitoring of affected patients [bib_ref] Findings of lung ultrasonography of novel corona virus pneumonia during the, Peng [/bib_ref]. However, the ultrasound unit can be a potential vector in the transmission of an infection [bib_ref] Can diagnostic ultrasound scanners be a potential vector of opportunistic bacterial infection, Skowronek [/bib_ref] [bib_ref] The ultrasound unit and infection control -Are we on the right track?, Westerway [/bib_ref] , and previous surveys have indicated a gap in knowledge of basic infection prevention measures in ultrasound [bib_ref] Medical ultrasound disinfection and hygiene practices: WFUMB global survey results, Westerway [/bib_ref]. Because of the highly contagious nature of COVID-19 and given the proximity necessary to perform an ultrasound examination, it is essential to take all safety precautions when undertaking routine clinical activity. Several national and international guidelines for general precautions in ultrasound infection prevention have been published [bib_ref] British Society of Echocardiography. Guidelines for transoesophageal echocardiographic probe cleaning and disinfection..., Kanagala [/bib_ref] [bib_ref] Ultrasound transducer disinfection in emergency medicine practice, Hoyer [/bib_ref] [bib_ref] Guidelines for reprocessing ultrasound transducers. Australas, Basseal [/bib_ref] [bib_ref] Infection prevention and control in ultrasound -best practice recommendations from the European..., Nyhsen [/bib_ref] [bib_ref] Policy statement guideline for ultrasound transducer cleaning and disinfection, Liu [/bib_ref] , and some societies have developed and published cleaning guidelines on their websites, but not in peer reviewed journals (e.g., American College of Emergency Physicians, American College of Radiology, International Society of Ultrasound in Obstetrics and Gynecology and the American Institute of Ultrasound in Medicine). More recently, specific guidance documents for COVID-19 have also been published on various websites (e.g., ISUOG). There are also national and international guidelines for the performance of routine or targeted ultrasound investigation ( This statement has been written on behalf of the World Federation for Ultrasound in Medicine and Biology (WFUMB) Safety Committee as official guidance with the collaboration of experts from various affiliated federations. While this statement ensures that a consistent approach to infection prevention and safe ultrasound practices are implemented during the COVID-19 pandemic, there may be some operational and organizational differences at the local level. ## Purpose This statement provides guidance on equipment cleaning and safe performance of ultrasound examination within the context of COVID-19. It is relevant to all practitioners (sonographers, physicians and allied health professionals) using ultrasound for diagnostic imaging during the COVID-19 pandemic (e.g., obstetrics, gynecology, point-of-care ultrasound, accident and emergency medicine, pediatrics, critical care and cardiology). This statement has been written to protect both patients and health care workers, particularly when scanning suspected or confirmed COVID-19 patients. As the evidence base for COVID-19 is rapidly evolving, this document is current at time of publication, and further updates may be provided as new evidence emerges. ## Properties and spread of sars-cov-2 (covid-19) SARS-CoV-2 [bib_ref] Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The..., Gorbalenya [/bib_ref] , a small lipid-based enveloped virus belonging to the coronavirus family, is least resistant to inactivation by common disinfectants used in low-level disinfection (LLD) (see guidelines on Centers for Disease Control and Prevention and Environmental Protection Agency [EPA] websites). The structure of these viruses includes a lipid envelope, which is easily disrupted by most disinfectants such as 62%À71% ethanol, 0.5% hydrogen peroxide or 0.1% sodium hypochlorite within 1 min. Other biocidal agents such as 0.05%À0.2% benzalkonium chloride or 0.02% chlorhexidine digluconate are less effective. The virus is involved in human-to-human transmission of the COVID-19 pandemic [bib_ref] SARS-CoV-2 and COVID-19: The most important research questions, Yuen [/bib_ref] , and there are increasing reports of asymptomatic carriers of the disease [bib_ref] First case of 2019 novel coronavirus in the United States, Holshue [/bib_ref]. As such, ultrasound practitioners need to implement appropriate infection prevention measures not only with confirmed but also suspected COVID-19 patients. The transmission of COVID-19 is thought to occur mainly through respiratory droplets that are generated by coughing and sneezing and via contact with contaminated surfaces. Once infected droplets have landed on surfaces, their viability depends on the type of surface and temperature [bib_ref] Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents, Kampf [/bib_ref]. Survival on dry inanimate surfaces such as metal, glass and plastic (and ultrasound systems) is, as far as is known, between 48 and 96 h [bib_ref] Infection prevention and control in ultrasound -best practice recommendations from the European..., Nyhsen [/bib_ref] [bib_ref] Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents, Kampf [/bib_ref]. However, SARS coronavirus, Middle East respiratory syndrome coronavirus or endemic human coronaviruses have been shown to persist on fomites for up to 9 d [bib_ref] Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents, Kampf [/bib_ref] , and this is an important consideration for ultrasound equipment used in all clinical settings. Furthermore, viral ribonucleic acid has been found in stool samples from infected patients [bib_ref] First case of 2019 novel coronavirus in the United States, Holshue [/bib_ref] , and this is a vital aspect to consider for any ultrasound practitioners involved in transrectal ultrasound or scanning infants within the pediatric setting. ## Scheduling of patients (general recommendations) Non-essential examinations should be deferred or cancelled to minimize exposure of an at-risk group of patients to potential COVID-19 contact in the hospital environment. Acute situations may require immediate point-of-care or other ultrasound examinations (e. g., acute abdomen, motor vehicle accident etc.). All patients and visitors should be screened using standardized checklists for symptoms of acute respiratory infection, significant travel history, occupation, contacts, etc., consistent with recommendations of local authorities. Ideally, triage should be undertaken before the patient arrives to the ultrasound unit. ## Standard and transmission-based precautions for covid-19 Aspects that should be considered when planning to perform an ultrasound in a clinical care setting in the context of COVID-19 are: Triage of patients to routine (delay is possible) or emergent examination How to protect the patient and ultrasound providers (physicians, sonographers and allied professions) How to prepare and clean the ultrasound room and equipment Note: It is evident that some of these recommendations may not be applicable to all practices. Furthermore, it is understandable that some may not be achievable in some locations'. ## Triage of patients Generally, how to prioritize patients into emergency or urgent examination versus examination that can be postponed must be determined by local facilities/authorities (see above). Some scientific societies may already have such recommendations published or in press at the time of this document preparation . ## Protecting the patient and ultrasound practitioner Preventing transmission of infection requires all health care practitioners to implement both standard and transmission-based precautions, regardless of suspected or confirmed COVID-19. Standard precautions for COVID-19 as outlined by the CDC in 2020 include: 1. Ultrasound practitioners with specific health problems that place them at greater risk (as detailed by local occupational health guidelines) are to be excluded from performing ultrasound. 2. Ensure the ultrasound practitioners have undergone infection control training and fit testing for respirators, if required (for example N95 and FFP3). 3. To reduce the risk of transmission, it is important to (i) respect the time of scheduled visits, (ii) widen the appointment intervals to prevent crowding in the waiting room and (iii) space the seats in the waiting room to at least 6 feet (2 meters) apart. 4. Limit the number of visitors in the examination room to a maximum of 1, preferably with no children. During the pandemic, it is reasonable not to allow trainees or students to participate. Encourage use of alternative mechanisms for patient and visitor interactions such as video-call applications on cell phones or tablets. 5. If the status of a patient is confirmed as infected, it would be preferable to scan the patient at the end of the clinic list so that the equipment and room will undergo vigorous cleaning and disinfection (see below, Preparing and cleaning the ultrasound room)). 6. Hand hygiene: All ultrasound practitioners should perform hand hygiene before and after all patient contact, contact with potentially infectious material (e.g., linen from patient room) and before and after removing personal protective equipment (PPE), including gloves. Hand hygiene should be performed using an alcohol-based hand rub (60%À95% alcohol) or washing hands with soap and water for at least 20 seconds. If hands are visibly soiled, use soap and water before the alcohol-based hand rub. Latex-free disposable gloves should be used during the ultrasound examination and changed after each patient. 7. Scanning should, as much as possible, be performed with one (clean) hand and transducer while having the other hand semi-clean but in contact with the keyboard. Gel application should occur with the semiclean hand dispensing clean gel (see below), with post-procedure thorough cleaning of the gel bottle using an LLD. See details on gel use below (Specific recommendations regarding ultrasound gel). 8. If required to scan the patient in an isolation room, ultrasound practitioners, as all attending medical staff, should don PPE (respirator, goggles, face protective shield, surgical gown and gloves) before entry of isolation room, where the level of PPE is set by institutional guidelines. 9. PPE: Any reusable PPE (e.g., gowns) must be properly cleaned and decontaminated. Specific PPE recommendations when caring for a patient with suspected or confirmed COVID-19 infection include: a. Respirator or face mask: As ultrasound practitioners are in close contact with patients, surgical face masks are essential to offer protection. These must be put on before entry into the patient room or care area. N95 respirators or respirators that offer a higher level of protection should be used instead of a face mask when performing or present for an aerosol-generating procedure, particularly for use in the intensive care unit. It is important to perform hand hygiene after removal of the respirator or face mask. b. Eye protection (for ultrasound practitioners in the critical care setting): This includes goggles or a disposable face shield that must be put on when entering the patient room or care area. Reusable eye protection (e.g., goggles) must be cleaned and disinfected according to the manufacturer's reprocessing instructions before re-use. Disposable eye protection should be discarded after use. An individual risk assessment should be carried out before or at the time of providing care to the patient. c. Gloves: Wearing clean, non-sterile gloves upon entry into the patient room or care area is essential for all ultrasound practitioners. Once the ultrasound examination is complete, remove and discard gloves when leaving the patient room or care area and immediately perform hand hygiene. d. Gowns: Wearing a clean isolation gown upon entry into the patient room or care area is essential. Reusable gowns should be discarded in a dedicated container for linen and laundered. Disposable gowns should be discarded after use. If there are shortages of gowns, they need to be prioritized for aerosolgenerating procedures and high-contact patient care activities that provide opportunities for transfer of pathogens to the hands and clothing. e. Donning and doffing training: Workers who need to use protective clothing and equipment must be trained on how to put it on, use and wear it and how to take it off correctly, including in the context of their current and potential duties. Training material should be easy to understand and available in the appropriate language and literacy level for all workers. Information may be found on the European Centre for Disease Prevention and Control and the Occupational Safety and Health Administration websites. ## Preparing and cleaning the ultrasound room Note: Protective eyewear and gloves should be used when cleaning and disinfecting any equipment, and hand hygiene is essential after removing protective wear. The ultrasound room should be cleaned thoroughly each morning, and all content should be wiped with a compatible LLD recommended by the CDC and EPA, such as quaternary ammonium compounds (see Preparing and cleaning of ultrasound equipment). Items for disinfection include monitors, computer keyboard and mouse, stretcher rails, gel container, door handles, cabinet knobs, light switches, chairs and counter tops. Extra attention should be given to high touch surfaces which should be cleaned vigilantly. Unnecessary accessories in the room should be removed and, where possible, individually stored in the cabinets. Fabric-covered chairs should be replaced with hardsurface chairs that can be wiped. The patient bed or couch should be wiped by an LLD before replacing the disposable paper cover. The disposable paper cover should be removed with gloved hands and folded and disposed of immediately at the end of each examination. At the end of the day, soiled linen should be handled double-gloved and disposed of in the appropriate container. The room and equipment should undergo terminal cleaning using an LLD. Hands are to be washed for 20 seconds afterward. ## Preparing and cleaning of ultrasound equipment Note: Protective eyewear and gloves should be used when cleaning, disinfecting or sterilizing any equipment, and hand hygiene is essential after removing protective wear. If feasible, it is recommended to have one (or more) dedicated machine(s) for patients with suspected or confirmed COVID-19. Equipment should be cleaned using an LLD with agents recommended by the CDC and EPA (see websites); this includes the ultrasound equipment monitor and user interface (e.g., keyboard, knobs, track ball and touch screen). In emergency medicine, primary care and critical care, handheld ultrasound instruments are often used for COVID-19 infected (and other) patients because of ease of transport and seemingly easier cleaning methods, secondary to a simpler user interface. If possible, keep the whole device and phone in a sterile transducer cover sleeve, which is available commercially. An example of how to place the transducer and ultrasound instrument in a sheath can be found on the Butterfly website (See below table of various ultrasound manufacturers). The hardware should be cleaned with an LLD, and transducers should be cleaned and disinfected as detailed below. If available, equipment covers, such as for the ultrasound scanner console, will enhance the workflow, as LLD of mechanical keyboards and console controls is time-consuming. It is important to note that if the cover is contaminated, it must be cleaned, and the presence of a cover does not preclude the need for cleaning the equipment at regular intervals. Reduce the number of transducers connected to the ultrasound machine to a minimum. All other transducers should be individually stored safely in a clean, closed cabinet and brought out as needed. Ultrasound transducers and cables should be cleaned (see Transducer cleaning and disinfection), and this should also be performed after each scan. ## Transducer cleaning and disinfection Reusable medical devices are classified into three categories based on the Spaulding classification system depending on the procedure and risk, which includes non-critical, semi-critical and critical (also referred to as low risk, medium risk and high risk). a. Non-critical devices are ultrasound transducers that come into contact with intact skin; examples include transducers used for trans-abdominal, musculo-skeletal (MSK), vascular and lung ultrasound, etc. As the risk of infection transmission is low, ultrasound transducers can be cleaned and disinfected using an LLD or intermediate-level disinfection, which will denature most bacteria, some fungi and some viruses, such as COVID-19, influenza A and human immunodeficiency virus. b. Semi-critical devices are ultrasound transducers that come into contact with non-intact skin, blood, body fluids and mucous membranes; examples include vaginal, esophageal and rectal ultrasound transducers and those used in interventional procedures that are at risk of contact with body fluids. As the risk is higher for infection transmission, ultrasound transducers must be cleaned and disinfected using a high-level disinfection (HLD) method. A single-use transducer cover is mandatory. c. Critical devices are ultrasound transducers that are used for invasive procedures (e.g., needle guidance during biopsies, aspirations and drainages) and where there is a risk of blood or body fluid exposure. These transducers must undergo sterilization if compatible or, if not, must undergo HLD, as per medical facility guidelines. Use of sterile transducer covers is mandatory. Reprocessing ultrasound transducers requires 2 steps: cleaning followed immediately by disinfection. Any product used for cleaning or disinfection must be compatible with the ultrasound equipment as determined by the ultrasound equipment manufacturer. Certain products may damage ultrasound equipment or transducers and invalidate warranties. It is also essential to follow the instructions for use to ensure the entire process has been successful (e.g., maintaining "wet" contact time for chemical disinfection and accurate time for a soak solution). Furthermore, it is important to wear gloves for cleaning and disinfection of ultrasound transducers and to perform hand hygiene upon removal of gloves. In the context of COVID-19, the normal practices of HLD are not changed (i.e., endocavitary transducers still require cleaning followed by HLD). The only change in the context of COVID-19 is that all external probes must undergo cleaning followed by LLD to denature any presence of SARS-CoV-2 (e.g., transducers used for trans-abdominal scanning, lung ultrasound or in the pediatric or emergency department setting). It is important to note that the LLD for COVID-19 is approved for use on ultrasound transducers and has proven viricidal efficacy. Cleaning. Cleaning is an important first step because any remaining gel can act as a barrier to the disinfectant, thus diminishing its efficacy. The CDC defines cleaning as "the removal of foreign material (e.g., soil and organic material) from objects and is normally accomplished using water with detergents or enzymatic products." Ineffective cleaning before disinfection can limit the effectiveness of the chemical disinfection. Current recommendations for cleaning transducers are as follows (steps to be performed with disposable gloves): After cleaning, store transducer in a clean closet or its case with foam inset to prevent damage and protect from contamination with dirt, if not immediately re-used. ## Specific recommendations regarding ultrasound gel Ultrasound gel has been associated with numerous outbreaks and, in the context of the COVID-19 pandemic, it is recommended that single-use, non-sterile gel packets are used for any external ultrasound examination with a probable or confirmed COVID-19 patients. Any unused portion should be discarded. If these are not available, use gel bottles for external scans only. It is essential that gel bottles are not topped off, refilled or heated. The lid must remain closed, and the external gel bottle must be disinfected with an LLD as per all other ultrasound machine components. For any interventional, internal or critical procedures, as per normal safe scanning recommendation, only single-use sterile gel packets are to be used.	None	http://www.umbjournal.org/article/S0301562920301496/pdf	None
282d15d4046315cb3b5dcb1b7f18c5aa0f7af7c5	pubmed	International consensus diagnostic criteria for neuromyelitis optica spectrum disorders	International consensus diagnostic criteria for neuromyelitis optica spectrum disorders Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS. Neurology ® 2015;85:177-189 GLOSSARY ADEM 5 acute disseminated encephalomyelitis; AQP4 5 aquaporin-4; IgG 5 immunoglobulin G; IPND 5 International Panel for NMO Diagnosis; LETM 5 longitudinally extensive transverse myelitis lesions; MOG 5 myelin oligodendrocyte glycoprotein; MS 5 multiple sclerosis; NMO 5 neuromyelitis optica; NMOSD 5 neuromyelitis optica spectrum disorders; SLE 5 systemic lupus erythematosus; SS 5 Sjögren syndrome.Neuromyelitis optica (NMO) is an inflammatory CNS disorder distinct from multiple sclerosis (MS). 1,2 It became known as Devic disease following a seminal 1894 report. 3,e1,e2 Traditionally, NMO was considered a monophasic disorder consisting of simultaneous bilateral optic neuritis and transverse myelitis but relapsing cases were described in the 20th century. 3 MRI revealed normal brain scans and $3 vertebral segment longitudinally extensive transverse myelitis lesions (LETM) in NMO. 4,e3 The nosology of NMO, especially whether it represented a topographically restricted form of MS, remained controversial.A major advance was the discovery that most patients with NMO have detectable serum antibodies that target the water channel aquaporin-4 (AQP4-immunoglobulin G [IgG]), 5,6 are highly specific for clinically diagnosed NMO, and have pathogenic potential. 7,e4-e6 In 2006, AQP4-IgG serology was incorporated into revised NMO diagnostic criteria that relaxed clinical From the requirements by permitting unilateral optic neuritis or asymptomatic brain MRI lesions but retained the requirement for both myelitis and optic neuritis. [bib_ref] Revised diagnostic criteria for neuromyelitis optica, Wingerchuk [/bib_ref] The 2006 criteria were validated in several different ethnic and racial cohorts worldwide and became the standard for clinical and research purposes. The specificity of AQP4-IgG facilitated observations that further broadened the clinical and neuroimaging spectrum of NMO. In 2007, the term NMO spectrum disorders (NMOSD) was introduced to include AQP4-IgG-seropositive patients with limited or inaugural forms of NMO (e.g., first-attack LETM or recurrent or bilateral optic neuritis) who were at high risk for future attacks. [bib_ref] The spectrum of neuromyelitis optica, Wingerchuk [/bib_ref] The NMOSD term also encompassed the cerebral, diencephalic, and brainstem lesions that occur in a minority of patients with otherwise typical NMO. It also included AQP4-IgG-seropositive patients with coexisting autoimmune disorders (e.g., systemic lupus erythematosus or Sjögren syndrome . Finally, NMOSD potentially included patients diagnosed with opticospinal MS, an MS phenotype prominent in Asia and distinguished from Western MS. [bib_ref] Epidemiologic and clinical studies of multiple sclerosis in Japan, Kuroiwa [/bib_ref] Further advances have rendered the 2006 criteria inadequate for contemporary practice and research. Improvement in AQP4-IgG sensitivity has allowed for refinement of the list of nonopticospinal disease characteristics. Moreover, loss of AQP4 immunoreactivity and astrocyte pathology in brain and spinal cord NMO lesions distinguish them from MS lesions. e19-e23 Together, these data suggest that non-opticospinal clinical and MRI characteristics should be incorporated into the diagnostic criteria. The term NMOSD has also been used variably in the literature and needs clarification. [bib_ref] The history of neuromyelitis optica, Jarius [/bib_ref] Other outstanding issues include whether there are distinctive features of pediatric NMO, the current value of the term opticospinal MS, and whether monophasic NMO can be defined. Finally, treatment strategies for attack prevention in NMO and MS differ. Some MS immunotherapies appear to aggravate NMO, indicating an imperative for early, accurate diagnosis. The International Panel for NMO Diagnosis (IPND) was convened and charged with revising NMO diagnostic criteria for clinical decision-making and to address the ancillary issues outlined above. This report represents the Panel's consensus recommendations. METHODS The IPND consisted of 18 members from 9 countries and was led by 2 co-chairs (D.M.W., B.G.W.). It convened 7 times between October 2011 and November 2013. Panel members participated in 6 Working Groups: Clinical Presentation, Neuroimaging, Laboratory Studies/Serology, Pediatrics, Systemic Autoimmunity, and Opticospinal MS. Initial consensus was reached on 2 points. First, NMO would be subsumed into the single descriptive term NMOSD because the clinical behavior, immunopathogenesis, and treatment of patients who have NMOSD are not demonstrably different than for those with NMO and patients with incomplete forms of NMO frequently later fulfill NMO criteria. The entrenched and historically significant phrase NMO would be retained by using NMOSD because, although the criteria would be broadened to include patients with neither optic neuritis or myelitis, [bib_ref] Clinical features of neuromyelitis optica in a large Japanese cohort: comparison between..., Nagaishi [/bib_ref] those syndromes eventually occur in almost all patients. Second, revised criteria would define a clinical diagnosis by integrating clinical, serologic, and neuroimaging data; diagnosis would not be based solely on detection of AQP4-IgG. Moreover, the Panel concluded that criteria must define NMOSD in instances where AQP4-IgG serologic testing is negative or unavailable, especially because of the treatment implications. The IPND established several goals, chief of which was developing revised consensus NMOSD criteria using the best available evidence. The Clinical Presentation Working Group conducted the primary task of establishing the spectrum and validity of clinical syndromes described in clinically diagnosed NMO or in association with AQP4-IgG; these data were used to establish new core clinical criteria. The other Working Groups each addressed a roster of focused questions that would contribute to final diagnostic criteria. Each Working Group conducted a systematic literature review, with expert librarian assistance, to address its assignments. Medical subject heading terms were used when possible and MEDLINE, EMBASE, and other databases were searched from 1946-January 2012 with quarterly updates through January 15, 2014 (see table e-1 on the Neurology ® Web site at Neurology.org for search strategies and results). Two individuals independently reviewed abstracts for relevance; discordant ratings were resolved by consensus. Relevant full-text articles were independently rated to identify those used for data extraction. Publications describing sensitivity and specificity of AQP4-IgG were included if they compared groups diagnosed with clinical NMO and MS. The Clinical Presentation and Neuroimaging Working Groups compiled a list of clinical syndromes and MRI characteristics reported by more than one publication to be associated with NMOSD or AQP4-IgG. Panel members rated the specificity of these characteristics for NMOSD diagnosis using 2 electronic surveys. Two additional surveys presented adult case vignettes that contained information on clinical symptoms and signs (1-3 discrete clinical events) with brain MRI, AQP4-IgG serostatus, and other potential supportive criteria (optic nerve or spinal cord MRI findings) or laboratory results (e.g., CSF data, visual evoked potentials). Panel members assigned a diagnosis for each vignette: definite NMOSD, indeterminate (requiring further data or follow-up for confident diagnosis), or other (e.g., MS). A roster of potential supportive clinical, MRI, and laboratory criteria was separately ranked for their influence on confidence in NMOSD diagnosis. Characteristics or scenarios endorsed by a two-thirds Panel majority as contributing to a confident clinical diagnosis of NMOSD were used to develop separate requirements for AQP4-IgG seropositive and seronegative patients. Recommendations from individual Working Groups regarding pediatric NMOSD, opticospinal MS, systemic autoimmunity, and monophasic disease were summarized. All IPND members endorsed the final criteria. RESULTS Consensus diagnostic criteria. Nomenclature. The Panel reaffirmed the decision to unify the terms NMO and NMOSD. Given the greater degree of diagnostic uncertainty and potential heterogeneity of seronegative NMOSD, criteria were developed for both NMOSD with AQP4-IgG and NMOSD without AQP4-IgG. An additional category of NMOSD with unknown AQP4-IgG status may be used for patients in whom serologic testing is unavailable. The nomenclature allows for future modifications based on potential discovery and validation of other biomarkers in AQP4-IgG-seronegative patients who have otherwise typical NMOSD clinical syndromes. Clinical presentation. Consensus diagnostic criteria for NMOSD are presented in table 1. Table e-2 contains a glossary of terms to guide interpretation of individual components of the criteria. The criteria allow NMOSD diagnosis with occurrence of at least 1 of 6 core clinical characteristics and detection of AQP4-IgG. The core clinical characteristics each implicate 1 of 6 CNS regions: optic nerve, 19,e28-e31 spinal cord, 20,e27,e32-e34 area postrema of the dorsal medulla, brainstem, 24,e35-e38 diencephalon, or cerebrum. Certain clinical presentations are particularly suggestive of NMOSD: optic neuritis that is simultaneously bilateral, involves the optic chiasm, causes an altitudinal visual field defect, or causes severe residual visual loss (acuity 20/200 or worse) 4,e49-e51 ; a complete (rather than partial) spinal cord syndrome, especially with paroxysmal tonic spasms ; and an area postrema clinical syndrome (16%-43% incidence) consisting of intractable hiccups or nausea and vomiting. Clinical judgment remains necessary because no characteristic is pathognomonic. For example, altitudinal visual field defects may result from ischemic optic neuropathy and bilateral simultaneous optic neuritis may occur in MS. Diagnostic requirements are more stringent for patients in whom AQP4-IgG is not detected or for whom testing is unavailable. Such individuals must experience 2 or more different core clinical characteristics (i.e., dissemination in space, affecting different neuroanatomic regions) and other supportive MRI characteristics meant to enhance diagnostic specificity must also be present. At least one of the clinical events must be one of the 3 most common clinical characteristics of NMOSD: optic neuritis, transverse myelitis (additional requirement: LETM MRI lesion), or an area postrema clinical syndrome (additional requirement: associated medullary MRI lesion). The 2 required core characteristics may occur with a single clinical attack (e.g., classic Devic syndrome with simultaneous optic neuritis and acute myelitis with LETM) or multiple attacks. The Panel reached several additional conclusions. First, at least 1 discrete clinical attack of CNS symptoms must occur to establish NMOSD diagnosis. Although asymptomatic AQP4-IgG seropositive status may exist for years before clinical NMOSD presentation, e54 the natural history of asymptomatic seropositivity is poorly understood. Second, NMOSD diagnosis is not warranted in asymptomatic patients with NMOSD-compatible MRI lesions because the expected clinical course in such individuals is unknown. Third, no clinical characteristic is pathognomonic of NMOSD. Accordingly, a single clinical manifestation is not diagnostic when AQP4-IgG is not detected. Finally, no single characteristic is exclusionary but some are considered red flags (table 2) that signal the possibility of alternative diagnoses. e55-e63 The main clinical red flags concern the temporal course of the syndrome rather than the actual manifestations. Most notably, a gradually progressive course of neurologic worsening over months to years is very uncommon (1%-2%) in NMOSD. [bib_ref] A secondary progressive clinical course is uncommon in neuromyelitis optica, Wingerchuk [/bib_ref] However, after NMOSD diagnostic criteria for adult patients Diagnostic criteria for NMOSD with AQP4-IgG 1. At least 1 core clinical characteristic 2. Positive test for AQP4-IgG using best available detection method (cell-based assay strongly recommended) 3. Exclusion of alternative diagnoses a Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4-IgG status 1. At least 2 core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements: a. At least 1 core clinical characteristic must be optic neuritis, acute myelitis with LETM, or area postrema syndrome b. Dissemination in space (2 or more different core clinical characteristics) c. Fulfillment of additional MRI requirements, as applicable 2. Negative tests for AQP4-IgG using best available detection method, or testing unavailable 3. Exclusion of alternative diagnoses a thorough investigation for potential competing disorders, the weight of evidence may justify NMOSD diagnosis despite presence of 1 or more red flags. The presence of systemic autoimmune diseases and certain CSF data and pathologic findings (see below) may also influence NMOSD likelihood. Regardless of AQP4-IgG serologic status, NMOSD should be diagnosed when criteria are fulfilled and alternative diagnoses for the clinical syndrome have been excluded. Neuroimaging and neurophysiologic testing. MRI lesion patterns are a major arbiter of CNS demyelinating disease differential diagnosis. Several brain, optic nerve, and spinal cord patterns are characteristic or highly suggestive of NMOSD associated with acute myelitis is the most specific neuroimaging characteristic of NMOSD and is very uncommon in adult MS. [bib_ref] Revised diagnostic criteria for neuromyelitis optica, Wingerchuk [/bib_ref] Such lesions typically involve the central gray matter and may be associated with cord swelling, central hypointensity on T1weighted sequences, and enhancement following IV gadolinium administration; extension of a cervical lesion into the brainstem is characteristic. In contrast, MS cord lesions are usually about 1 vertebral segment long or less, occupy peripheral white matter tracts such as the dorsal columns, and may be asymptomatic (see for neuroimaging red flags relevant to MS and other diseases). Although the LETM pattern is characteristic of NMOSD, 7%-14% of initial and 8% of subsequent myelitis attacks in AQP4-IgG-seropositive patients do not meet the LETM definition. [bib_ref] Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders, Flanagan [/bib_ref] [bib_ref] Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study..., Jarius [/bib_ref] Therefore, NMOSD must be considered in the differential diagnosis in patients presenting with short myelitis lesions. The timing of an individual MRI scan must be correlated with clinical status. Occasionally, lesions of less than 3 segments are detected in NMOSD because the MRI was performed early in the evolution of acute myelitis or in clinical remission, during which a LETM lesion may fragment into discontinuous lesions. 37,e71 Some patients with progressive MS have coalescent cord lesions that can superficially suggest a LETM pattern e72 ; both axial and sagittal plane images should be used to judge lesion extent. A LETM MRI pattern may also occur in patients with infectious, granulomatous, neoplastic, and paraneoplastic diseases, acute disseminated encephalomyelitis (ADEM), spinal cord infarction, and dural arteriovenous fistula. During optic neuritis attacks, increased signal within the optic nerve may be detected with fatsuppressed T2-weighted orbital MRI sequences, typically with gadolinium enhancement seen on T1weighted sequences (figure 1). Bilateral optic nerve involvement, posterior nerve predominance (especially with extension into the optic chiasm), or extensive lesions of the optic nerve (more than half of its length) are all suggestive of NMOSD . e51,e73,e74 According to the 2006 diagnostic scheme, a normal brain MRI or detection of only nonspecific white matter lesions was a key supportive criterion. [bib_ref] Revised diagnostic criteria for neuromyelitis optica, Wingerchuk [/bib_ref] Sixty percent of patients with NMOSD accumulate asymptomatic white matter lesions on longitudinal study and as many as 16% fulfill Barkhof MS MRI criteria. Detection of brain MRI white matter lesions compatible with MS does not exclude the diagnosis of NMOSD but is considered a red flag, indicating that additional evidence may be required to confidently distinguish NMOSD from MS in individual cases. 33,38,e64,e76,e77 Analysis of qualitative features of lesions assists in distinguishing NMOSD 2. Comorbidities associated with neurologic syndromes that mimic NMOSD Sarcoidosis, established or suggestive clinical, radiologic, or laboratory findings thereof (e.g., mediastinal adenopathy, fever and night sweats, elevated serum angiotensin converting enzyme or interleukin-2 receptor levels) Cancer, established or with suggestive clinical, radiologic, or laboratory findings thereof; consider lymphoma or paraneoplastic disease (e.g., collapsin response mediator protein-5 associated optic neuropathy and myelopathy or anti-Ma-associated diencephalic syndrome) Chronic infection, established or with suggestive clinical, radiologic, or laboratory findings thereof (e.g., HIV, syphilis) Red flags (conventional neuroimaging) [bib_ref] Characteristic brain magnetic resonance imaging abnormalities in central nervous system aquaporin-4 autoimmunity, Kim [/bib_ref] [bib_ref] The usefulness of brain MRI at onset in the differentiation of multiple..., Huh [/bib_ref] Large, confluent, or tumefactive cerebral lesions may suggest NMOSD but in isolation may not be discernable from atypical MS lesions, especially in AQP4-IgG-seronegative patients. Second, some MRI lesion patterns considered typical of MS are rarely seen in NMOSD, including perpendicular orientation of periventricular lesions (Dawson fingers), periventricular lesions located in the inferior temporal lobe, and cortical lesions. Recent 7T MRI studies revealed differences between NMOSD and MS specifically regarding cortical lesions (frequent in MS but absent in NMOSD) and white matter lesions (MS plaques are periventricular and traversed by a central venule whereas NMOSD lesions are subcortical and lack a central venule). e84,e85 However, this technology is not widely available and further validation is needed. The Panel considered evidence for use of other imaging modalities, such as nonconventional MRI techniques and optical coherence tomography, and neurophysiologic tests such as visual evoked potentials. None of these modalities were included in the revised diagnostic criteria because of concerns regarding lack of evidence, specificity, or reliability. Considerations for AQP4-IgG serologic and other laboratory testing. Technological advances in AQP4-IgG assays have improved diagnostic sensitivity without compromising specificity. [bib_ref] Evaluation of aquaporin-4 antibody assays, Waters [/bib_ref] The Panel recommended testing with cell-based serum assays (microscopy or flow cytometry-based detection) whenever possible because they optimize autoantibody detection (mean sensitivity 76.7% in a pooled analysis; 0.1% false-positive rate in a MS clinic cohort). [bib_ref] Aquaporin-4 antibodies (NMO-IgG) as a serological marker of neuromyelitis optica: a critical..., Jarius [/bib_ref] [bib_ref] Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays, Waters [/bib_ref] [bib_ref] Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders, Sato [/bib_ref] [bib_ref] Evaluation of aquaporin-4 antibody assays, Waters [/bib_ref] [bib_ref] Seroprevalence of aquaporin-4-IgG in a northern California population representative cohort of multiple..., Pittock [/bib_ref] However, cell-based assays are not yet widely available. Indirect immunofluorescence assays and ELISAs have lower sensitivity (mean sensitivity 63%-64% each) and occasionally yield false-positive results (0.5%-1.3% for ELISA), often at low titer. The Panel strongly recommended interpretative caution if such assays are used and when low-titer positive ELISA results are detected in individuals who present with NMOSD clinical symptoms less commonly associated with AQP4-IgG (e.g., presentations other than recurrent optic neuritis, myelitis with LETM, or area postrema syndrome) or in situations where clinical evidence suggests a viable alternate diagnosis. Confirmatory testing is recommended, ideally using 1 or more different AQP4-IgG assay techniques. Cell-based assay has the best current sensitivity and specificity and samples may need to be referred to a specialized laboratory. Patients who fulfill NMOSD criteria but do not have detectable AQP4-IgG despite use of the best available assays, or for whom serologic testing is unavailable, sometimes represent a diagnostic challenge. [bib_ref] Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity, Marignier [/bib_ref] A greater proportion of patients with NMO who have monophasic disease appear to be AQ-P4-IgG-seronegative compared to those with established relapsing disease. [bib_ref] Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study..., Jarius [/bib_ref] A minority of patients with clinical characteristics of NMO, almost all AQP4-IgG-seronegative, have been reported to have detectable serum myelin oligodendrocyte glycoprotein Neuroimaging characteristics of NMOSD (MOG) antibodies and might have different characteristics (younger age, less frequently female, and less likely to relapse) from those with AQP4-IgG. These findings might suggest that some AQP4-IgGseronegative patients with clinical and neuroimaging features of NMOSD have a different underlying pathogenesis [bib_ref] Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity, Marignier [/bib_ref] ; the role of MOG or other antibodies in disease pathogenesis remains undetermined. The IPND nomenclature is designed to allow incorporation of cases of NMOSD associated with other validated biomarkers (e.g., NMOSD with a specific autoantibody). Occasionally, patients without detectable serum AQP4-IgG are later found to be seropositive. There may be technical explanations in some cases but antibody levels also increase with clinical relapses and decrease with immunosuppressive therapy in some patients. [bib_ref] Antibody to aquaporin-4 in the long-term course of neuromyelitis optica, Jarius [/bib_ref] Therefore, retesting should be considered before B-cell or antibody-targeted therapies (plasma exchange, immunosuppressive drugs) are instituted and in seronegative patients who relapse. [bib_ref] Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica, Jiao [/bib_ref] Cases of clinical NMO in which AQP4-IgG was detected in CSF, but not serum, have been reported but this appears to be rare. 52,e89-e91 Routine CSF testing of AQP4-IgG-seronegative patients is not recommended but might be considered in selected seronegative cases, especially those with additional confounding serum autoantibodies that may lead to uninterpretable or false-positive assay results. The Panel considered absence of CSF oligoclonal bands as supportive evidence for NMOSD (although they are sometimes transiently detectable at the time of an attack) and presence of bands a red flag, but sensitivity and specificity are modest. 4,53 CSF pleocytosis .50 leukocytes/mL (incidence approximately 35% in NMOSD) or the presence of neutrophils or eosinophils (either .5/mL; incidence 44% and 10%, respectively, in attack-associated samples) are particularly useful in distinguishing NMOSD from MS. [bib_ref] The clinical course of neuromyelitis optica (Devic's syndrome), Wingerchuk [/bib_ref] [bib_ref] Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: results from 211..., Jarius [/bib_ref] CSF glial fibrillary acidic protein also shows promise as a diagnostic and prognostic biomarker but is elevated only for days to weeks following an attack. e92,e93 Pediatric NMOSD criteria. The Pediatric Working Group members noted that most clinical, neuroimaging, and laboratory characteristics of pediatric NMOSD are similar to those of adult-onset disease. The female preponderance may be of lower magnitude (;3:1 female:male ratio compared with up to 9:1 for adults), 54,e94 a greater proportion of children may have monophasic disease, and acute CSF abnormalities in pediatric MS may mimic those ordinarily considered suggestive of NMOSD. [bib_ref] Long-term follow-up of neuromyelitis optica with a pediatric onset, Collongues [/bib_ref] [bib_ref] Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders, Banwell [/bib_ref] [bib_ref] CNS aquaporin-4 autoimmunity in children, Mckeon [/bib_ref] The Working Group identified caveats to application of the adult NMOSD criteria in children, noting especially that detection of a LETM MRI lesion associated with acute myelitis may be less specific for NMOSD. Approximately 15% of children with MS may have LETM during relapse, LETM can accompany monophasic ADEM, and AQP4-IgG is rarely detected in children with monophasic LETM. [bib_ref] Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders, Banwell [/bib_ref] In children diagnosed with ADEM according to international consensus criteria, which require a polyfocal demyelinating clinical presentation with encephalopathy, [bib_ref] International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and..., Krupp [/bib_ref] the presence of AQP4-IgG favors a diagnosis of NMOSD, although prospective validation studies are required to determine risk of recurrent NMOSD events. In one study of AQP4-IgG-seropositive children, 45% Diencephalic and cerebral lesions in neuromyelitis optica spectrum disorder A variety of brain lesion patterns are associated with neuromyelitis optica spectrum disorder. Axial T2-weighted fluidattenuated inversion recovery (FLAIR) MRI from 2 patients demonstrates lesions involving the right thalamus (A; arrow) and the hypothalamus (B; arrows). Axial T2-weighted FLAIR MRI shows an extensive subcortical white matter lesion (C; arrow) that enhances after gadolinium administration on T1-weighted sequences (D; arrow). Chronic longitudinally extensive and linear corpus callosum lesions are depicted on sagittal T2-weighted FLAIR MRI (E; arrows). Coronal T2-weighted FLAIR MRI shows longitudinal involvement of the corticospinal tract extending to the cerebral peduncle and pons (F; arrows). Acute periependymal cerebral lesions from one patient are depicted using sagittal (G; arrow) and axial (H; arrows) T2-weighted FLAIR MRI and axial T1-weighted MRI with gadolinium (I; arrows). experienced recurrent cerebral manifestations including encephalopathy. [bib_ref] CNS aquaporin-4 autoimmunity in children, Mckeon [/bib_ref] Aside from these caveats, the currently proposed diagnostic criteria for NMOSD are appropriate for pediatric patients. Longitudinal observation of the clinical course for dissemination in time and retesting the AQP4-IgG status of some children, especially AQP4-IgG-seronegative individuals presenting with an ADEM-like event that includes optic neuritis and LETM, may be required to achieve confident diagnosis. Monophasic NMOSD. The occurrence of a second clinical attack, which defines a relapsing disorder, was often considered sufficient to revise the diagnosis to MS in otherwise typical NMO cases. Approximately 5%-10% of contemporary cases are described as monophasic, although the optimal definition for monophasic NMOSD remains elusive. It is unclear whether the occurrence of bilateral optic neuritis and myelitis at initial presentation are helpful or essential to distinguish such cases from relapsing NMOSD. Similarly, the interval between index clinical events that is compatible with monophasic NMO has not been consistently defined or adequately examined as a predictor of future clinical course. Although early risk of relapse is high in AQP4-IgG-seropositive cases (e.g., about 60% within 1 year after LETM), [bib_ref] Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis, Weinshenker [/bib_ref] cases have been documented in whom more than a decade elapsed between the index events and relapse. e34 Several studies show a pattern of apparently monophasic NMO being associated with a more equitable sex distribution, relatively younger age at disease onset, tendency to present with simultaneous myelitis and bilateral optic neuritis (rather than unilateral optic nerve involvement), lower frequency of other autoimmune diseases, and lower prevalence of serum AQP4-IgG compared to relapsing NMO. 4,37,e96 A fraction of these patients may have other serum antibodies such as MOG-IgG. [bib_ref] Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype, Kitley [/bib_ref] The Panel concluded that monophasic NMOSD is a recognizable clinical entity but that criteria that accurately predict long-term adherence to a monophasic course cannot currently be defined. An interval longer than 4 weeks between index attacks indicates relapsing disease. The Panel also recommended that at least 5 years (preferably longer) of relapse-free clinical observation after the index events be required before a monophasic course is assumed with any degree of confidence. Patients who are AQP4-IgGseropositive should be assumed to be at risk for relapse indefinitely and preventive treatment should be considered, even in the setting of a prolonged clinical remission. Systemic autoimmunity associated with NMOSD. Based on evidence from several observational studies, the Panel concluded that clinical diagnoses of SLE, SS, or myasthenia gravis may coexist with NMOSD clinical syndromes in AQP4-IgG-seropositive patients and, in fact, their presence strengthens confidence about a NMOSD diagnosis. The underlying cause of CNS symptoms and signs is more likely to be co-associated NMOSD than a direct complication (e.g., associated vasculitis) of SLE or SS. In a patient suspected of having NMOSD, the presence of clinical myasthenia gravis or detectable serum acetylcholine receptor antibodies is considered supportive of NMOSD diagnosis. e99-e101 Pathology. Pathologic findings in biopsy or autopsy tissue obtained from patients with AQP4-IgG-seropositive NMOSD demonstrate loss of AQP4 immunoreactivity and evidence of perivascular complement activation in actively demyelinating lesions. e20,e21 Additionally, findings supportive of astrocytopathy such as truncated astrocyte processes or cell loss may be detected by immunostaining for glial fibrillary acidic protein. These findings in active lesions distinguish AQP4-IgGpositive NMOSD from MS; data from seronegative individuals are not yet available. [bib_ref] The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica, Lucchinetti [/bib_ref] Necrosis and lesion infiltration with neutrophils and eosinophils are supportive characteristics, e102 but may not be present. Spinal cord lesions may differ from supraspinal lesions in this respect. e103 Serum AQP4-IgG testing usually obviates the need for biopsy in severe myelitis and leukoencephalopathy syndromes. e19,e104,e105 Aquaporin-4 immunostaining is not a routine procedure in CNS biopsy processing and is available only in select centers. The Panel does not recommend CNS biopsy but recognizes that in atypical cases, expert pathologic review of biopsy tissue of brain or spinal cord might help establish NMOSD and exclude competing diagnoses. [bib_ref] Diagnostic utility of aquaporin-4 in the analysis of active demyelinating lesions, Popescu [/bib_ref] Opticospinal MS. The term opticospinal MS was introduced in Japan to refer to a pattern of MS that is relatively more common in Asian countries. It was defined by recurrent optic neuritis and myelitis attacks with no brain involvement, although some investigators allow occurrence of certain brainstem syndromes. e107 The description of opticospinal MS represented an important milestone because it recognized that there was a relapsing illness distinct from conventional MS that selectively targeted the optic nerve and spinal cord at a time when relapses were deemed to be incompatible with a diagnosis of NMO in both Western countries and Japan. Contemporary NMO criteria that include MRI criteria for length of spinal cord lesions and detection of AQP4-IgG are more specific than historical opticospinal MS criteria. Clinicians and investigators in many Asian countries now use the term NMO rather than opticospinal MS in research and practice. When similarly defined in Asia, NMO clinical syndromes and brain MRI lesions are both analogous to those encountered in Western countries. The Panel concluded that opticospinal MS is a historically important but now superseded term, especially in light of the need to distinguish NMO from MS to guide treatment decisions. DISCUSSION The high specificity of AQP4-IgG has been exploited to expand the clinical and neuroimaging spectrum of NMO. The consensus definition of NMOSD unifies traditional NMO and modern NMOSD definitions. It allows for NMOSD diagnosis in AQP4-IgG-seropositive patients with involvement of almost any CNS region as well as in those with restricted involvement of a single region (e.g., recurrent transverse myelitis). For the first time, criteria allow for NMOSD diagnosis in patients who have not experienced clinical involvement of either optic nerves or spinal cord. The Panel reached these conclusions for the following reasons: (1) there are no established biological differences between patients diagnosed with NMO compared with NMOSD (using 2006 and 2007 definitions, respectively) in AQP4-IgG-seropositive patients; (2) limited NMOSD syndromes affecting CNS regions other than the optic nerve and spinal cord often herald subsequent clinical attacks consistent with conventional NMO in AQP4-IgG-positive patients; and (3) current immunotherapeutic strategies are the same for relapsing NMO and NMOSD, regardless of AQP4-IgG serologic status. To enhance criteria specificity, AQP4-IgG-seronegative patients must have experienced at least one of the 3 most common clinical characteristics of seropositive NMOSD, namely optic neuritis, transverse myelitis with LETM, or area postrema syndrome with associated MRI lesions. These criteria are appropriate for adults and, with minor caveats, children. Finally, the Panel cautions against making a diagnosis of monophasic NMOSD, especially in AQP4-IgG-seropositive patients, and recommends abandonment of the term opticospinal MS for cases that meet NMOSD criteria. The IPND criteria are expected to facilitate earlier and more accurate diagnosis by identifying individuals who would have been diagnosed with idiopathic transverse myelitis, idiopathic optic neuritis, or atypical MS. This will be particularly true for AQP4-IgGseropositive patients experiencing their first CNS attack (such patients will now meet NMOSD criteria), leading to a specific treatment path with immunotherapy for attack prevention. The criteria should also provide greater specificity for distinguishing both AQP4-IgG-seropositive and AQP4-IgG-seronegative NMOSD from MS. Early-stage diagnostic specificity is critical because recent observational data suggest that interferon-b, natalizumab, and fingolimod may worsen NMO. The IPND criteria are expected to facilitate more comprehensive and comparable epidemiologic studies by supplying a uniform case definition and a glossary of defined terms. For AQP4-IgG-seronegative cases diagnosed using the new NMOSD scheme, detailed clinical, neuroimaging, and laboratory descriptions of patients will be necessary to better characterize this heterogeneous population. This is particularly important to identify the frequencies with which seroconversion to AQP4-IgG positivity or detection of other autoantibodies of interest occur and to identify phenocopies later diagnosed as other conditions. Many observations used to construct the IPND criteria were derived from relatively small case series. The Panel recommends several large-scale prospective validation and assessment strategies. These include but are not limited to studies that (1) systematically apply the criteria to consecutive cases of NMOSD, with and without AQP4-IgG, to determine whether the diagnosis is confirmed or another alternative diagnosis emerges in follow-up; (2) validate the association and potential immunopathogenesis of serum MOG-IgG (and other future potential laboratory and neuroimaging biomarkers) with clinically diagnosed NMOSD; (3) identify clinical settings in which false-negative and false-positive AQP4-IgG results are more likely; (4) validate different definitions predictive of clinical course (monophasic vs relapsing) and determine the distinguishing characteristics of these subtypes; and (5) further examine the immunopathology of NMOSD to determine whether there is unrecognized heterogeneity to inform its classification, especially of AQP4-IgG-seronegative cases. These and other approaches to criteria validation will allow future refinement of NMOSD diagnostic criteria commensurate with the next era of scientific advances. # Author contributions D. Wingerchuk participated in study concept and design, obtaining funding, acquisition and analysis of data, drafting and revising the manuscript, and coordinating the study. B. Banwell participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. J. Bennett participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. P. Cabre participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. W. Carroll participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. T. Chitnis participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. J. de Seze participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. K. Fujihara participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. B. Greenberg participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. A. Jacob participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. S. Jarius participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. M. Lana-Peixoto participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. M. Levy participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. J. Simon participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. S. Tenembaum participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. A. Traboulsee participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. P. Waters participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. K. Wellik participated in the acquisition and analysis of data and writing and critical review of the manuscript for important intellectual content. B. Weinshenker participated in study concept and design, obtaining funding, acquisition and analysis of data, drafting and revising the manuscript, and coordinating the study. [fig] Figure 1: Spinal cord and optic nerve MRI patterns in neuromyelitis optica spectrum disorder Spinal cord imaging in the context of acute myelitis in neuromyelitis optica spectrum disorders (NMOSD) usually reveals a longitudinally extensive transverse myelitis (LETM) lesion extending over 3 or more vertebral segments. Sagittal T2weighted MRI of the thoracic spinal cord (A) demonstrates a typical LETM lesion involving most of the thoracic spinal cord (arrows). LETM lesions have a predilection for the central cord, as shown by axial T2-weighted (B; arrowhead) and T1weighted MRI with gadolinium (C; arrowhead). Cervical LETM may extend into the medulla, a characteristic NMOSD pattern demonstrated in D (arrows; sagittal T2-weighted MRI) and E (arrows; sagittal T1-weighted MRI with gadolinium). Acute LETM lesions can be associated with intralesional hypointensity as shown by sagittal T1-weighted MRI (F; arrow); in this example, a rim of gadolinium enhancement surrounds the hypointense region. Chronic sequelae of LETM may include longitudinally extensive segments of spinal cord atrophy as shown by T2-weighted MRI using sagittal (G; the 2 arrowheads indicate the atrophic segment and the top arrow indicates the normal diameter of unaffected cervical spinal cord) and axial planes (H; arrowhead shows an atrophic spinal cord). Fast spin echo fat-suppressed T2-weighted MRI in the axial (I) and coronal (J) planes shows increased signal throughout most the length of the left optic nerve, especially its posterior portion (arrows). Axial T1-weighted MRI with gadolinium shows enhancement of the optic chiasm (K; arrows). These images are from 2 different patients experiencing acute optic neuritis in the setting of NMOSD. [/fig] [table] Table 2: Red flags: Findings atypical for NMOSD Red flags (clinical/laboratory) 1. Clinical features and laboratory findings Progressive overall clinical course (neurologic deterioration unrelated to attacks; consider MS) Atypical time to attack nadir: less than 4 hours (consider cord ischemia/infarction); continual worsening for more than 4 weeks from attack onset (consider sarcoidosis or neoplasm) Partial transverse myelitis, especially when not associated with LETM MRI lesion (consider MS) Presence of CSF oligoclonal bands (oligoclonal bands occur in ,20% of cases of NMO vs .80% of MS) [/table]	None	http://n.neurology.org/content/neurology/85/2/177.full.pdf	Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.
c2eec6120186217e5fefa1abcc5bfbeee7037676	pubmed	Consensus on the treatment of autoimmune bullous dermatoses: bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita - Brazilian Society of Dermatology*	Consensus on the treatment of autoimmune bullous dermatoses: bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita - Brazilian Society of Dermatology* Bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita are subepidermal autoimmune blistering diseases whose antigenic target is located at the basement membrane zone. Mucous membrane pemphigoid and epidermolysis bullosa acquisita can evolve with cicatricial mucosal involvement, leading to respiratory, ocular and/or digestive sequelae with important morbidity. For each of these dermatoses, a literature review covering all therapeutic options was performed. A flowchart, based on the experience and joint discussion among the authors of this consensus, was constructed to provide treatment orientation for these diseases in Brazil. In summary, in the localized, low-risk or non-severe forms, drugs that have immunomodulatory action such as dapsone, doxycycline among others may be a therapeutic option. Topical treatment with corticosteroids or immunomodulators may also be used. Systemic corticosteroid therapy continues to be the treatment of choice for severe forms, especially those involving ocular, laryngeal-pharyngeal and/or esophageal mucosal involvement, as may occur in mucous membrane pemphigoid and epidermolysis bullosa acquisita. Several immunosuppressants are used as adjuvant alternatives. In severe and recalcitrant cases, intravenous immunoglobulin is an alternative that, while expensive, may be used. Immunobiological drugs such as rituximab are promising drugs in this area. Omalizumab has been used in bullous pemphigoid. # Introduction Bullous pemphigoid (BP) accounts for 80% of subepidermal bullous dermatoses. It typically presents as generalized pruritus and tense bullous eruptions and may be associated with a 20% to 40% mortality rate. It primarily affects those aged above 70 years, and its annual incidence is estimated to be at least 13 to 62 new cases per million persons, rising significantly after 60 years old. [bib_ref] Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous..., Alpsoy [/bib_ref] [bib_ref] Bullous pemphigoid and pemphigus vulgaris-incidence and mortality in the UK: population based..., Langan [/bib_ref] ## Etiopathogenesis In the etiopathogenesis of BP, IgG autoantibodies are produced against antigens of the basement membrane zone (BMZ) -180kDa and 230kDa -collagen XVII, COL17 or BPAg2, and BPAg1, respectively. BP180 is the most relevant antigenic determinant, whereas BP230 appears to be more related to cytoskeletal function and signaling of the dermoepidermal transition. The involvement of mast cells and IgE in the development of BP lesions has recently been described. [bib_ref] IgA and IgE autoantibodies against the ectodomain of BP180 in patients with..., Christophoridis [/bib_ref] [bib_ref] Identification of a potential effector function for IgE autoantibodies in the organ-specific..., Dimson [/bib_ref] [bib_ref] The Autoimmune Skin Disease Bullous Pemphigoid: The Role of Mast Cells in..., Fang [/bib_ref] [bib_ref] IgE autoreactivity in bullous pemphigoid: eosinophils and mast cells as major targets..., Freire [/bib_ref] [bib_ref] Mechanisms of Disease: Pemphigus and Bullous Pemphigoid, Hammers [/bib_ref] [bib_ref] Clinical significance of immunoglobulin E in bullous pemphigoid, Hammers [/bib_ref] [bib_ref] Induced autoimmune bullous diseases, Hashimoto [/bib_ref] [bib_ref] Immunoglobulin E Autoantibodies in Bullous Pemphigoid Detected by Immunoglobulin E Enzyme-Linked Immunosorbent..., Hashimoto [/bib_ref] [bib_ref] Detection of IgE autoantibodies to BP180 and BP230 and their relationship to..., Hashimoto [/bib_ref] [bib_ref] Circulating anti-bullous pemphigoid 180 autoantibody can be detected in a wide clinical..., Liu [/bib_ref] [bib_ref] BP180 Is Critical in the, Liu [/bib_ref] [bib_ref] Eosinophils Mediate Tissue Injury in the Autoimmune Skin Disease Bullous Pemphigoid, Lin [/bib_ref] [bib_ref] Human eosinophils express the high affinity IgE receptor, FcεRI, in bullous pemphigoid, Messingham [/bib_ref] [bib_ref] In vivo analysis of IgE autoantibodies in bullous pemphigoid: a study of..., Moriuchi [/bib_ref] [bib_ref] Update on the pathogenesis of bullous pemphigoid: an autoantibodymediated blistering disease targeting..., Nishie [/bib_ref] [bib_ref] IgE autoantibodies and their association with the disease activity and phenotype in..., Saniklidou [/bib_ref] The association of malignancies with BP is likely to be related to the incidence of both diseases in the elderly, although some reports have suggested an increase in the frequency of certain cancers, such as those in the digestive tract, lung, and bladder and lymphoproliferative diseases. [bib_ref] Hospitalization, inpatient burden and comorbidities associated with bullous pemphigoid in the U.S.A, Ren [/bib_ref] [bib_ref] Association between bullous pemphigoid and malignancy: A meta-analysis, Lucariello [/bib_ref] BP is rarely described in patients with inflammatory or autoimmune diseases. In certain patients, it appears to be triggered by trauma, burns, radiotherapy, or irradiation by ultraviolet rays. BP has also been observed in association with psoriasis and lichen planus. [bib_ref] Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies, Lo Schiavo [/bib_ref] In some patients, systemic medications may lead to the development of BP, including diuretics (furosemide), antibiotics (amoxicillin, ciprofloxacin), potassium iodide, and captopril. The mechanism by which drugs induce BP has not been determined.Of greater interest, BP has been associated with neurological diseases, such as dementia, stroke, multiple sclerosis, epilepsy, and Parkinson disease, but the underlying pathophysiological mechanism is not completely understood. It is possible that the BP antigens BPA 1 and BPA 2 act as autoreactive antigens in the central nervous system and in tegument. [bib_ref] Risk factors for bullous pemphigoid in the elderly: a prospective case-control study, Bastuji-Garin [/bib_ref] [bib_ref] Bullous pemphigoid and internal diseases -A case-control study, Jedlickova [/bib_ref] [bib_ref] Neurological disorders in patients with bullous pemphigoid, Cordel [/bib_ref] [bib_ref] Bullous pemphigoid and its association with neurological diseases: a systematic review and..., Lai [/bib_ref] [bib_ref] Bullous pemphigoid and neurological disease: statistics from a dermatology service, Tarazona [/bib_ref] [bib_ref] Bullous pemphigoid and comorbidities: a case-control study in Portuguese patients, Teixeira [/bib_ref] [bib_ref] Immunopathological characteristics of patients with bullous pemphigoid and neurological disease, Taghipour [/bib_ref] [bib_ref] Bullous Pemphigoid Associated with Ischemic Cerebrovascular Accident and Dementia: Exclusive Blistering Lesions..., Vernal [/bib_ref] [bib_ref] The association between bullous pemphigoid and neurological disorders: a systematic review, Milani-Nejad [/bib_ref] [bib_ref] Neurological and psychiatric associations in bullous pemphigoid-more than skin deep?, Försti [/bib_ref] [bib_ref] BPAG1, a distinctive role in skin and neurological diseases, Ali [/bib_ref] [bib_ref] Increased Levels of the Bullous Pemphigoid BP180 Autoantibody Are Associated with More..., Kokkonen [/bib_ref] [bib_ref] Biological predictors shared by dementia and bullous pemphigoid patients point out a..., Julio [/bib_ref] The HLA class II DQB103:01 allele is more prevalent in Caucasian patients with BP than in the general population and has also been associated with neurological diseases.Localized involvement is uncommon. [bib_ref] Bullous Pemphigoid Associated with Ischemic Cerebrovascular Accident and Dementia: Exclusive Blistering Lesions..., Vernal [/bib_ref] Oral involvement is observed between 10% and 30% of affected patients. The eyes, nose, pharynx, esophagus, and anogenital regions are rarely affected. [bib_ref] Update on the pathogenesis of bullous pemphigoid: an autoantibodymediated blistering disease targeting..., Nishie [/bib_ref] [bib_ref] Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies, Lo Schiavo [/bib_ref] [bib_ref] Risk factors for bullous pemphigoid in the elderly: a prospective case-control study, Bastuji-Garin [/bib_ref] [bib_ref] Pemphigoid diseases, Schmidt [/bib_ref] by DIF or IIF. [bib_ref] Pemphigoid diseases, Schmidt [/bib_ref] [bib_ref] Immunofluorescence testing in the diagnosis of autoimmune blistering diseases: overview of 10-year..., Arbache [/bib_ref] [bib_ref] Importance of serological tests in diagnosis of autoimmune blistering diseases, Ishii [/bib_ref] In most patients, DIF of non-impaired perilesional skin will demonstrate linear and continuous IgG or C 3 deposition along the BMZ. Furthermore, the salt-split skin (SSS) IIF technique, when treating normal human skin with 1 M NaCl, followed by incubation with the patient's serum, may be useful in distinguishing BP from other subepidermal bullous autoimmune diseases, primarily epidermolysis bullosa acquisita and bullous lupus erythematosus. [bib_ref] Immunofluorescence testing in the diagnosis of autoimmune blistering diseases: overview of 10-year..., Arbache [/bib_ref] [bib_ref] Importance of serological tests in diagnosis of autoimmune blistering diseases, Ishii [/bib_ref] In BP, immune deposits are found on the epidermal side or on both sides of the cleavage (dermal and epidermal). In 60% to 80% of patients, IgG autoantibodies and, less frequently, IgA and IgE are circulating; these autoantibodies also often bind to the cleavage on the epidermal side.ELISA using recombinant proteins that contain specific re- [bib_ref] Treatment of bullous pemphigoid with lowdose oral cyclophosphamide: a case series of..., Gual [/bib_ref] The combination of nicotinamide and minocycline or tetracycline can be used as a therapeutic alternative. ## Laboratory diagnosis Dapsone can be administered, especially when there is mucosal involvement, and the value of topical immunomodulators, such as tacrolimus, should be confirmed. [bib_ref] Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with..., Feliciani [/bib_ref] [bib_ref] Meeting Report of the Pathogenesis of Pemphigus and Pemphigoid Meeting in Munich, Schmidt [/bib_ref] In cases of treatment resistance, intravenous immunoglobulin, plasmapheresis, or anti-CD20 immunotherapy (rituximab) may be prescribed. Based on the immunopathogenesis of BP, new compounds are being proposed. [bib_ref] Meeting Report of the Pathogenesis of Pemphigus and Pemphigoid Meeting in Munich, Schmidt [/bib_ref] [bib_ref] Treatment of bullous pemphigoid with rituximab: critical analysis of the current literature, Shetty [/bib_ref] [bib_ref] Emerging treatments for pemphigoid diseases, Ludwig [/bib_ref] Recently, a European consensus was developed for the treatment of BP. [bib_ref] Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with..., Feliciani [/bib_ref] The figure 1 that is presented here depicts this consensus with modifications, in addition to the revisions that have been incorporated for the treatment of BP. [bib_ref] Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with..., Feliciani [/bib_ref] # Introduction Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid, refers to a group of chronic autoimmune diseases that predominantly affect the mucous membranes and, occasionally, skin.It is part of a group of autoimmune dermatoses that present with subepidermal bullous lesions, characterized by the formation of antibodies against structures of the basement membrane zone (BMZ). In MMP, antibodies bind more frequently to BP-180 and laminin 332 (laminin 5). [bib_ref] Subepidermal autoimmune bullous diseases: overview, epidemiology, and associations, Kridin [/bib_ref] Scarring of lesions on the mucous membranes is common-hence, the term "cicatricial"-which may lead to decreased visual acuity, blindness, supraglottic stenosis with hoarseness, or airway obstruction. 50 ## Epidemiology MMP usually has a late onset, between age 60 and 80 years. Women appear to be more commonly affected than men, from 1.5 to 2 times more frequently, with no racial or geographic preference. European data show an incidence of approximately 1:1,000,000 people annually. The initial signs and symptoms may be subtle and non-specific, with irreversible and often debilitating consequences. It is associated with high morbidity and mortality if treatment is not initiated early and aggressively. 52 Lesions usually present as erythematous plaques, with the formation of recurrent blisters and erosions and consequent atrophic scarring. [bib_ref] Mucous Membrane Pemphigoid, Xu [/bib_ref] Scarring of the laryngeal mucosa can lead to hoarseness, cough, dyspnea, and even acute respiratory failure. Scarring of the anogenital mucosa usually presents as blisters, erosions, and scars and can significantly affect a patient's quality of life. [bib_ref] Mucous membrane pemphigoid, Chan [/bib_ref] Esophageal involvement in MMP is rare and is observed in patients with disseminated disease. The most common changes that occur are multiple membranes and esophageal constriction. [bib_ref] Mucous Membrane Pemphigoid, Xu [/bib_ref] Selection of the appropriate treatment depends on several factors, including the site that is involved, disease severity, and its progression. [bib_ref] The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic..., Chan [/bib_ref] Patients can be divided into a low-risk group, with lesions that are restricted to the oral mucosa, and a high-risk group, with ocular, pharyngeal, laryngeal, esophageal, and genital lesions. The treatment for the low-risk group is conservative, prioritizing topical treatment when possible, whereas in the high-risk group, treatment should be aggressive, with early initiation of systemic agents. [bib_ref] The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic..., Chan [/bib_ref] [bib_ref] Alves Mde F. Mucous membrane pemphigoid with severe esophageal stricture, Barbosa Ldo [/bib_ref] Due to the absence of large, multicenter, randomized, and controlled clinical trials for this disease group, the treatment strategy is based on expert experience and literature reports. [bib_ref] The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic..., Chan [/bib_ref] [bib_ref] Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international..., Murrell [/bib_ref] Topical treatment ## Corticosteroids Moderate-to high-potency topical corticosteroids are the first-line treatment for low-risk patients who have the disease limited to the oral mucosa with or without cutaneous involvement. A conservative approach is recommended, because there is less risk of scarring in these regions. These agents may also be useful as adjunctive therapy in the most severe cases, constituting important components of the therapeutic arsenal. Corticosteroid gels, ointments, or elixirs can be used 2 to 3 times a day. Gels are applied more easily and better tolerated in the oral cavity. It is important to guide the patient to dry the mucosa before application, rub the medication gently at the site for 30 seconds, and refrain from eating or drinking for 30 minutes. One of the applications should be performed before bedtime, because oral secretions are diminished during sleep. This step may allow the medication to remain longer in the treated area. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] Alternative methods of administering corticosteroids include trays that are made by dentists to provide medicines under occlusion, for patients with gingival involvement. Trays should be inserted into the dental arch and held for 10 to 20 minutes. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] If the patient does not respond adequately to topical therapy, injections of intralesional corticosteroids, which have had some success, may be used. The application should be superficial, just below the erosions; if it is deeper, it may increase the risk of mucosal atrophy. Injection of triamcinolone hexacetonide at 5 to 10mg/ml every 2 to 4 weeks is recommended. The total dose that is administered on a per-session basis should not exceed 20mg. [bib_ref] The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic..., Chan [/bib_ref] [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] Some adverse effects of topical corticosteroids are known, such as mucosal atrophy, oropharyngeal candidiasis, and reactivation of herpes simplex virus. Usually, patients improve in several weeks with the use of topical corticosteroids. As improvement occurs, the patient can gradually decrease the frequency of applications and substitute them for less potent agents, avoiding mucosal atrophy. If treatment discontinuation is not possible due to relapses, the patient should be maintained with the lowest effective topical or systemic maintenance regimen. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] Management and prevention of recurrent herpes labialis in immunocompetent patients, Gilbert [/bib_ref] [bib_ref] The treatment of herpes simplex infections: an evidence-based review, Cernik [/bib_ref] Consensus on the treatment of autoimmune bullous dermatoses: bullous pemphigoid, mucous membrane pemphigoid... ## Tacrolimus Topical tacrolimus, a calcineurin inhibitor, appears to be effective in patients with localized oral disease, effecting complete remission within 2 to 3 months of treatment. However, topical corticosteroids are more effective. The high cost of tacrolimus in relation to many topical corticosteroids makes it difficult for some patients to use this therapy. Tacrolimus is generally indicated for patients who experience relapse of lesions as the application frequency and potency of the corticosteroids are reduced. A maintenance regimen, in which corticosteroid treatment is alternated with topical tacrolimus, may help keep the patient in remission and reduce the risk of the long-term side effects of corticosteroids. Topical tacrolimus 0.1% ointment should be initially applied twice daily, according to the patient's tolerance, because a transient burning sensation may occur soon after application. [bib_ref] Topical tacrolimus for oral cicatricial pemphigoid, Assmann [/bib_ref] [bib_ref] Successful treatment of mucous membrane pemphigoid with tacrolimus, Suresh [/bib_ref] [bib_ref] Oral mucous membrane pemphigoid: complete response to topical tacrolimus, Lee [/bib_ref] Oral care When there is oral cavity involvement, the patient needs to be encouraged to exercise good hygiene. Frequent toothbrushing is indicated using soft-bristled brushes, proper technique, toothpaste that does not contain sodium lauryl sulfate, alcohol-free mouthwash, and flossing to avoid plaque build-up, acceleration of dental caries, and loss of gums and teeth. Topical anesthetics (e.g., lidocaine) may be used to reduce pain by applying them to lesions before meals, brushing, dental procedures, and other occasions. Mild debridement of necrotic mucosal tissue can be performed to prevent infection. Oral cavity trauma using ill-fitting dentures can lead to the formation of new erosions. Thus, regular dental evaluations are imperative in patient care. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] Therapeutic approaches to patients with mucous membrane pemphigoid, Kourosh [/bib_ref] Extraoral care In addition to pharmacological treatment, other interventions may be useful in the management of patients with extraoral involvement. Early referral to specialists is essential to prevent scars and sequelae in these regions. When there is nasal involvement, lavage with saline, application of emollients, and the use of corticosteroids in spray form may be useful. Esophageal involvement justifies a liquid-pasty diet, measures for preventing gastroesophageal reflux, and dilatation of stenosis. When there is involvement of the anogenital region, corticosteroids, and even topical calcineurin inhibitors, can be indicated. The patient should be guided to consume a laxative diet that is rich in water and fiber intake for digestion and stool excretion. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] Therapeutic approaches to patients with mucous membrane pemphigoid, Kourosh [/bib_ref] Systemic treatment Antibiotics Antibiotics, such as dapsone, other sulfonamides, and tetracyclines with or without nicotinamide, may be effective in the treatment of MMP. Dapsone is often used as first-line therapy to control localized conditions that have not responded to local therapy or extensive, slowly progressing conditions that benefit from systemic agents. If there is a partial response, systemic corticosteroids or immunosuppressive agents may be combined. Local therapy should be maintained as an adjunct. Most patients respond to dosages of dapsone of between 50 and 200mg per day. Therapy should be started at a low dose, 25 to 50mg per day, and gradually increased (25 to 50mg per week), depending on the patient's tolerance and age. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] The management of oral mucous membrane pemphigoid with dapsone and topical corticosteroid, Arash [/bib_ref] [bib_ref] Efficacy of dapsone in the treatment of pemphigus and pemphigoid: analysis of..., Gürcan [/bib_ref] Due to the potential for severe hematological side effects, laboratory monitoring is required for patients who receive dapsone. A complete differential blood count and hepatic function and renal function tests should be requested prior to the initiation of therapy, with the differential blood count repeated weekly during the first month of treatment and twice monthly for the following 2 months. Before initiating dapsone, patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency. A reduction of 1 to 2g/dL of hemoglobin is often observed in dapsone users with normal G6PD levels. Provided that there are no significant comorbidities, patients tolerate it well. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] Dapsone efficacy and adverse events in the management of mucous membrane pemphigoid, Hegarty [/bib_ref] If the disease is not adequately controlled, tetracycline (1 to 2g per day) or doxycycline 100mg/day and nicotinamide (2 to 3g per day) may be used. The adverse effects of tetracycline include gastrointestinal discomfort and phototoxicity. [bib_ref] Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international..., Murrell [/bib_ref] [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] Systemic corticosteroids Systemic corticosteroids are the first-line treatment for patients with severe, extensive, rapidly progressing MMP and those who do not respond to initial therapies. The dosage may vary depending on the patient's clinical context, and it can be started at 0.5mg/kg/day for moderate conditions, reaching 1-2mg/kg/day for more severe conditions. It should be administered in a single morning dose and maintained until the disease is controlled, with healing of all lesions and no emergence of new lesions. A rapid response is usually observed when treatment is started. Pulse therapy with methylprednisolone (at 500mg to 1g/day for 3 days) has been frequently employed with good results, effecting a clinical response more rapidly. Yet, treatment may be necessary over a long period, accompanied by the risk of adverse effects of prolonged corticosteroid therapy. Steroid-sparing immunosuppressive agents, such as azathioprine, mycophenolate mofetil, cyclophosphamide, and methotrexate, may be combined early to help maintain disease control and allow a gradual reduction in corticosteroids. Decreases of 5 to 10mg per week, over several weeks, are recommended. These immunosuppressive agents are maintained over the long term, whereas corticosteroids are tapered over 6 to 12 months. The ultimate goal is to administer monotherapy with an immunosuppressive agent. Topical therapy can also be maintained as adjuvant treatment throughout this regimen. A rigorous clinical monitoring protocol is necessary for all patients during therapy. Treatment strategies are recommended to protect patients from the many adverse effects of prolonged corticotherapy. These approaches include the use of an H2 blocker or proton pump inhibitor for gastric ulcer prophylaxis and bisphosphonate supplementation (daily, weekly, or monthly), calcium (1000 to 1500mg daily), and vitamin D (800 to 1000IU per day) for prophylaxis of osteoporosis and strongyloidiasis before immunosuppression. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] Therapeutic approaches to patients with mucous membrane pemphigoid, Kourosh [/bib_ref] Immunosuppressants Azathioprine Azathioprine is one of the choices for adjuvant therapy in MMP, as long as the disease is not progressing rapidly or is threatening vision. A delay in its introduction, up to 8 weeks, limits its initial use as monotherapy. The dose of azathioprine (1-3 mg/kg/day) should be individualized, based on the activity of thiopurine methyltransferase (TPMT), an enzyme that is involved in drug metabolism. The main side effects of azathioprine include hepatotoxicity, hypersensitivity syndrome, and neutropenia. Regular laboratory monitoring should be performed for early detection of adverse effects. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] Therapeutic approaches to patients with mucous membrane pemphigoid, Kourosh [/bib_ref] Mycophenolate mofetil Mycophenolate mofetil is an immunosuppressive agent that reversibly inhibits inosine monophosphate dehydrogenase. Unlike other cell lines, T and B lymphocytes depend on this pathway for purine synthesis, which is essential for cell proliferation. Its use has had good results in disease control, with a favorable safety profile and limited side effects compared with other immunosuppressants, such as azathioprine and methotrexate. [bib_ref] Treatment of cicatricial pemphigoid with mycophenolate mofetil as a steroid-sparing agent, Megahed [/bib_ref] [bib_ref] Treatment of mucous membrane pemphigoid with mycophenolate mofetil, Nottage [/bib_ref] Treatment with low doses should be started by gradually, increasing the dose according to the clinical effect and the appearance of adverse effects; in certain cases, it will be necessary to switch to mycophenolate sodium. The daily dosage can reach 2 to 3g/day, divided into 2 doses. Once disease control is achieved and maintained for several months, mycophenolate mofetil can be reduced gradually and even discontinued. [bib_ref] Therapeutic approaches to patients with mucous membrane pemphigoid, Kourosh [/bib_ref] The most common side effects of mycophenolate mofetil are gastrointestinal complaints. But the cytopenias are the major concerns and require regular monitoring. A complete blood count with differential can be obtained at baseline and every two weeks during the first two to three months of therapy, then once monthly within the first year, and every three months thereafter. 73 ## Methotrexate Although the use of methotrexate is simple and although dermatologists are familiar with its administration, it is not commonly used as adjuvant therapy in mucous membrane pemphigoid. However, it can be considered as an option in patients with contraindications or those who have failed other adjuvant agents. The dose of methotrexate is more suitable for patients with mild to moderate disease. Low weekly dosages (10 to 17.5mg per week) have been effective and well tolerated. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] Methotrexate therapy for ocular cicatricial pemphigoid, Mccluskey [/bib_ref] Folic acid supplementation helps prevent gastrointestinal adverse effects and elevated transaminase levels. Patients should be monitored regularly by laboratory testing, adjusting the dose as necessary. [bib_ref] Treatment strategies in mucous membrane pemphigoid, Neff [/bib_ref] [bib_ref] Effect of folic or folinic acid supplementation on methotrexateassociated safety and efficacy..., Prey [/bib_ref] Cyclophosphamide Cyclophosphamide is a rapid and effective therapeutic agent and is reserved for patients with severe, rapidly progressing disease or those who have not responded to other immunosuppressive agents. It can be administered alone (1-2mg/kg/day) or in combination with corticosteroids in high doses (prednisone 1-1.5mg/ kg per day). [bib_ref] The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic..., Chan [/bib_ref] In some cases, more aggressive treatment with pulse therapy is required at 1g/day or 10-15mg/kg/day, in combination with dexamethasone 100mg on the first day, followed by dexamethasone only on the other 2 days; this cycle may be repeated every 26 days, depending on symptomatology. Regular laboratory moni-toring includes a complete differential blood count and urinalysis. Due to its potential toxicity, cyclophosphamide should be used as a short-term therapy and replaced with an alternative adjuvant after disease control has been achieved. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] Oral cyclophosphamide without corticosteroids to treat mucous membrane pemphigoid, Munyangango [/bib_ref] Immunoglobulin Intravenous immunoglobulin (IVIG) is an immunomodulatory agent that is composed of polyclonal antibodies and derived from the plasma of a large group of healthy donors. Its mechanism of action is unclear; it appears to regulate the immune system in various ways. It is not a first-line treatment, but it may be beneficial for patients with severely debilitating, potentially fatal, and rapidly progressing disease. Patients who do not respond to conventional therapy, discontinue it due to severe side effects, or have contraindications are also candidates for IVIG. Immunosuppressive agents increase the risk of the reactivation of chronic infections, such as HBV and HCV. Therapeutic combination with IVIG reduces the risk of reactivation and contributes to clinical improvement. [bib_ref] The role of intravenous immunoglobulin in treatment of mucous membrane pemphigoid: A..., Tavakolpour [/bib_ref] IVIG has a relatively safe response and rapid efficacy compared with conventional treatments. The suggested dose is 2/kg per cycle. One cycle consists of the total dose divided into equal doses over a period of 3 to 5 days. The need for subsequent cycles should be assessed according to the clinical response. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] Treated patients have shown excellent results, with significantly shorter treatment durations, fewer relapses, higher remission rates, fewer adverse effects, and better quality-of-life assessments compared with conventional therapy. [bib_ref] Comparison between intravenous immunoglobulin and conventional immunosuppressive therapy regimens in patients with..., Ahmed [/bib_ref] Most patients do not have serious adverse effects, rendering the treatment safe. The major limitation of IVIG use is its high cost. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] The role of intravenous immunoglobulin in treatment of mucous membrane pemphigoid: A..., Tavakolpour [/bib_ref] Rituximab Rituximab is a chimeric monoclonal antibody (murine and human) that is directed against CD20 on pre-B and B lymphocytes, depleting these cells from circulation for 6 to 12 months. It is not a first-line treatment, due to the absence of confirmatory studies. However, it has been used successfully for the treatment of severe pulmonary arterial hypertension, especially in patients who have not responded to conventional therapy or have had serious side effects or contraindications. A rituximab cycle is administered at a dose of 375mg/m², administered weekly for 4 consecutive weeks. IVIG, systemic corticosteroids, and other immunosuppressive agents are often given concomitantly with rituximab. After the induction cycle, long-term infusion therapy every 4 or 12 weeks may be performed or according to clinical need. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] Rituximab for patients with refractory mucous membrane pemphigoid, Roux-Villet [/bib_ref] The most common adverse effects are associated with infusion reactions, often related to the rate of administration and hypersensitivity reactions (fever, chills, bronchospasm, pruritus, and hypotension). Rituximab is contraindicated in pregnancy; patients of childbearing age should use effective contraception during its use and up to 12 months afterward. [bib_ref] The management of mucous membrane pemphigoid and pemphigus, Knudson [/bib_ref] [bib_ref] Off-label use of rituximab in dermatology: pemphigus treatment, Bomm [/bib_ref] Anti-TNF alpha agents In addition to conventional treatments, anti-TNF alpha agents have been reported to be effective in mucous membrane pemphigoid, perhaps merited by the high serum TNF-alpha levels In the latter, an early aggressive approach helps stop the inflammatory process and prevent scarring. [bib_ref] The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic..., Chan [/bib_ref]. We believe that long-term follow-up of these patients should be performed to detect relapses and initiate early therapeutic intervention, and previous pulses or cycles may be repeated. ## Figure 2: Mucous membranes pemphigoid treatment algorithm. Low risk: disease limited to oral mucosa with or without cutaneous involvement High risk: ocular, pharyngeal, laryngeal, esophageal, and/or genital lesions * Prednisone at a dosage of 1-2mg/kg/day should be maintained between pulse therapy intervals ## I) The classical or mechanobullous form is observed in approximately one-third of EBA patients and is characterized by skin fragility in trauma-prone areas, with tense blisters, erosions, atrophic scars, milia formation, anonychia, and digital contracture, especially on the fingers. [bib_ref] Epidermolysis bullosa acquisita, Kim [/bib_ref] [bib_ref] Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita, Ludwig [/bib_ref] II) The bullous pemphigoid-like variant presents as vesicles and blisters with erythematous or urticarial lesions, usually without skin fragility or milia formation, mainly in the extremities, trunk, and skin folds. 93 ## Iii) The cicatricial pemphigoid-like form presents with exclusive or predominant mucous involvement, affecting any stratified squamous cell epithelia, such as ocular, oral, nasal, laryngeal, esophageal, and genital mucosa. 94 ## Iv) The Brunsting-Perry pemphigoid-like variant is defined as a vesiculobullous eruption on the head and neck, which may eventually have oral involvement. [bib_ref] Epidermolysis Bullosa Acquisita (Brunsting-Perry Pemphigoid Variant) Localized to the Face and Diagnosed..., Asfour [/bib_ref] The linear IgA bullous dermatosis-like form is characterized by edematous plaques with tense blisters and vesicules that can present in annular or polycyclic arrangement. In this form of EBA, the direct immunofluorescence demonstrates linear IgA deposition in the BMZ. [bib_ref] Clinical features and diagnosis of epidermolysis bullosa acquisita, Vorobyev [/bib_ref] The differential diagnosis of EBA includes bullous systemic lupus erythematosus, porphyria cutanea tarda, and other subepidermal bullous dermatosis, as mentioned in the clinical variants. ## Diagnosis The ## Ii) general skin care Local care should be encouraged for better disease control. Similar to inherited epidermolysis bullosa, the general care includes the prevention of local trauma and infection and the use of non-adherent dressings. 98 ## Iii) systemic treatment a) introduction A Cochrane systematic review found 11 non-randomized studies of treatment for EBA, involving interventions in 20 adults and 11 children.Adult patients were treated with various therapeutic modalities, including systemic corticosteroids, immunosuppressants, dapsone, colchicine, and intravenous immunoglobulin. Most children were treated with systemic corticosteroids and/or dapsone. The authors concluded that there is no recommendation for treating EBA, based on reliable evidence. ## B) medications Corticosteroids EBA patients, especially those of the mechanobullous form, usually do not experience a good therapeutic response to systemic corticosteroids, such as in other autoimmune blistering diseases. Despite this limitation, systemic corticosteroids are still considered the first-line treatment for EBA, with usual dosages of 0.5-1.5mg/kg/day; they can be used as monotherapy in some cases of mild disease. [bib_ref] Epidermolysis bullosa acquisita: what's new?, Ishii [/bib_ref] A retrospective Spanish study of 12 patients with EBA showed that a dosage greater than 15mg/day is required to control disease activity. [bib_ref] Epidermolysis bullosa acquisita: a retrospective analysis of 12 patients evaluated in four..., Iranzo [/bib_ref] However, most patients require adjuvant treatment for better disease control or to avoid undesirable side effects of prolonged use of corticosteroids, such as obesity, hypertension, and osteoporosis. One study demonstrated that the use of methylprednisolone at a high dosage (> 8mg/day) led to earlier remission compared with low-dose use (≤ 8mg/day) and that some patients obtained a good response to pulse therapy with methylprednisolone (500mg for 3 days). 102 ## Anti-inflammatory agents (dapsone, colchicine, tetracycline) The main anti-inflammatory benefits of these medications are exerted by an antineutrophilic action. [bib_ref] Management of epidermolysis bullosa acquisita, Intong [/bib_ref] Dapsone use has been described in several cases of EBA. [bib_ref] Epidermolysis bullosa acquisita: a retrospective analysis of 12 patients evaluated in four..., Iranzo [/bib_ref] [bib_ref] Epidermolysis bullosa acquisita: a retrospective clinical analysis of 30 cases, Kim [/bib_ref] [bib_ref] Clinical and immunopathological evaluation of epidermolysis bullosa acquisita, Delgado [/bib_ref] The commonly used dosages range from 25-100mg/ day or 1-2mg/kg/day, with a favorable response being reported in adult and pediatric cases. [bib_ref] Current concepts in the treatment of epidermolysis bullosa acquisita, Gürcan [/bib_ref] It should be noted that unlike the condition in adults, EBA in childhood tends to have a better prognosis, usually with a good response to dapsone and systemic corticosteroid. [bib_ref] Childhood Epidermolysis Bullosa Acquisita: Confirmation of Diagnosis by Skin Deficient in Type..., Goyal [/bib_ref] [bib_ref] Childhood epidermolysis bullosa acquisita: report of a Chinese case, Yang [/bib_ref] The proposed protocols for the treatment of EBA in the literature include dapsone as one of the first therapeutic options, combined with systemic corticosteroid therapy, primarily for the mild forms of EBA. [bib_ref] Epidermolysis bullosa acquisita: what's new?, Ishii [/bib_ref] [bib_ref] Epidermolysis bullosa acquisita: a retrospective analysis of 12 patients evaluated in four..., Iranzo [/bib_ref] Common medication side effects include hemolysis and methemoglobinemia. [bib_ref] Autoimmune bullous dermatoses in the elderly: an update on pathophysiology, diagnosis and..., Mutasim [/bib_ref] The efficacy of colchicine in EBA was reported for the first time in 1989, with dosages ranging from 0.5-2mg/day. [bib_ref] Colchicine: an ancient drug with novel applications, Dasgeb [/bib_ref] Among adjuvant treatments, colchicine is considered a first-line agent and is frequently associated with systemic corticosteroids. [bib_ref] Epidermolysis bullosa acquisita: what's new?, Ishii [/bib_ref] Although it is less common, colchicine has also been reported as a monotherapy, yielding a good clinical response. [bib_ref] Oral colchicine monotherapy for epidermolysis bullosa acquisita: Mechanism of action and efficacy, Adachi [/bib_ref] However, its side effects, especially diarrhea, can limit its use, making it difficult to achieve a sufficient dose to control the disease in certain patients. [bib_ref] Treatment of subepidermal immunobullous diseases, Culton [/bib_ref] Minocycline is a broad-spectrum tetracycline that inhibits the recruitment of neutrophils and eosinophils as well as cytokine production. [bib_ref] Inflammatory epidermolysis bullosa acquisita effectively treated with minocycline, Kawase [/bib_ref] A Japanese study that evaluated the clinical and immunological aspects of 105 patients with EBA described minocycline as one of the most common therapeutic options, having been used in 16 patients; however, details regarding the therapeutic response were not specified. [bib_ref] Clinical and immunological studies for 105 Japanese seropositive patients of epidermolysis bullosa..., Hashimoto [/bib_ref] A recent case report showed a patient with an inflammatory form of EBA who was treated with various therapeutic options, such as systemic corticosteroid, cyclosporine, and dapsone, responding to the combination of minocycline (200mg/day) and systemic corticosteroid. [bib_ref] Inflammatory epidermolysis bullosa acquisita effectively treated with minocycline, Kawase [/bib_ref] This study suggested that minocycline may be considered as a therapeutic option in EBA, mainly as an adjuvant in inflammatory forms of the disease. ## Immunosuppressants (azathioprine, mycophenolate mofetil, cyclosporine, methotrexate) These medications are commonly used as systemic corticosteroid-sparing agents. Azathioprine has varying results in the literature. [bib_ref] Epidermolysis bullosa acquisita: a retrospective analysis of 12 patients evaluated in four..., Iranzo [/bib_ref] [bib_ref] Clinical and immunopathological evaluation of epidermolysis bullosa acquisita, Delgado [/bib_ref] [bib_ref] Epidermolysis bullosa acquisita with moderately severe Dysphagia due to esophageal strictures, Tu [/bib_ref] Although its use is well established in pemphigus vulgaris, its application in EBA is less convincing, with other medications, such as dapsone and mycophenolate mofetil, being preferred more often. [bib_ref] Immunosuppressive therapy for autoimmune bullous diseases, Meurer [/bib_ref] Mycophenolate mofetil (MMF) is an immunosuppressive agent that alters the proliferation of B and T lymphocytes. [bib_ref] Treatment of subepidermal immunobullous diseases, Culton [/bib_ref] In EBA, MMF has been reported to be effective in some refractory cases. 105 A recent study described 4 patients with EBA who were treated with MMF at 2 to 3g/day, with success. [bib_ref] Mycophenolate mofetil (MMF) in the treatment of epidermolysis bullosa acquisita (EBA) long-term..., Sami [/bib_ref] One of the limiting factors of its use in daily practice is its high cost. Cyclosporine is usually used at doses of 4-9mg/kg, leading to disease improvement in recalcitrant cases. [bib_ref] Management of epidermolysis bullosa acquisita, Intong [/bib_ref] [bib_ref] Current concepts in the treatment of epidermolysis bullosa acquisita, Gürcan [/bib_ref] A report of 2 patients with the rare association of EBA and acquired hemophilia A demonstrated a good therapeutic response with prednisone and cyclosporine, with no adverse effects. [bib_ref] Coexistence of acquired hemophilia A and epidermolysis bullosa acquisita: Two case reports..., Yan [/bib_ref] In addition, cyclosporine is considered a relatively safer immunosuppressive drug in pregnancy. [bib_ref] Immunosuppressive therapy for autoimmune bullous diseases, Meurer [/bib_ref] Methotrexate is a folic acid analogue and antimetabolite that inhibits the synthesis of DNA and RNA, impairing lymphocyte function. [bib_ref] Autoimmune bullous dermatoses in the elderly: an update on pathophysiology, diagnosis and..., Mutasim [/bib_ref] There are no reports of monotherapy in patients with EBA and no data that documents its effectiveness as a systemic corticosteroid-sparing agent in EBA, reserving its use for refractory cases of the disease. 92 ## Intravenous immunoglobulin (ivig) IVIG modulates the autoimmune response, reducing and neutralizing antibodies. [bib_ref] Intravenous immunoglobulin for treatment of severe acquired bullous epidermolysis refractory to conventional..., Mosqueira [/bib_ref] It is usually administered at 2g/kg/ cycle over 3 to 5 days as monotherapy or in combination with other drugs, such as systemic corticosteroid and dapsone, with good response in patients with recalcitrant disease. [bib_ref] Management of epidermolysis bullosa acquisita, Intong [/bib_ref] [bib_ref] Intravenous immunoglobulin for treatment of severe acquired bullous epidermolysis refractory to conventional..., Mosqueira [/bib_ref] One long-term study evaluated 10 patients with EBA that were resistant to conventional therapy after IVIG administration, resulting in a satisfactory response in all cases. [bib_ref] Treatment of epidermolysis bullosa acquisita with intravenous immunoglobulin in patients non-responsive to..., Ahmed [/bib_ref] ## Extracorporeal photopheresis (ecp) ECP is an immunomodulatory therapy that was initially used in cutaneous T cell lymphoma that consists on the separation of a peripheral blood leukocyte/lymphocyte-enriched cellular fraction, extracorporeal treatment of 8-MOP/UVA cells, and subsequent reinfusion of cells into the patient. [bib_ref] Remission of severe autoimmune bullous disorders induced by long-term extracorporeal photochemotherapy, Sanli [/bib_ref] Its main effect in EBA appears to be associated with inhibiting the production of pathogenic autoantibodies by B lymphocytes and producing regulatory T cells. [bib_ref] Epidermolysis bullosa acquisita: current diagnosis and therapy, Mehren [/bib_ref] ECP has proven to be efficient in inducing partial to complete remission in patients with recalcitrant EBA and is considered a well-tolerated therapy, with promising results. [bib_ref] Long-term efficacy of extracorporeal photochemotherapy in a patient with refractory epidermolysis bullosa..., Baroudjian [/bib_ref] [bib_ref] The successful use of extracorporeal photopheresis in a 12-year-old patient with refractory..., Liszewski [/bib_ref] [bib_ref] Extracorporeal photopheresis for the treatment of autoimmune diseases, Adamski [/bib_ref] In the literature, a recent review revealed that 8 patients with severe and refractory EBA were treated with ECP, all of which progressed with clinical improvement. [bib_ref] Extracorporeal photopheresis for the treatment of autoimmune diseases, Adamski [/bib_ref] European guidelines on ECP states that such treatment can be used in severe and refractory cases of EBA. 124 ## Rituximab Rituximab is a chimeric anti-CD20 monoclonal antibody that causes B cell depletion through various mechanisms and is approved for the treatment of B cell lymphoma, rheumatoid arthritis, and granulomatosis with polyangiitis. [bib_ref] Effectiveness and Safety of Rituximab in Recalcitrant Pemphigoid Diseases, Lamberts [/bib_ref] In the context of autoimmune bullous diseases, its use was initially described for recalcitrant cases of pemphigus and, recently, as first-line treatment in combination with short term prednisone, being effective and potentially safer than a standard regimen of high doses of corticosteroids in patients with moderate to severe pemphigus. [bib_ref] First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment..., Joly [/bib_ref] [bib_ref] Rituximab in pemphigus, Hebert [/bib_ref] Rituximab use in subepidermal bullous diseases, however, is more limited. In EBA, a few promising case reports have been described, usually in patients with recalcitrant disease who have undergone several treatments before rituximab (such as systemic corticosteroid, dapsone, azathioprine, cyclosporine, mycophenolate, and cyclophosphamide), with an effective response. [bib_ref] Refractory epidermolysis bullosa acquisita: successful treatment with rituximab, Saha [/bib_ref] [bib_ref] Successful treatment of epidermolysis bullosa acquisita with rituximab therapy, Kim [/bib_ref] [bib_ref] A case of recalcitrant epidermolysis bullosa acquisita responsive to rituximab therapy, Mckinley [/bib_ref] [bib_ref] Successful use of combined corticosteroids and rituximab in the treatment of recalcitrant..., Cavailhes [/bib_ref] The therapeutic scheme was usually 375mg/m 2 weekly, administered over 4 weeks. Another proposed scheme is 1g, administered on Days 0 and 14. Rituximab (375mg/m 2 weekly, managed over 4 weeks), combined with IVIG (2g/kg/monthly cycle), was given to 4 patients who were resistant to conventional therapy, showing an effective and efficient response. [bib_ref] Longterm results of rituximab-intravenous immunoglobulin combination therapy in patients with epidermolysis bullosa..., Oktem [/bib_ref] In addition, rituximab combined with protein A immunoadsorption has, in some cases, resulted in favorable outcomes. [bib_ref] Premonitory epidermolysis bullosa acquisita mimicking eyelid dermatitis: successful treatment with rituximab and..., Kubisch [/bib_ref] [bib_ref] Treatment of severe autoimmune blistering skin diseases with combination of protein A..., Kolesnik [/bib_ref] In the authors' personal experience, 5 patients with EBA were treated with rituximab. All patients presented with mechanobullous form, severe mucosal impairment and were resistant to conventional therapy, including systemic corticosteroid therapy (1mg/kg/day), dapsone (100mg/day), cyclosporine (5mg/kg), azathioprine (150mg/day), and mycophenolate mofetil (3g/day). In most cases, rituximab was administered following the rheumatoid arthritis protocol, at 1g IV on Day 0 and 1g IV on Day 14. All patients needed a new drug cycle after 6 months. At present, 2 patients are in complete remission, 1 is in partial remission, and 2 experienced disease relapse after being in complete remission for 1 year. ## Iv) classification of eba severity There is no standardized severity score for EBA; 2 recent classifications have been proposed in the literature: Classification I: [bib_ref] Management of epidermolysis bullosa acquisita, Intong [/bib_ref] -Mild EBA: < 5% of body surface affected, without mucosal involvement. -Moderate EBA: 5% to 15% of body surface affected with at most 2 affected mucous membrane sites, not including ocular involvement. -Severe EBA: > 5% of body surface affected and > 2 mucous membrane sites involved or ocular involvement. In mild forms of EBA, use of prednisone (0.5-1mg/kg/day) with additional colchicine and dapsone is suggested. Prednisone In the non-severe localized form, topical corticosteroids are suggested, whereas in the non-severe, more diffuse form, the use of colchicine, dapsone, sulfasalazine, and topical corticosteroid is advised. In severe EBA, cyclosporine or IVIG is recommended; rituximab or ECF can be considered as an alternative. Systemic corticosteroid therapy is reserved for urgent cases, such as laryngeal edema. The authors of this consensus propose the following classification of EBA severity: -Non-severe EBA: up to 10% of total body surface involved without functional alteration (flexion contracture of fingers) and absence of severe mucosal involvement (ocular, laryngeal, or esophageal). -Severe EBA: greater than 10% of total body surface area affected, and/or presence of functional alteration (flexion contracture of fingers), and/or severe mucosal involvement (ocular, laryngeal, or esophageal), or non-severe EBA that is unresponsive to the proposed treatment. This classification was used for the treatment algorithm below. ## V) proposed treatment algorithm In the non-severe form of EBA, the first treatment option suggested by the authors is colchicine (0.5-2mg/day) or dapsone (50-100mg/day). If a partial response occurs, prednisone should be added at 0.5-1mg/kg/day. If absence of clinical response and/or side effect, treatment should be replaced for prednisone (0.5-1mg/kg/day). [fig_ref] Figure 3: Proposed treatment algorithm for epidermolysis bullosa acquisita [/fig_ref] In the severe form of EBA, the first treatment option suggested is IVIG (2g/kg over 5 days) in combination with oral systemic corticosteroid (1-1.5mg/kg/day) or pulse therapy with methylprednisolone (1g IV for 3 days). If partial or absence of response occurs, an immunosuppressant, such as mycophenolate mofetil (2-3g/day), cyclosporine (5mg/kg/day), or azathioprine (100-200mg/day), should be introduced. In refractory cases, rituximab is suggested, at the dosage of 1 g IV on Days 0 and 14 or 375mg/m 2 weekly over 4 weeks, every 6 months. Immunosuppressive therapy (MMF, cyclosporine, or azathioprine) should be discontinued in case of no thera-Consensus on the treatment of autoimmune bullous dermatoses: bullous pemphigoid, mucous membrane pemphigoid... peutic response or side effects. In cases of partial response to such immunosuppressants, they may be maintained in combination with rituximab. However, one should consider the possible side effects of this association, especially infectious ones. The possibility of infectious prophylaxis should be considered. Oral corticosteroids should be maintained at a dosage of 1mg/kg/day until the development of new lesions is interrupted and pre-existing lesions begin to heal (average of 4 weeks). Afterward, a reduction of 10mg every 2 weeks should be made until the dose reaches approximately 0.5mg/kg. Thereafter, reductions should be made by 10mg every 4 weeks, according to the patient's clinical evolution. When the dosage reaches 7.5 to 5mg/day of prednisone, absolute care should be taken due to adrenal gland suppression. Prednisone at a dosage of 5mg/day should be replaced with hydrocortisone at 20mg at 8 hours and 10mg at 14 hours until the serum cortisol level exceeds 10µg/dL or, ideally, 18µg/dL. Attention should be given to stressful situations (such as surgeries and infections), in which the dose of hydrocortisone should be doubled. In the case of pulse therapy, at the end of 3 days, corticosteroid therapy should be maintained through oral administration of prednisone at 0.5 to 1mg/kg/day. ## Evolution and prognosis EBA is a disease that can evolve with high morbidity due to its potential for scarring. The cutaneous involvement in EBA can progress with extensive erosions, atrophic scars, nail dystrophies, and fibrosis, with flexion contracture of fingers, limiting adequate mobility. Different mucosal sites with stratified squamous epithelium may be affected, such as the conjunctival, upper airway, oral, esophageal, genital, and anal areas. Ocular involvement in EBA is frequent, with various forms of presentation, including conjunctivitis, symblepharon, keratitis, subepithelial vesiculation, perforation, and corneal opacification. [bib_ref] Ocular involvement in IgA-epidermolysis bullosa acquisita, Bauer [/bib_ref] [bib_ref] IgA-epidermolysis bullosa acquisita in a child resulting in blindness, Caux [/bib_ref] In severe cases, blindness may occur. [bib_ref] Ocular involvement in IgA-epidermolysis bullosa acquisita, Bauer [/bib_ref] [bib_ref] IgA-epidermolysis bullosa acquisita in a child resulting in blindness, Caux [/bib_ref] [bib_ref] Severe ocular involvement in a patient with epidermolysis bullosa acquisita, Lang [/bib_ref] Upper airway involvement can occur, with formation of synechia, erosions, thickening of the epiglottis, and supraglottic stenosis. [bib_ref] Beware the blistering patient with dysphonia, Benton [/bib_ref] Some cases result in acute airway obstruction, requiring a tracheostomy. [bib_ref] Beware the blistering patient with dysphonia, Benton [/bib_ref] [bib_ref] Epidermolysis bullosa acquisita--a case with upper airways obstruction requiring tracheostomy and responding..., Clement [/bib_ref] Esophageal involvement may present as the formation of erosions and stenosis and dysphagia. [bib_ref] Epidermolysis bullosa acquisita with moderately severe Dysphagia due to esophageal strictures, Tu [/bib_ref] [bib_ref] Oesophageal involvement in epidermolysis bullosa acquisita, Ishii [/bib_ref] Sometimes, patients must undergo periodic esophageal dilations and, in extreme cases, gastrostomy. Mucosal involvement may occur in a silent, chronic manner and progress to life-threatening complications. [bib_ref] Mucosal morbidity in patients with epidermolysis bullosa acquisita, Luke [/bib_ref] Such impairments worsen the patients' prognosis, impacting their quality of life and requiring long-term clinical and laboratory follow-up. [bib_ref] Clinical and immunopathological evaluation of epidermolysis bullosa acquisita, Delgado [/bib_ref] In this context, multidisciplinary follow-up becomes mandatory for the early diagnosis and detection of subclinical lesions, thus preventing subsequent severe complications. In addition, mucosal involvement may render the disease more difficult to control, requiring aggressive immunosuppressive therapy. # Conclusion [fig] , 38 CLINICAL: CONDITION The tegumentary manifestations of BP are extremely polymorphic. In the non-blistering phase, the signs and symptoms are usually nonspecific, presenting as isolated pruritus, sometimes intractable or associated with excoriations, papules, or urticarial lesions, which may persist from weeks to months. Vesicles or blisters on apparently normal or erythematous basis, in addition to infiltrated papules and plaques that occasionally assume annular and figurative patterns, can characterize the bullous phase of BP. The blisters are smooth, with diameters ranging from 1 to 4cm, containing clear fluid, leaving crusted and eroded areas. The lesions often have a sym-metrical distribution, predominating in the limb flexures and chest. [/fig] [fig] Figure 1: The flowchart represents the modified consensus of bullous pemphigoid (BP) treatment DIF IIF-SSS ELISA anti-BP180/230 [/fig] [fig] ETIOPATHOGENESIS: MMP is characterized by the linear deposition of IgG, IgA, or C3 along the epithelial basement membrane area.53 Current evidence suggests that this process develops as a consequence of the loss of immune tolerance to structural proteins of the epidermal basement membrane, culminating in the development of circulating autoantibodies that bind to the epidermal basement membrane, causing inflammation and weakening the adhesion of the overlying epidermis.52 Studies have shown that the target antigens in the epithelial basement membrane area include bullous pemphigoid antigen 1 (BP230), bullous pemphigoid antigen 2 (BP180), laminin 5 (α3, β3, γ2 chains), laminin 6 (α3 chain), type VII collagen, and the β4 integrin subunit.53 BP180 is a transmembrane protein that crosses the lamina lucida and protrudes into the dense lamina of the epidermal basement membrane zone; it is usually the target antigen in approximately 70% of MMP patients. Serum from patients with generalized and ocular MMP recognizes the β-4 integrin subunit, whereas serum from those with oral MMP recognizes the α-6 integrin subunit. The pathogenicity of anti-laminin 332 has been documented in vivo. Passive transfer of anti-laminin 332 IgG to mice induces subepidermal blistering on the skin and mucous membranes, mimicking the clinical, histopathological, and immunological characteristics of patients with MMP. 54 Fibroblasts also appear to be activated, secondary to the production of cytokines, such as transforming growth factor beta, which is known to induce fibrosis. The collagen that is produced can lead to scars. Several studies have shown a predominance of CD4 T lymphocyte and Langerhans cell infiltrates in the conjunctiva of patients with MMP, indicating the involvement of cellular immunity in its pathogenesis. Studies have linked MMP and the human leukocyte antigen (HLA) class II HLA-DQB1 * 0301 allele. 55 CLINICAL CONDITION MPP can affect the mucous membrane from several sites, occasionally with skin involvement. It is a chronic, progressive condition that most often affects the oral mucosa (85% of patients), followed by the ocular conjunctiva (65%), nasal mucosa (20-40%), skin (25-30%), anogenital region and pharynx (20%), larynx (5-15%), and esophagus (5-15%). There is a wide range in the variability and severity of presentations among patients, who can present with localized and generalized involvement. Those who present with only oral mucosal or skin involvement with a lower tendency toward scarring are defined as "low risk," whereas in patients who are at "high risk," the disease occurs in general ocular, esophageal, laryngeal, nasopharyngeal, and anogenital mucosae. The propensity for generating scars in these sites is associated with a poor prognosis, despite treatment. 56 Involvement of the oral mucosa typically manifests as erythematous plaques and erosions that are covered by pseudomembranes, most commonly located on the gum and palate and less frequently on the lips, tongue, and cheek mucosa. Gingival lesions are often described as desquamative gingivitis, also found in lichen planus and pemphigus vulgaris. The most common ocular lesions are conjunctival inflammation and erosions, forniceal shortening with formation of symblepharon, trichiasis, entropion, and cornea neovascularization, which may result in blindness. The most frequently affected skin areas are the scalp, face, neck, and upper chest. [/fig] [fig] -: diagnosis of EBA comprises histopathological analysis and direct (DIF) and indirect (IIF) immunofluorescence, which allow the diagnosis of subepidermal bullous dermatosis. However, they are not always conclusive for the diagnosis of EBA. The definite diagnosis of EBA requires additional techniques that are only available in research centers. The histopathological evaluation of injured skin in patients with EBA shows subepidermal cleavage, with varying degrees of inflammatory infiltrate. In the mechanobullous form, the inflammatory infiltrate is absent or minimal, whereas in the inflammatory forms of EBA, it is composed of neutrophils with variable numbers of eosinophils, monocytes, and lymphocytes. 94 DIF of perilesional skin reveals linear deposition of IgG and C3 along the BMZ. Occasionally, IgA and/or IgM may be present. Serration pattern analysis by DIF allows a differential diagnosis between EBA and bullous pemphigoid, which present as U and N patterns, respectively. 96 IIF of normal human skin also identifies IgG deposits with a linear pattern in the BMZ. The saltsplit skin technique, which produces BMZ cleavage in the lamina lucida, shows IgG deposition on the dermal side of the cleavage in EBA, whereas in bullous pemphigoid, this deposit is present on the epidermal or epidermal and dermal side of the cleavage. TREATMENT EBA is often refractory to various therapeutic modalities, which makes its longterm remission a challenge. Because it is a rare disease with several clinical presentations, there are no randomized clinical trials in the literature, compromising the selection of an ideal treatment. The inflammatory form of EBA apparently has a more favorable clinical response to conventional therapy with corticosteroids and corticosteroidsparing agents than the mechanobullous form. 97 I) Clinical and laboratory evaluation prior to immunosuppressive therapy Multidisciplinary evaluation for diagnosis of mucosal involPregnancy (pregnancy test and contraception) ePIdermolYsIs Bullosa aCQuIsIta t An Bras Dermatol. 2019;94(2 Suppl 1):S3347. [/fig] [fig] Figure 3: Proposed treatment algorithm for epidermolysis bullosa acquisita (EBA) IVIG -intravenous immunoglobulin [/fig]	None	http://www.scielo.br/pdf/abd/v94n2s1/0365-0596-abd-94-02-s1-0033.pdf	Bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita are subepidermal autoimmune blistering diseases whose antigenic target is located at the basement membrane zone. Mucous membrane pemphigoid and epidermolysis bullosa acquisita can evolve with cicatricial mucosal involvement, leading to respiratory, ocular and/or digestive sequelae with important morbidity. For each of these dermatoses, a literature review covering all therapeutic options was performed. A flowchart, based on the experience and joint discussion among the authors of this consensus, was constructed to provide treatment orientation for these diseases in Brazil. In summary, in the localized, low-risk or non-severe forms, drugs that have immunomodulatory action such as dapsone, doxycycline among others may be a therapeutic option. Topical treatment with corticosteroids or immunomodulators may also be used. Systemic corticosteroid therapy continues to be the treatment of choice for severe forms, especially those involving ocular, laryngeal-pharyngeal and/or esophageal mucosal involvement, as may occur in mucous membrane pemphigoid and epidermolysis bullosa acquisita. Several immunosuppressants are used as adjuvant alternatives. In severe and recalcitrant cases, intravenous immunoglobulin is an alternative that, while expensive, may be used. Immunobiological drugs such as rituximab are promising drugs in this area. Omalizumab has been used in bullous pemphigoid.
ed3f00ec119df00701450a98d40f9611c777c464	pubmed	Standards of Care for Patients with Neurological Disease: A Consensus. Report of a Working Group	Standards of Care for Patients with Neurological Disease: A Consensus. Report of a Working Group ## Systems of care The management of all the neurological diseases under discussion involves both family doctor and consultant neurologist. Some patients with Parkinson's disease may be under the care of a consultant geriatrician, and some cases of epilepsy under a consultant paediatrician. The consultant is usually involved in confirming or making the diagnosis and deciding upon appropriate investigation. Each health district should formulate a policy for caring for those with chronic physical disabilities, with active rehabilitation services for those who can be improved, and with organised systems of care for these, and also for those whose diseases, like motor neurone disease, are advancing. Disabled people may be less handicapped if relatively modest adjustments to their homes are made, and if physical aids are promptly provided after skilled assessment. Every district should have a hospital based assessment team, including a physiotherapist and an occupational therapist, who can determine, together with the patient, the relatives and the family doctor, the patient's present and likely future needs. Professional care must be shared. The neurologist and family doctor must liaise about advice on employment, eligibility to hold a driving licence, recreation, diet, and treatment of associated symptoms and diseases. Continuity of care is essential so that, even though care of the neurologically disabled patient is shared, the patient knows whom to contact, and how to make contact, for further advice. The extent to which the long-term care of each patient is hospital or community based will vary depending on the particular manifestations of the disease and the expectations held by individual patients and their relatives. We believe that some districts should appoint and evaluate the effectiveness of 'keyworkers' assigned to individual patients. Keyworkers might have professional training in one of a number of disciplines, such as nursing, social work or physiotherapy, but would need to acquire some expertise across all relevant disciplines so that they could give 'first level' advice to their patients. Keyworkers should be appointed by and be professionally and managerially accountable to consultant members of a department of neurology. Keyworkers could be appointed within existing resources by replacing, for example, a physiotherapist. Since the Government has adopted the Griffiths report, budgetary arrangements for keyworkers' domiciliary care will need to be made with local authorities. The keyworkers should be part of the District Disability Assessment Team, and would seek advice from team members in other professions. The keyworker would devise and help maintain a record card held by the patient, on which all relevant professions made entries. Arrangements for outpatient care should be flexible but, for the diseases considered here, consultant neurological supervision should be available at intervals that are determined by the rate of progression of the illness or by the difficulty in controlling symptoms. Patients and their relatives, their family doctors and neurologist must all define and agree on the objectives of outpatient visits. Outpatient appointments for 'old' patients may more readily be found if patients in remission with, for example, multiple sclerosis or epilepsy are not seen needlessly on a 'routine' basis. Particular problems arise in providing continuity of care for patients with epilepsy. Patients with continuing seizures are too often relegated to management by registrars, and therefore tend to suffer because of frequent, and often ill-advised, changes and additions to drug therapy. It is important that the consultant sees and reviews such patients at least once per year so as to provide other less experienced staff with a policy for ongoing management of that patient. Neurologists and others should be more ready to advise by telephone patients known to them, and their family doctors, so that the rigours of an outpatient appointment can be avoided. Other novel systems of care that should be tried and evaluated include the use of 'walk in' clinics, similar to those now popular with diabetic patients, at which advice can be obtained without prior appointment. Such clinics could be based upon a local neurological rehabilitation centre, or a unit with beds for the younger patient with chronic disabilities. All concerned with the management of chronic neurological illness can help the patient by counselling, focussing in particular on helping the patient's expectations adjust to the new realities brought about by his illness. All team members should also have sufficient knowledge to advise about how chronic neurological illnesses affect personal and sexual relationships. Local branches of voluntary patient associations (for addresses, see below) should be encouraged to form partnerships with the local neurological services. At an appropriate stage in their illness, patients should be offered the opportunity to meet representatives of these associations. Members of patient associations offer valuable support to the patient, and often also to carers, by allowing both to know that there are others to share the problems created by the disease. The associations may also be a useful source of advice about obtaining appropriate welfare benefits, about employment, and about changing personal relationships. Members and volunteers may offer practical help, for example, with transport, with gardening and with collecting pension payments, and the association may also be able to help with respite care or a holiday for a carer. However, we do not believe that the voluntary sector, as exemplified by these associations, should have to make up for deficiencies in the provision of appropriate National Health Service care. Many patients with neurological illness are concerned to know about recent advances in the management of their condition, and the results of current Corticosteroids, given as short pulses of high dose intravenous methylprednisolone, intramuscular ACTH or oral steroids in diminishing doses over a few weeks, improve the rate of recovery in the context of recent symptomatic change [bib_ref] A double blind controlled trial of high dose methylprednisolone in patients with..., Milligan [/bib_ref] [bib_ref] Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute..., Thompson [/bib_ref]. There does seem to be a selective effect on pyramidal function, especially spasticity. On the present evidence, their use is not limited by adverse effects. These drugs have little role in patients with slowly progressive or persistent disability. In general, there is no place for the long-term use of steroids. It must be remembered that not every change in symptoms is necessarily due to relapse. A worsening of spasticity, for example, may be due to an intercurrent infection. The rare short-lived paroxysmal events (eg trigeminal neuralgia or dysarthria lasting a few minutes) are well prevented by carbamazepine. Experimental treatments designed to influence the long-term course of multiple sclerosis are not usually considered until disability is well established [bib_ref] Diagnostic and therapeutic trials in multiple sclerosis: a new look, Weiner [/bib_ref] [bib_ref] A referendum on clinical trial research in multiple sclerosis: the opinion of..., Noseworthy [/bib_ref] -The agents currently in use are of uncertain benefit and carry an appreciable risk of adverse effects. It is noteworthy that, when those researching in multiple sclerosis were asked to consider themselves as patients, many said that they would not be prepared to be randomised into trials of immunosuppression or treatment with interferon [bib_ref] Diagnostic and therapeutic trials in multiple sclerosis: a new look, Weiner [/bib_ref]. Patients and clinicians are therefore understandably cautious early in the illness, even though that may be the best time for influencing the prognosis. Very occasionally, when the disease is pursuing a rapidly advancing malignant course, it is reasonable to try and stem progression with cyclophosphamide [bib_ref] Controlled pilot trial of monthly intravenous cyclophosphamide in multiple sclerosis, Killian [/bib_ref]. Symptomatic treatment. Treatment can be given at any stage to relieve persistent symptoms which, although they adversely affect daily living, do not cause overt disability. The complications of multiple sclerosis which are most amenable to symptomatic treatment include involvement of the bladder and relief of spasticity and paroxysmal symptoms. Approximately 80% of patients describe urinary urgency or frequency which modifies or completely dominates social, domestic and economic life. A combination of mild urgency with moderate immobility usually results in incontinence and disturbed sleep, as a result of which all symptoms are tolerated less well and fatigue may develop. Bladder symptoms usually arise from loss of spinal inhibition or reflex emptying, resulting in the urge frequently to empty a partially filled bladder. If the normal mechanism of detrusor contraction and sphincter opening is uncoupled, hesitancy, retention and incontinence also occur. Drugs which inhibit detrusor contractions and maintain urethral tone (anticholinergics, such as propantheline) successfully relieve these symptoms but the therapeutic window is narrow, especially if sphincter dyssynergia co-exists. Full bladder emptying can occasionally be achieved by manual abdominal pressure or other manoeuvres, but a useful and under-used technique is intermittent self-catheterisation which achieves several hours freedom from urinary symptoms and thus enhances social activities and improves sleep. This technique requires some motivation, adequate vision and the use of one good arm. It can be performed by a partner, and may obviate the need for indwelling catheterisation or urinary diversion. Urinary infections should be promptly treated. In general, urinary problems are so prominent in patients with chronic multiple sclerosis that help from a urologist with a particular interest in neurological disease is often useful. Spasticity may be relieved by the use of muscle relaxants, acting peripherally (dantrolene) and centrally (baclofen or diazepam), by physiotherapy, and by the use of high dose intravenous methylprednisolone. Occasionally, motor end point injections with procaine or tenotomy may be needed to release an abnormal flexed posture of the lower limbs. Motor neurone disease Pharmacological treatment. No pharmacological treatment influences the natural history of the disease. Symptomatic treatment [bib_ref] Motor neurone disease: can we do better? A study of 42 patients, Newrick [/bib_ref]. Pain may be helped by appropriate gentle exercises, support, and by carefully adjusted analgesic treatment. Dysarthria may be helped, temporarily, by speech therapy, by intra-oral devices and, at a later stage of the disease, by the provision of appropriate aids to communication such as a CANON light-writer or POSSUM equipment linked to a microcomputer, which can also be used to control some aspects of the environment, such as lighting. Drooling of saliva may be helped by anticholinergic drugs, by radiotherapy to the salivary glands, or by surgical diversion of salivary ducts. Nutrition can be maintained via a nasogastric tube or a gastrostomy. Some patients may be helped by a cricopharyngeal myotomy, but experience shows that this is only effective if some tongue movement remains. Many patients suffer from insomnia, partly due to muscle pain and inability to get comfortable in bed. An electrically operated turning bed may be very useful. Some patients suffer from night terrors associated with hypoxia, and these may be helped by nasal catheters through which air is delivered at positive pressure. Very occasionally respiratory muscles fail before limb and bulbar muscles, and for these few patients support by a cuirasse ventilator is reasonable. Emotional lability may be helped by clomipramine. It is helpful to explain to both patient and carer that incontinence seldom occurs, that mental clarity usually persists to the end, and that although choking attacks cause concern they are usually not fatal. Most patients die peaceably of respiratory failure. The severity of the symptoms can be conveniently separated into mild, moderate, severe, and terminal. 'Mild' is defined as with symptoms but no disability; 'moderate' is disability (that is restriction of activity) but preservation of personal independence; 'severe' is when the disease has deprived the patient of personal Patients with established disease often have more problems with associated symptoms than they do with the symptoms of Parkinson's disease. Constipation is common, especially in the elderly, and especially in patients taking anticholinergic drugs. Depression is common and frequently overlooked, even though it may well be relieved by tricyclic antidepressants. The retardation of depression may be mistaken for the bradyphrenia and bradykinesia of Parkinson's disease. Equally the limited range of facial expression and slow movements of a patient with Parkinson's disease may falsely suggest that the patient is depressed. Akathisia (pathological restlessness) due to the disease may disturb sleep for patient and household. It may be mistaken for insomnia but seldom responds to sedative drugs. Reversal of sleep rhythm may occur because the akathisia is relieved in the day-time by levodopa, so allowing the patient to sleep. Levodopa may exacerbate depressive symptoms, especially when treatment with this drug is first initiated. Levodopa induced dyskinesias, 'on-off fluctuations in response, or wearing off effects are difficult to treat. Small frequent doses of levodopa, or the addition of doses of bromocriptine or selegiline timed to the patient's daily activities, may help. Apomorphine by subcutaneous injection or infusion may become a more generally available and useful method of controlling these symptoms. The side effects of treatment usually require hospital outpatient supervision, with occasional admission to analyse the patient's response to treatment. The mono-amine oxidase inhibitor selegiline has been shown to prevent the establishment of damage to the substantia nigra of experimental animals produced by l-methyl-4-phenyl-l ,2,3,6-tetrahydropyridine (MPTP), and there is now evidence that the course of Parkinson's disease in man may also be slowed by this drug. However, larger scale prospective studies are required before this type of medication should be recommended as standard. Symptomatic management. Patients will often need advice about a new symptom arising in the course of their disease. Depression of mood responds reasonably well to appropriate drugs, or may be due to levodopa. Confusion may be an adverse effect of medication, particularly the anticholinergic drugs. Constipation is often a problem, but may be helped by bulking or by stimulant laxatives. Advice may be needed about sexual dysfunction, incontinence, driving and interpersonal relationships. Day centre care may provide valuable relief for the home carer of a severely affected patient. Holiday relief in a nursing home or geriatric or neurological ward may also be highly desirable. Early planning of these arrangements increases the family's trust in the neurologist's sympathetic understanding of their needs. As the disease progresses, a visit by a district nurse or occupational therapist is often helpful. Home nursing assistance, especially for bathing, is often essential in the severe or terminal case, and hospice care is appropriate for some for the terminal stages of the illness. Home help, volunteer assistance and health visitors all have an important place in aiding and assisting the main carer. The patient and family should feel that there are others with whom they can share the problems the disease creates. At present the family doctor is best placed to organise the provision of these services, but a 'keyworker', as described above, could play a useful role. ## Epilepsy Pharmacological treatment. There is little knowledge of the prognosis of untreated epilepsy. This makes it difficult to know when to begin drug treatment. In practical terms this is decided on an individual basis after discussion with the patient. For patients with occasional seizures or with seizures causing relatively minor symptoms, social factors such as the requirement for a driving licence and types of employment are important when reaching a decision. Similar factors apply to the decision to withdraw drugs after a period of remission of seizures. Treatment should be limited to a single appropriate drug wherever possible, although, in patients whose seizures are refractory to single drugs, brief trials of drugs in combination may be undertaken. In view of the known adverse effects, treatment should not now be initiated with phenobarbitone or primidone. These drugs also seem particularly difficult to withdraw without recurrent seizures. Sodium valproate may be preferable to these drugs for the primary generalised epilepsies (simple absences, epilepsy, juvenile myoclonic epilepsy). There is little evidence that for other adult epilepsies there is any difference in efficacy between anticonvulsant drugs. The choice is determined by considering what potential adverse effects are particularly relevant to the patient. Estimation of serum levels of anticonvulsant drugs, although performed more often than is necessary, is useful if seizures are continuing, if there is doubt about the patient's compliance, or concern about whether symptoms are due to toxicity, or whether the patient will be able to tolerate an increase in dosage. Symptomatic management. Most patients with intractable epilepsy will be in the community. Patients with added intellectual, neurological or psychiatric disability require liaison with professionals in ancillary disciplines social workers, day training centre staff, mental handicap teams, etc. Here again a keyworker would be valuable. The medical role of the neurologist should be: ? to optimise pharmacological treatment of epilepsy in any given individual as quickly as possible ? to consider at an early stage (within two or three years) whether a patient's epilepsy is medically refractory, and to explore the advisability of surgical treatment. Such patients almost always have complex partial seizures. About 70% of carefully selected patients are cured by surgery. Current information suggests that, of the 50 per 100,000 population developing seizures each year, 1-2 per year would benefit from surgery to the temporal lobe. Adequate assessment of so many patients has resource implications for neurology, neurophysiology, neurosurgery, neuropsychology and neuroradiology. Regional and supra-regional teams will be required to fulfil a demand for surgery. For patients with medically refractory epilepsy unsuitable for a surgical approach, the neurologist's role is to ensure minimisation of therapy compatible with optimal control, so as to avoid an excessive incidence of chronic adverse effects from the drugs used in treatment. There may come a time when, because of adverse effects, it is just not worthwhile pursuing new combinations of drugs, and patients may feel better tolerating a few seizures rather than such effects. Patients who are unlikely ever to achieve a long-term remission should be told of this. It is especially important that family doctors and neurologists are aware of the particular problems of women with epilepsy, notably the interaction between anticonvulsant drugs and oral contraceptives, the effect of pregnancy on epilepsy and on anticonvulsant drug metabolism, and the teratogenic effect of anticonvulsant drugs. Status epilepticus continues to have a high mortality. District general hospitals should have protocols for prompt and adequate therapy. Points of particular concern to patients The Working Group felt that a number of aspects of care were not well handled by neurologists at present. ## Points raised included: ? a lack of a co-ordinated plan for management shared between family doctor and hospital ? a lack of continuity of care in hospital clinics poor transport facilities to outpatient clinics at which attendance is often inappropriate, and felt to be inappropriate ? the slow provision of physical aids, structural alterations to the home, or supporting services such as community physiotherapy ? the lack of adequate local facilities for welfare counselling, home nursing and physiotherapy, day care and holiday relief. Some patients feel that the most frustrating aspect of contact with some consultant neurologists is their nihilistic approach. Clinicians need to strike a balance between therapeutic optimism, based on an increasingly active research initiative, and the exposure of vulnerable individuals to improbable or overly hazardous approaches to treatment. Priority areas for research Some areas are common to all the diseases we considered. We need better measures of functional status and of the quality of life, so that the quality of supportive management can be measured and become more appropriate. We need to evaluate more carefully the effectiveness of our present systems of care, and of newer proposals the effectiveness of 'keyworkers' and of special clinics such as epilepsy clinics. ## Multiple sclerosis The priority for research into multiple sclerosis is to find an effective treatment. Because there has been no serendipitous breakthrough, systematic work on the mechanisms of demyelination is still required. The disorder has a reputation for poorly conducted and unimaginative research. The literature is contaminated by elaborate hypotheses often constructed merely to justify a particular therapeutic hunch. Understanding the mechanisms of myelin injury through an integrated approach using tissue culture, animal models and analysis of human samples may eventually lead to effective treatments. These may not immediately benefit the large number of patients in whom the disease is well established but, in the long term, learning about the aetiological factors genetic or environmental ? which render some individuals susceptible to multiple sclerosis may lead to prevention of the disease. ## Motor neurone disease The issues for motor neurone disease are similar to those for multiple sclerosis. In addition, at a simpler level, we need more information about the relative merits of techniques used to deal with dysphagia, including nasogastric tubes and the relative merits of pharyngostomy versus gastrostomy. The symptomatic management of drooling is also unsatisfactory and requires further research. Parkinson's disease Research priorities here are the structure and formation of the Lewy body ubiquitinated proteins and their relevance to exogenous toxins and the cause of Parkinson's disease. We also need further research into the biology of striatal implants, and the more effective delivery of dopamine agonists to the central nervous system. ## Epilepsy Further research is needed into when it is appropriate both to start and to stop anticonvulsant treatment. Auditing the care of patients We have here laid down standards for the treatment of four neurological illnesses. Much of what we have written about systems of care is likely to be relevant to other chronic diseases, the care of which is shared by family and hospital doctors. With defined standards, the quality of care may be audited. The following are examples of general measures that could be used in audit: ? Accessibility to specialist care (eg waiting times and distance to travel for a neurological consultation). ? Accessibility to other aspects of care (eg availability of counselling, community physiotherapy, day hospitals, waiting times for provision of aids etc). ? Continuity of care (eg proportion of outpatient visits at which a patient is seen by the consultant). ? Information (eg information given about patients' associations; patients' understanding of their diagnosis; the family doctor's satisfaction with information received from the neurological clinic). Adverse outcomes (eg drug-induced confusional states; pressure sores). Inappropriate provision of medication (eg long continued steroids in multiple sclerosis, patients with continuing juvenile myoclonic epilepsy in whom sodium valproate has not been tried; inappropriate polytherapy for epilepsy). ? Adequate record of plan of investigation and management. ## Resource implications Data on some of these audit measures (for example, on waiting times) can be obtained by simple secretarial work, and are suitable for routine recording for which a computer would be helpful. Other measures, such as a review of the medical records to ascertain whether these contain a written plan for future management, require first the retrieval of sets of notes and then the time of a skilled person, who may or may not be medically qualified, to review their contents. Yet other measures, such as an audit of patients' understanding of their diagnosis, require specific focused research projects. Such research audit may be small scale, but the methodology must be sound. All such initiatives will require time, and hence either additional resources or the displacement of more traditional clinical work. And yet there is evidence of an underprovision of neurological care at present. There are currently 190 neurologists in the United Kingdom, including six fulltime academic posts, for a population of 56.8 million ? roughly one per 373,000. The Association of British Neurologists has recently recommended that there be one neurologist per 200,000. An attempt has been made by some neurologists in the United Kingdom to judge the amount of time that they 'ought' to spend with patients [bib_ref] Norms of care in British and American neurological practice, Menken [/bib_ref] , but the following example will suffice. With three clinics a week, a neurologist will have available about 480 hours of outpatient time each year. And yet, with the prevalence of 240 patients with multiple sclerosis in a population of 200,000, half of this time would be used up if just one hour were spent each year with each patient with this one disease. If the community wishes to improve neurological care to the standards proposed in this paper, then there should be an increase in the number of consultant neurologists, and their training in the management of epilepsy and other causes of chronic disability should improve. Resources will also be necessary to pay keyworkers and therapists. [table] Table 1: Drug treatment in Parkinson's disease [/table]	None	None	Paper for Patients' requires that each district have in place by 1991 some system of medical audit, defined therein as 'a systematic critical analysis of the quality of medical care, including the procedures used for diagnosis and treatment, the use of resources, and the resulting outcome for the patient.' Such critical analysis presupposes the definition of standards against which the quality of care can be assessed.
3dea1abfc0a3425f3d74dac1233f67c1d27451b2	pubmed	Telemedicine in Audiology. Best practice recommendations from the French Society of Audiology (SFA) and the French Society of Otorhinolaryngology-Head and Neck Surgery (SFORL)	Telemedicine in Audiology. Best practice recommendations from the French Society of Audiology (SFA) and the French Society of Otorhinolaryngology-Head and Neck Surgery (SFORL) a b s t r a c tObjectives: Access to diagnosis and treatments for auditory disorders and related pathologies has regressed in France during the COVID-19 pandemic, posing a risk to the patient's chance of recovery. This best practice recommendations guide aims to list the existing technological solutions for the remote examination of a patient with hearing complaint, and to outline their benefits and, where applicable, their limitations. Methods: The recommendations were developed both from the clinical experience of the medical experts who drafted the guide, and from an extensive review of the literature dealing with clinical practice recommendations for tele-audiology. Tele-audiometry solutions were identified on the basis of a search engine query carried out in April 2020, prior to verification of their availability on the European market. Results: Video otoscopy solutions allow for the teletransmission of images compatible with a high-quality diagnosis, either by connecting via internet to a tele-health platform or using a smartphone or a tablet with an iOS or Android operating system. Using the same telecommunication methods, it is possible to remotely conduct a pure-tone audiometry test in accordance with standard practice, a speech-in-quiet or a speech-in-noise audiometry test, as well as objective measures of hearing. Clinical and paraclinical examinations can be accessed by the physician to be interpreted on a deferred basis (asynchronous teleaudiology). Examinations can also be conducted in real time in a patient, at any age of life, as long as a caregiver can be present during the installation of the transducers or the acoumetry. Tele-audiology solutions also find application in the remote training of future healthcare professionals involved in the management of deafness and hearing impairment.Conclusion: Under French law, tele-otoscopy is a medical procedure that is either a tele-expertise (asynchronous adive) or a teleconsultation act (synchronous advice). Subjective and objective evaluation of the patient's hearing functions can be done remotely provided that the listed precautions are respected. # Introduction One of the significant consequences of the COVID-19 pandemic is the increased number of medical teleconsultations and the greater consideration given to their development. In teleaudiology, as in all specialities, digital healthcare aims to use technological innovations to perform medical procedures and organise treatment. Until recently, the practice of medical audiology could be pursued only in the codified framework of a face-to-face meeting between the patient and their practitioner in adapted premises with technical facilities enabling the conduct of clinical ENT examinations and of audiovestibular testing in accordance with standard practice. Tele-medicine calls the principles of traditional medical practice into question, namely i) unity of place, the patient and practitioner not being present together in the same place, ii) unity of time, the patient and practitioner being able to work synchronously or not and iii) unity of action, the patient and practitioner being even more encouraged to work in a coordinated way. In this context, tele-audiology can be conceived as having three distinct levels of granularity depending on what is prioritised: self-screening for sensory disability and its consequences, help from a caregiver or medical/paramedical staff managing the patient in their everyday life, or the opinion of the expert consulted to interact remotely with the patient. This practice recommendations guide drawn up by a group of medical experts from the French Society of Audiology and the French Society of Otorhinolaryngology Head and Neck Surgery will address the current conditions for remotely performing and interpreting (directly i.e. then and there, or deferred) clinical otoscopic examinations and subjective and objective measures of hearing (including the necessary equipment), the remote training of healthcare professionals, as well as the characteristics specific to children and elderly subjects. ## Best practice recommendations 2.1. Tele-examination in audiology 2.1.1. The practice of otoscopy in telehealth 2.1.1.1. Literature review. The use of tele-otoscopy is not a recent practice; it was described at the end of the 70s. However, the development of high-speed internet has enabled its more widespread use. Tele-otoscopy involves capturing an image or a short video recording that will be sent to the remote physician. In most publications, this image is captured by a "facilitator", who is not an expert in otoscopy, but a health worker with a variable level of training depending on the health service. This image is then assessed by the remote physician either directly (synchronous procedure) or later on (asynchronous procedure). Most of the studies used an asynchronous assessment for a mass screening of otologic pathologies in regions where access to treatment is difficult. In studies, assessing the asynchronous analysis of image capture, the authors conclude that there is a good correlation between remote and face-to-face examinations, but with a high rate of poor quality or uninterpretable images. Aronzon et al. [bib_ref] Diagnosis of middle ear disease using tympanograms and digital imaging, Aronzon [/bib_ref] found a sensitivity of 90 and 91%, respectively, with the video and the microscopic examination, but a better specificity with the face-to-face examination (93% versus 79%). Patricoski et al. [bib_ref] A comparison of in-person examination and video otoscope imaging for tympanostomy tube..., Patricoski [/bib_ref] used video otoscopy to monitor transtympanic ventilation tubes. The correlation between remote and face-to-face otoscopy was high (79-85%, = 0.67-0.76). However, 18% of the images were of insufficient quality for diagnosis. Kokesh et al. [bib_ref] Digital images for postsurgical followup of tympanostomy tubes in remote Alaska, Kokesh [/bib_ref] come to the same conclusion with a concordance of 76-80% ( = 0.64-0.71), with 21% of the images being of poor quality. This poor image quality is linked to different factors such as the presence of earwax, a particular orientation of the ear canal, but also technical aspects such as poor focus or an image capture that doesn't include all of the tympanic area. To resolve these technical issues, the use of short videos was evaluated. The rate of poor quality images falls to 14% for Smith et al. [bib_ref] Accuracy of pre-recorded video images for the assessment of rural indigenous children..., Smith [/bib_ref] and 13% for Biagio et al. [bib_ref] Video-otoscopy recordings for diagnosis of childhood ear disease using telehealth at primary..., Biagio [/bib_ref] , while maintaining a good concordance when the remote evaluator was an ENT specialist ( = 0.70-0.74) or a general practitioner ( = 0.68-0.75). All of the studies agree that prior training on the basics of otoscopy and on the removal of earwax blockage improves the quality of the tele-otoscopy procedure [bib_ref] A tele-otology course for primary care providers, Eikelboom [/bib_ref] [bib_ref] Remote hearing screenings via telehealth in a rural elementary school, Lancaster [/bib_ref]. 2.1.1.2. Application in the specific context of French healthcare system. From a regulatory point of view, the otoscopy procedure is a medical procedure [fig_ref] Figure 1: Examples of video-otoscopy [/fig_ref]. Its conduct cannot be delegated to another healthcare professional. This regulatory constraint makes it impossible to rely on a facilitator, as is done in other countries, and de facto compromises any tele-otoscopy procedure carried out on French soil. As for clearing out excess of earwax, this can only be performed by a physician or by a nurse through medical prescription (article. R.4311-7 of the Public Health Code and decree 2004-802 dated 29/07/2004). In the practice of telemedicine, there is a separation between the technical service (performed by the facilitator) and the intellectual service of interpreting the examination (conducted by the remote physician). The absence of dissociation between the technical and intellectual services in the medical technical procedures defined by the French National Authority for Health is a massive obstacle to the development of telemedicine procedures in otology. Whereas nurses and care assistants are authorised to take tympanic temperature, the same procedure conducted to capture an image or a video is not authorised by law. In keeping with the law, the facilitator must be a physician (generalist or specialist) and the remote opinion requested will be a specialist or subspecialist one. As part of amendment 6 to the Medical Convention dated 14 June 2018 defining telemedicine procedures, if the opinion is given during an instance of video communication with the patient, this is a teleconsultation. The physician consulted may have received documents beforehand, including otoscopic images. The medical convention provided for the possibility of a joint consultation: the patient in the presence of one physician and at the same time in teleconsultation with a second physician. If the opinion is given by a requested physician to a requesting physician via secure message exchanges, without a video link with the patient, this is an instance of tele-expertise. Regarding equipment, besides what is required to establish a secure two-way connection necessary for a teleconsultation, the remotely-used otoscope needs only have features allowing it to record images in a standard electronic format (jpeg, tif, mpeg, avi, etc.), or video in a format greater than 640 × 480 pixels and a recording of at least 25 frames per second. Real-time video-otoscopy was performed using a 4-mm, 0 - endoscope (Hopkins Optic) and a high-definition video recorder for different pathologies: perforated eardrum (A), serous otitis media (C), and cholesteatoma (E). Images of the same eardrums were acquired using a digital otoscope connected to a smartphone (perforated eardrum (B), serous otitis media (D) and cholesteatoma (F)). These can be easily transmitted wirelessly to a computer or to any equipment connected to the Internet via Wifi or 3/4G network for remote interpretation. 2.1.2. Audiometry in telemedicine: levels of service, tests that can be conducted, and equipment required The following tele-audiometry solutions were identified on the basis of a search engine query carried out in April 2020, when the most recent system could be offered to users in the context of the COVID-19 pandemic. They are all available on the European market. For the most part, their technological development had been closely monitored in recent years by the French Society of Audiology, in direct contact with their designers. 2.1.2.1. Self-administered screening tests. There are apps available in French, on smartphones and tablets using an iOS or Android operating system, which comply with the French National Authority for Health's framework on the best practices for healthcare apps and connected devices. After verifying a sufficiently low level of background noise, they enable a self-administered air conduction test with a pair of off-the-shelf headphones [fig_ref] Table 1: Tele-audiometry solutions for screening purposes [/fig_ref]. One of these apps enables the patient to perform a speech-in-noise audiometry test using an adaptive procedure. It is validated by increments of 2 dB and does not call on mental substitution as it uses series of digits triplets [bib_ref] Improving sensitivity of the digits-in-noise test using antiphasic stimuli, Sousa [/bib_ref]. Its special feature is to enable the detection of asymmetrical or conductive hearing impairments thanks to an antiphasic presentation between the two ears which invokes the principle of binaural unmasking. According to this physiological principle, when speech signals are supplied binaurally in noise but in phase inversion, there is usually an improvement in the signal-to-noise ratio at which the speech signal is correctly recognized 50% of the time. As this improvement is absent in cases of unilateral or conductive hearing loss, it is thus possible to detect them [bib_ref] A comparison between the Dutch and American-English digits-in-noise (DIN) tests in normal-hearing..., Smits [/bib_ref]. Where the subject is identified as not having normal hearing for their age, these self-administered tests have a screening purpose leading to the recommendation of a medical consultation. ## 2.1.2.2. Tele-audiometry for an assisted patient. In this configuration, the patient can agree to a healthcare structure where a caregiver assists not only with installation (verifying the quality of the sound environment, launching the tele-audiometry software installed on a connected electronic device, preparing the air and bone conduction tests), but also to ensure that responses to auditory stimulations are correctly given . If necessary, the caregiver can enter this information in place of the patient. In a synchronous tele-audiology mode, the practitioner connects via the web to the tele-audiology platform to which the caregiver will give access. The practitioner then controls the audiometry software remotely to conduct the examination. In an asynchronous tele-audiology mode, it is the patient alone or the caregiver who performs the test, the practitioner accessing the hearing test results on a deferred basis to interpret them. ## 2.1.2.3. Interaction between the practitioner and the patient without a third party. From the practice, the practitioner remotely accesses the patient's electronic device, on which the tele-audiometry software is installed, in order to start it. Thanks to this remote control, all of the audiometric tests gathered on the patient's electronic device can be administered. Their results are immediately analysed as part of a teleconsultation. In this synchronous tele-audiology mode, the practitioner can see multiple patients from one place as long as they have access to the tele-audiometry solution that the practitioner has chosen. [fig_ref] Table 2: Tele-audiometry solutions for diagnostic purposes [/fig_ref] outlines the various existing teleaudiometry solutions, assisted or not, specifying the audiometric procedure used for each one, the types of hearing impairment detected, the tests that can be carried out (pure-tone, supraliminal pure-tone, speech-in-quiet and/or speech-in-noise, dichotic), as well as advanced features. An effective audiometry system should meet the following criteria, at a minimum. First, it has to provide high-quality visual contact to allow the tester to verify that the transducers are correctly positioned, and the patient or caregiver to correctly understand the instructions. It also has to be able to measure, even monitor the patient's background noise level. The tester must carry out a pure-tone audiogram in accordance with standard practice as per the modified Hughson-Westlake procedure (Down 10 -Up 5), with systematic contralateral masking for bone conduction and also for air conduction as soon as there is transcranial transmission loss above 50 dB. He has to provide validated lists of words in the relevant language for speech-in-silence and speech-in-noise audiometry tests (with an adaptive procedure for the most recent speech-in-noise audiometry tests). Finally, this system must have calibrated and easily replaceable transducers (headset, intra-auricular inserts, bone vibrators). Traditionally, carrying out a pure-tone audiometry requires monitoring the sound environment to determine the 0 dB HL threshold for all the normal frequencies tested. Typically, to meet these requirements, the audiometry is conducted in a soundproof booth adapted to these standards [bib_ref] The acoustic test environment for hearing testing, Margolis [/bib_ref]. Unless the installation of audiometric booths is being considered throughout the country, tele-audiometry must adapt to not having a booth. Several methods can be used to overcome this condition. It is possible to not test the threshold between 0 and 25 dB HL in order to only target hearing-impaired subjects. Using supraliminal test is less impacted by background noise, especially if monitoring background noise is part of the procedure. Finally, technology development that allow for sound attenuation comparable to a booth will allow to replace it. Some authors have suggested using inserts with builtin circumaural headphones in quiet rooms [bib_ref] Hall 3rd JW. Puretone audiometry outside a sound booth using earphone attenuation,..., Swanepoel De [/bib_ref] or with passive attenuation devices in addition to the test transducer [bib_ref] Noise-excluding enclosure for audiometry, Stark [/bib_ref]. Active noise-canceling devices have also been tested [bib_ref] Use of noise cancellation earphones in out-of-booth audiometric evaluations, Clark [/bib_ref]. According to in an environment with 30 dB of background noise, these devices enable a pure-tone audiometry with a quality equivalent to one carried out in a soundproof booth [bib_ref] Active noise reduction audiometry: a prospective analysis of a new approach to..., Bromwich [/bib_ref]. Supraliminal audiometry poses fewer technical issues with the sound environment. In any case, the audiometric data can be stored only on a server located in Europe with the Healthcare Data Hosting accreditation from the Health Ministry and in accordance with the European regulation (EU 2016/679) on the Protection of Personal Data (GDPR). ## Tele-acoumetry and remote detection of asymmetrical hearing Tuning fork acoumetry is one of the basic steps in otologic examination, and likely constitutes one of the simplest ways to assess a subject's hearing. With a tuning fork and a trained examiner, the type of hearing impairment can most often be identified. While it obviously cannot replace a traditional audiometric assessment, its results in the context of a pandemic, where they suggest sensorineural or conductive hearing impairment, will help to determine the degree of urgency with which the patient should be treated. Its contribution can be invaluable in the diagnosis of sudden sensorineural hearing loss requiring urgent treatment. Tuning fork acoumetry traditionally combines the Weber test and the Rinne test. The sensitivity of the Weber test when it is carried out alone to detect a unilateral sensorineural hearing impairment is evaluated at between 75 and 80% [bib_ref] Recommended procedure for Rinne and Weber tuning fork tests. British Society of..., Turton [/bib_ref] , which justifies the additional Once percussed, the base of the tuning fork is firmly applied on a centreline point of the cephalic end, typically the middle of the forehead or the vertex. The subject then indicates the localisation of the sound as it is perceived. In the case of normal bilateral hearing or symmetrical hearing impairment, the sound will be perceived in the centre of the head or equally in both ears. In the event of asymmetrical or unilateral hearing impairment with a conductive origin, the sound will be lateralised on the side with the impaired ear. In the event of asymmetrical or unilateral sensorineural hearing impairment, the sound will be lateralised on the side with the better ear. It is recognised that the Weber test thus enables the detection of asymmetries in bone conduction for a minimal interaural difference of 5 dB [bib_ref] Diagnostic accuracy of tuning fork tests for hearing loss: a systematic review, Kelly [/bib_ref]. ## Rinne test. This test involves assessing the difference in perceived loudness between air conduction and bone conduction for each ear separately, by starting with the ear towards which the Weber test was lateralised, if applicable. Once vibrating, the tuning fork is positioned approximately 2 cm from the external acoustic meatus, its major axis placed perpendicularly to the axis of the external auditory canal. It is held here for 2 seconds. Immediately after these 2 seconds and without interrupting the vibrations, the base of the tuning fork is firmly applied against the mastoid for a further 2 seconds. The subject must then indicate if the sound was perceived as stronger in front of the external auditory canal or on the mastoid. If the sound was perceived as louder through air conduction, the Rinne test is said to be positive, which indicates normal hearing or a sensorineural hearing impairment. In contrast, if the sound was perceived as louder through bone conduction, the Rinne test is said to be negative, indicating a conductive hearing impairment. ## Remote transmission and interpretation of brainstem auditory evoked potentials and otoacoustic emissions 2.1.4.1. Brainstem auditory evoked potentials (BAEPs). Most experiments conducted in this area have shown the feasibility, reliability, and effectiveness of interpreting BAEPs via telemedicine [bib_ref] Tele-ABR using a satellite connection in a mobile van for newborn hearing..., Ramkunar [/bib_ref] [bib_ref] The use of telehealth service to facilitate audiological management for children: a..., Govender [/bib_ref] [bib_ref] Telehealth-enabled auditory brainstem response testing for infants living in rural communities: the..., Hatton [/bib_ref]. The application of BAEPs via telemedicine has primarily been dedicated to helping diagnose neonatal hearing impairment [bib_ref] The use of telehealth service to facilitate audiological management for children: a..., Govender [/bib_ref]. Real-time viewing is especially useful to determine the reliability of a BAEP wave, once it is close to the threshold and with weak amplitude, because its reproducibility can be judged on its stability throughout its real-time construction. Prior knowledge of other auditory measures is extremely helpful if diagnosing a suspected auditory neuropathy (ANSD: auditory neuropathy spectrum disorder), because with these patients, BAEPs are altered while the evoked otoacoustic emissions (eOAEs) and the cochlear microphonic potential (CMP) are present most of the time [bib_ref] Auditory neuropathy, Starr [/bib_ref]. ## Otoacoustic emissions (oaes). Click-evoked otoacoustic emissions (eOAEs) have been very rarely used in telemedicine to date. The advantage of eOAEs is that their straightforward data collection gives a result that is not easily confused, based on the recommendations for their correct use and interpretation. The loudness of the signal presented to the ear must be sufficient so that the eOAEs stand out clearly from the background noise, generally around 45-50 dB SPL (sound pressure level) on average with crests around 80 dB SPL. The acoustic quality of the signal supplied must be correct, producing a biphasic intra-meatal signal and not an "accordion" one, which may give rise to too much occlusion of the ear canal and interfere with the cochlear response. The surrounding noise must be low, ideally ≤ 40 dB SPL, but a soundproof booth is not necessary. The patients themselves must avoid making "intrinsic" noises (swallowing, sucking, sniffing, etc.) preventing detection of the eOAEs. The number of non-noisy sweeps during the acquisition procedure should be sufficient (≥ 260) before concluding on the absence of eOAEs. However, wide OAEs, standing out from background noise with more than 50% reproducibility, prove that the cochlea functions even with a number of sweeps < 260. The acoustic probe must be stable during data collection. A recent diagnostic use of eOAEs is to highlight their phase shift depending on the body position of the patient, in the event of hydrops [bib_ref] Acoustic phase shift: objective evidence for labyrinthine pressure disturbance in Menière's disease..., Mom [/bib_ref]. The signal spectrum must be filtered around 1 kHz (between 800-1200 Hz) in an area where it stands out from the noise. Acoustic phase shift can then be directly measured on the screen [fig_ref] Figure 3: Screenshot of otoacoustic emissions filtered around 1 kHz [/fig_ref]. A phase shift of > 40 - between the two body positions, sitting and lying, is pathological. eOAEs can also be used in the same way in the event of suspected intracranial hypertension [bib_ref] Otoacoustic emissions: a new tool for monitoring intracranial pressure changes through stapes..., Büki [/bib_ref]. The clinical applications of OAEs are quite numerous and likely still underutilised today [bib_ref] Otoacoustic emissions in clinical and surgical practice, Mom [/bib_ref]. Most applications should lend themselves to telemedicine rather easily, following the recommendations above. ## Distorsion product otoacoustic emissions (dpoaes). To date, only one team has reported using DPOAEs via telemedicine and only for auditory screening in children [bib_ref] Validation of DPOAE screening conducted by village health workers in a rural..., Ramkumar [/bib_ref]. The authors compared the validity of DPOAEs used for screening children and newborns by comparing them to BAEPs also interpreted via telemedicine. However, it is quite feasible to use DPOAEs for direct remote analysis of a possible acoustic phase shift for suspected inner ear or intracranial pressure disorders as with eOAEs, with the aid of body tilt to expose the instability of the DPOAEs' phase [bib_ref] Unstable distortionproduct otoacoustic emission phase in Menière's disease, Avan [/bib_ref]. In conclusion, the remote interpretation of acoustic and electrophysiological recordings is feasible and reliable, provided that the person positioning the patient for collecting the signals is trained in it, that verification is possible, if necessary, and that the video-conferencing equipment is of sufficient quality to analyse the waveforms generated in real-time. Nevertheless, we have strong reservations regarding the use of some of these objective measures via telemedicine for complex diagnosis cases. ## Remote training Simulation is used in many professions for the acquisition of knowledge and skills. Medicine has developed simulation systems, particularly to respect the adage "Never on the patient the first time". Mentoring remains the basis of medical training, and currently it must be accompanied by simulation methods to avoid conducting the first procedure on a patient. This factual situation rests on a recommendation by the French Health Authority (HAS) (https://www.has-sante.fr/upload/docs/application/pdf/2012-01/ simulation en sante -rapport.pdf). Here, we describe remote training courses and the categories of simulators available in audiology. Free live or webinar classes are available in English, (https://www.audiologyonline.com/) as well as lessons (http:// audprof.com/). In French, recommendations for the practice of audiometry have been published by the French Audiology Society (https://sfaudiologie.fr/). Such training courses improve students' theoretical knowledge in various areas of audiology, from performing audiometry and objective measures of hearing function to treating patients with hearing impairments, as well as dealing with research topics in audiology. Websites also provide clinical audiometry cases in the form of online exercises (http://audstudent.com/). Simulation allows students to practice and to learn from their mistakes in a safe environment that is risk-free for the patient. As a matter of fact, training in audiometry is not without risks for the patient. These exist during the procedure (unintentional trauma of the eardrum, noise trauma); and after, an inaccurate audiometric diagnosis potentially leading to serious consequences [bib_ref] Problematic medical expertise concerning simulation and aggravation in audiology, Streppel [/bib_ref] in the event of inappropriate treatment. In addition, audiometry is a difficult examination which brings a lot of knowledge (physiology, mathematics) and skills (procedural, interpersonal) into play. Nevertheless, there are few simulators to develop students' skills in audiometry. Some twodimension audiometry simulation software can be found online, either free-access or paid (CounselEAR or AudSim, for example). They allow students to train on the research principle of audiometric thresholds, and sometimes otoscopy or tympanometry analysis. Other simulators are more immersive and use low or high-fidelity dummies allowing the student to practice handling an otoscope, or procedures such as removing earwax build-up. However, few of these solutions allow for the total simulation of an audiometry consultation. Interviewing the patient, managing different instruments, analysing imaging and audiometric data to obtain a complete diagnosis, and treatment are all aspects that are not represented in existing simulators. This lack of consideration prevents clinical reasoning. This is why other systems using virtual reality [bib_ref] Using virtual reality in audiological training: our experience in 22 otolaryngology residents, Aussedat [/bib_ref] , in particular, have been developed to provide an additional training tool for students in audiology, just like flight simulators for pilots. They add an immersive quality and feedback in the event of mistakes. In any event, all of these audiology simulation models allow the students to be better prepared for their future clinical activity. The majority of studies carried out on the benefit of simulation systems, even if there is currently only a handful, have shown an improvement in knowledge and skill scores after simulation sessions [bib_ref] Using virtual reality in audiological training: our experience in 22 otolaryngology residents, Aussedat [/bib_ref]. [fig_ref] Table 3: Different simulation systems available for audiometry [/fig_ref] summarises the different simulation systems available to date for training in audiology, particularly in the context of students in lockdown. ## Tele-audiology over the lifespan ## Decision tree in audiophonology for children The current development of telemedicine makes it possible to consider expanding the clinical situations in which these remote consultations can be implemented. In the area of audiophonology for children, some teleconsultations could be considered. Several arrangements are possible: i) calling the parents/observing the child via videoconference and sending documents via secure platforms; ii) interaction with health care providers who are trained to use screening tools in case of dedicated programs; iii) verification of audiograms or hearing aid fitting parameters; and eventually iv) remote fitting of cochlear implants. Currently in France, there is no routine teleconsultation programme dedicated to paediatrics. This teleconsultation should be done through adapted, easy to use tools, and through local health practitioners close to the patients. For the moment, therefore, teleconsultation generally only allows for assessing patients, responding to families' questions, and prioritising requests for appointments. There are two aspects to this support. ## Consultations and interview. To better understand the needs of tele-audiology for children, it is necessary to classify the context of possible requests for consultations. It is particularly important to detect "sensory emergencies" that must be quickly referred to specialised care services: massive speech and language delay in a child over 18 months of age, sudden deafness in older children, post-traumatic deafness, hearing assessment for bacterial meningitis, acute balance disorders in children [fig_ref] Table 4: Child audiophonoloy clinical orientation questionnaire [/fig_ref]. . For the youngest patients, in the absence of local medical services equipped with screening devices (eOAEs, automated BAEPs, or screening audiometer), the consultation focuses on questioning and collecting medical and developmental data, which allows for the preparation of a specialised consultation in the best possible conditions [fig_ref] Table 5: Child audiophonology clinical contexts [/fig_ref]. ## Tele-assessment of elderly subjects Medical teleconsultation in audiology can be particularly useful for elderly subjects with difficulties travelling for a face-to-face consultation. However, an INSEE (National Institute of Statistics and Economic Studies) survey published in 2019 shows that 15% of those aged 60-74 and 53% of subjects aged 75 and over do not have internet access (https://www.insee.fr/fr/statistiques/4241397). Digital illiteracy affects 17% of the general population, but 27% of those aged 60-74, and 67% of subjects aged 75 and over. This is why it is important to develop networks to help the elderly and those least equipped to use digital tools in order to develop telemedicine. The use of teleconsultation requires the choice of the digital referent: either the elderly person himself or herself, or a relative or caregiver. The different referring care providers of the patient may be involved: general practitioners, geriatricians, healthcare facility advisors, and care providers. ENT physicians, hearing aid dispensers, and often speech therapists are jointly involved in treating hearing disorders. 2.3.2.1. Detecting sensory and cognitive impairments. Among the methods for detecting sensory and cognitive impairments, there are several tools available. They should be easy and quick to use. At least two methods have been developed: questionnaires and remote hearing screening tests. The AVEC (Audition Vision Équilibre Cognition: Hearing Vision Balance Cognition) questionnaire (see Online material) is a detection kit that can be used by all care providers [bib_ref] Sensory functions and Alzheimer's disease: a multi-disciplinary approach, Kenigsberg [/bib_ref]. It relies on four pillars: two self-administered questionnaires on hearing and vision, the results of which determine referral to the ENT physician for clinical and audiometric evaluation, or to the ophthalmologist; an assessment of balance using the [bib_ref] The cognitive disorders examination (CODEX) is a reliable 3-minute test for detection..., Belmin [/bib_ref] , which allows for a decision on the need for specialised assessment (Geriatric consultation, Neuropsychological assessment). The AVEC test expands detection beyond hearing impairment alone: it allows for an individual hierarchy of priorities in the process of treating sensory impairments and their cognitive impact, as well as quality of life. Audiometric assessment tests in the form of self-administered screening tests have been outlined above. Their adaptation for the characteristics specific to elderly people must be taken into account: in particular, attention span and level of alertness. 2.3.2.2. Formalisation of diagnosis and treatment orientation. After detection and depending on the circumstances, diagnosis can be carried out face-to-face or via teleconsultation, using the teleotoscopy and tele-audiometry methods outlined above. They are adapted to the specificities of elderly people. This allows for the identification of different audiological situations where further investigations are sometimes necessary (objective tests, imaging, etc.). At the end of this stage, hearing aids are prescribed if needed, potentially associated with speech and language therapy, which can be performed with digital tools. ## Monitoring patients presenting with a hearing impairment. Teleconsultation can ensure that the patient is wearing and maintaining their hearing aids, reminding the patient and their close ones of the need to wear the hearing aids at all times and to have it maintained regularly by the hearing aid dispenser. This can be adapted and coordinated in healthcare facilities where professionals, particularly hearing aid dispensers, are called on. This consultation can remind the patient of the negative impact of hearing impairment on cognitive function and quality of life, with an increased risk of social isolation and depression, in order to enlighten them and their caregivers as to the benefit of hearing rehabilitation [bib_ref] Hearing impairment, mild cognitive impairment and dementia: a meta-analysis of cohort studies, Wei [/bib_ref]. In a subject with a cochlear implant, teleconsultation can take place between 2 adjustments in order to ensure that the processor(s) are being worn and maintained regularly and to remind them of what they should do in the event of the processor malfunctioning. Teleconsultation may be an opportunity to suggest continuing speech and language therapy or taking it up again; this is possible through telecare via videoconferencing during the COVID-19 pandemic for patients who are already being followed-up. Different publications have demonstrated the feasibility of tele-audiology methods for elderly people, for monitoring people with implants, and in particular for adjusting devices [bib_ref] The role of Telemidicine in auditory rehabilitation: a systematic review, Bush [/bib_ref] [bib_ref] Teleaudiology in the veterans health administration, Pross [/bib_ref]. # Conclusion The development of tele-audiology is occurring in a context where the physician and the surgeon must, in many clinical situations, measure the loss of chance that would result from a failure in diagnosis, surveillance, or treatment. With the COVID-19 pandemic, after the necessity of stopping ongoing and scheduled medical consultations for a time, except for emergencies, it is now necessary to treat ill people at risk of "loss of chance". From a medical standpoint, loss of chance can be apprehended through its cause, namely diagnosis, treatment, monitoring, etc., because any delay can be qualified as loss of chance. As such, loss of chance becomes the privileged domain of dereliction of duty (by delayed diagnosis, by negligence in the prescription of additional examinations, etc.). The medical approach to loss of chance includes three concepts: the possibility of better results than dereliction (diagnosis, treatment), respecting the patient's rights (reaffirmed by the French law dated 4 March 2002) and the assessment of loss of chance as per bibliographic documents (recommendations from learned societies, cohorts studied, and spontaneous development). To suit the subject matter, the concept of "loss of chance" has become "loss of chance of recovery or survival". Loss of chance is halfway between damage and causality. It does not stand in for the causal link but makes up for the disappearance of a likelihood of refusing a treatment, achieving a recovery, or suffering less harm. In this outbreak context, the new telemedicine tools undoubtedly help limit this loss of chance, making it possible to ensure even more regular follow-up [bib_ref] Telemedicine for ENT: effect of quality of care during COVID-19 pandemic, Fieux [/bib_ref]. In a recent telemedicine experiment conducted in ENT during the COVID-19 pandemic, it was reported that otological and audiological symptoms (otalgia, hearing impairment, dizziness) were the most frequent reasons for teleconsultation [bib_ref] Impact of the SARS-CoV-2 epidemic on private ENT consulting practice during the..., Rubin [/bib_ref]. Tele-otoscopy, an essential prerequisite for any teleconsultation in otoneurology [bib_ref] Guidelines of the French Society of Otorhinolaryngology (SFORL) for teleconsultation in patients..., Bertholon [/bib_ref] , is a telemedicine tool that has already proved its worth. However, the regulations in force make its use still marginal in France and an evolution of this latter appears essential if we wish to be able to extend it on a larger scale. Technical solutions already exist to remotely perform both subjective and objective assessment of the patient's hearing function. # Disclosure of interest The authors declare that they have no competing interest. [fig] Figure 1: Examples of video-otoscopy (A, C and E) and smartphone otoscopy (B, D and F). [/fig] [fig] Figure 3: Screenshot of otoacoustic emissions filtered around 1 kHz (ILO 98) in a patient with endolymphatic hydrops on the left side. The red and black graphs are recorded in the lying and sitting position. The abnormal phase shift here is largely > 40 • . [/fig] [table] Table 1: Tele-audiometry solutions for screening purposes. [/table] [table] Table 2: Tele-audiometry solutions for diagnostic purposes (CE marked medical devices). [/table] [table] Table 3: Different simulation systems available for audiometry. [/table] [table] Table 4: Child audiophonoloy clinical orientation questionnaire. [/table] [table] Table 5: Child audiophonology clinical contexts. First time, auditory confirmation/opinion Monitoring a hearing-impaired child (hearing impairment confirmed) or a child who has already been seen Request for review following newborn screening (0-3 months old) Suspicion of hearing impairment in an infant under 18 months old Suspicion of hearing impairment in a child aged 18 months to 5 years old Speech and language delay in a child aged 18 months to 5 years old Suspicion of hearing impairment in a child aged 6 to 18 years old Sudden hearing loss Opinion for difficulty in noisy environments Opinion for hyperacusis Assessment as part of bacterial meningitis/cytomegalovirus (CMV) fetopathy/cleft palate/malformation syndrome/Karyotype anomalies (including Trisomy 21/Down's syndrome) Assessment before or after otologic surgery or placement of a tympanostomy tube (TT) Assessment before or after chemotherapy, or other ototoxic treatment Hearing examination after a trauma Hearing examination in the context of vertigo or psychomotor retardation Second opinion by an ENT specialist after diagnosis of a hearing impairment Assessment of overall delay, learning disorders, behavioural problems, attention deficit with or without hyperactivity, autism spectrum disorder Traditional monitoring of a hearing-impaired child with a hearing aid or implant Child with a hearing aid, opinion sought for a cochlear implant Child with a hearing aid, opinion sought for a suspected deterioration in hearing Request for equipment renewal Child with a hearing aid, opinion sought for an aetiological assessment Hearing-impaired child without a hearing aid, opinion sought for how to arrange treatment Monitoring of bacterial meningitis/CMV fetopathy/cleft palate/malformation syndrome/Karyotype anomalies (including Down's syndrome) (hearing-impaired or not) Monitoring after otologic surgery or TT placement Monitoring after chemotherapy, or other ototoxic treatment Monitoring of speech delay unipedal stance test, and a cognitive test, the Codex [/table]	None	None	None
2f4d6f26ea3ba88e4809c3d2cef2b913c1af5fb0	pubmed	Clinical practice guidelines for duodenal cancer 2021	Clinical practice guidelines for duodenal cancer 2021 Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient). # Introduction Duodenal cancer, a representative rare cancer in gastrointestinal malignancies, is considered to be a small intestine carcinoma clinicopathologically; however, in Japan, there are no established guidelines for its treatment based on sufficient scientific evidence, and evidence, such as epidemiological data and phase III clinical trials that serve as the basis for such guidelines, are also lacking. Therefore, in daily clinical practice, its treatment is based on the experience of individual physicians and is similar to that of gastric and colorectal cancers. However, with advances in diagnostic modalities, such as gastrointestinal endoscopy and imaging, it is anticipated that opportunities for its detection will increase in future. We started to develop guidelines for management of duodenal cancer because this disease is considered to have high health-care demand by both healthcare providers and patients to provide appropriate medical care to patients. This guideline was compiled for patients with suspected non-ampullary duodenal epithelial malignancies (including adenomas and intramucosal carcinomas) and patients diagnosed with nonampullary duodenal epithelial malignancies. The guidelines were developed for use in actual clinical practice, without limiting the gender or age of the target population. In this study, the practice guideline was developed in accordance with the Minds Practice Guideline Development Manual 2017 . In accordance with the manual, we developed a practice algorithm , Figs. 1, 2 and 3) and formulated Clinical Questions (CQs) for each area of epidemiology, diagnosis, endoscopic treatment, surgical treatment, and drug (chemo-and radiation)-therapy. An exemplary method was used to conduct a literature search using PubMed and medical journals, followed by a systematic review, draft recommendations, and a vote on the recommendations. For all CQs, we established relevant keywords and conducted an exhaustive primary screening of English and Japanese articles from 1945 to December 2018 (PubMed, The Cochrane Library) and from 1983 to December 2018 (Central Journal of Medicine). Reports from major international conferences and important papers were added by hand search as necessary, even outside the search period. The guideline development committee members and cooperating members independently conducted a secondary screening of the literature after the search to determine the articles to be adopted, and a systematic review was conducted. For each important outcome included in each CQ, the evidence presented by individual articles were categorized by study design, evaluated at the literature level and in aggregates, and the certainty (strength) of evidence for the CQ was ultimately determined. For those studies that had the same study design and for which efficacy measures could be evaluated quantitatively, a quantitative systematic review was conducted independently. Regarding those for which quantitative evaluation was not possible, only qualitative systematic reviews were conducted to evaluate the logic, certainty, etc. from the context. In the manual for developing medical practice guidelines, it is assumed that a draft recommendation is prepared based on available evidence, and that the recommendation is discussed thoroughly to determine the level of recommendation. However, duodenal cancer is a rare disease, and there is little evidence based on randomized controlled trials and many retrospective studies. Therefore, the decision was based in part on discussions and a majority vote of specialists in each field. For each CQ, ''balance of benefits and harms,'' ''patient preference,'' and ''impact of resources'' were also comprehensively judged, and judgments were made more in line with actual clinical practice so that decisions on recommendations were not influenced solely by the level of evidence. The committee comprised members from multiple disciplines, including internal medicine, surgery, radiology, and pathology, to minimize bias in opinions. Furthermore, all recommendation decisions were made by unanimous vote, with the exception of the chairperson and supervisory committee members, to emphasize consensus. Abstentions were allowed. Members with financial/academic conflicts of interest abstained from voting. The strength of the recommendation was based on the GRADE Grid method. After consensus meetings with the committee members, a draft of guidelines was written and uploaded on the websites of the Japanese Gastric Cancer Association Society of Gastroenterology, the Japanese Society of Hepato-Biliary-Pancreatic Surgery, the Japan Gastroenterological Endoscopy Society, the Japanese Society for Radiation Oncology, and the Japanese Society for Cancer of the Colon and Rectum from February 15 to March 1, 2021, for public hearing. Taking into account the comments received from public hearing and committee members, the final revision was developed. Finally, the guidelines written in Japanese were published in August 2021. The age of onset is in the 60-70 years age range, with a slightly higher incidence in male individuals. In Europe and the United States, it is reported that 10-22% of cases are localized at the time of diagnosis, but in Japan, 56% of cases were localized in 2016, and about half of them were treated endoscopically. ## Diagnosis and endoscopic treatment (Background Question) Comment: The incidence is reported to be 3.0-3.7 per million population in North America [bib_ref] Small intestinal cancer: a population-based study of incidence and survival patterns in..., Qubaiah [/bib_ref] [bib_ref] The epidemiology and pathogenesis of neoplasia in the small intestine, Schottenfeld [/bib_ref] and 2.9-4.3 per million population in Europe [bib_ref] Incidence of phenotypes of and survival from small bowel cancer in Denmark,..., Bojesen [/bib_ref] [bib_ref] Trends in incidence, treatment, and survival of small bowel adenocarcinomas between 1999..., Legué [/bib_ref] [bib_ref] Incidence patterns of small bowel cancer in a population-based study in Sweden:..., Lu [/bib_ref]. According to data from the National Cancer Registry of Japan, 3005 cases of duodenal cancers were diagnosed in 2016, with an extremely high crude rate of 23.7 per million population (calculated based on a total population of 126,993,000). Although reports from Europe indicate that there seems to be almost no difference between male and female patients [bib_ref] Incidence of phenotypes of and survival from small bowel cancer in Denmark,..., Bojesen [/bib_ref] [bib_ref] Incidence patterns of small bowel cancer in a population-based study in Sweden:..., Lu [/bib_ref] , data from the Japanese cancer registry show that male patients tend to be 1.5 times more common than female patients. The disease has been reported to be more common in people in their 60 and 70 s, accounting for approximately 55% of this age group, and the incidence increases with age [bib_ref] Small intestinal cancer: a population-based study of incidence and survival patterns in..., Qubaiah [/bib_ref] [bib_ref] Incidence of phenotypes of and survival from small bowel cancer in Denmark,..., Bojesen [/bib_ref]. Approximately 10-22% of all cases have been reported to remain localized to the duodenum at the time of detection [bib_ref] Small intestinal cancer: a population-based study of incidence and survival patterns in..., Qubaiah [/bib_ref] [bib_ref] Incidence of phenotypes of and survival from small bowel cancer in Denmark,..., Bojesen [/bib_ref]. In Japan, 56.4% of cases remain localized to the duodenum, 5.6% involve regional lymph nodes, 15.8% involve distant metastasis, 8.6% involve invasion of surrounding organs, and 13.6% are unknown. Additionally, approximately 48.0% of tumors that remained in the duodenal region were treated endoscopically [bib_ref] The incidence of non-ampullary duodenal cancer in Japan: the first analysis of..., Yoshida [/bib_ref]. ## Cq1-2. What are the risks of duodenal cancer? - There are no known risk factors for non-ampullary duodenal cancer other than familial adenomatous polyposis of the colon (FAP). (Background Question) Comment: A systematic review of small intestinal cancers, including duodenal cancer, in the general population with low risk of bias reported associations with smoking, alcohol consumption, and various diseases (FAP, Crohn's disease, cholecystectomy, peptic ulcer, cystic fibrosis, etc.). However, compared to the general population, the risk ratio for duodenal cancer in patients with FAP is 330.8 (132.7-681.5) [bib_ref] The risk of upper gastrointestinal cancer in familial adenomatous polyposis, Offerhaus [/bib_ref]. The cumulative incidence of duodenal cancer (including papillary carcinoma) has been reported to be 7.7% (3.5-16.5%) [bib_ref] Upper gastrointestinal tumours in Japanese familial adenomatous polyposis patients, Yamaguchi [/bib_ref] at the age of 50 years, with a lifetime risk of 18% [bib_ref] Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis, Bulow [/bib_ref]. In patients with FAP, the presence of duodenal adenoma (Risk ratio, RR 13.2 [1.6-107.2]) is a risk factor for duodenal cancer [bib_ref] Upper gastrointestinal tumours in Japanese familial adenomatous polyposis patients, Yamaguchi [/bib_ref]. Spigelman's classification is used as the clinicopathologic classification of duodenal adenomas in patients with FAP [bib_ref] Upper gastrointestinal cancer in patients with familial adenomatous polyposis, Spigelman [/bib_ref]. In a retrospective cohort study [bib_ref] Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis, Bulow [/bib_ref] CQ2-1. Are duodenal adenomas eligible for treatment? - Weak recommendation for treating non-ampullary duodenal adenomas. (Recommendation: weak, 100% agreed, evidence level C) Comment: Duodenal adenomas are divided into sporadic and familial forms. FAP is the most frequent familial form, and the Spigelman classification is usually used for duodenal adenomas associated with it. Furthermore, the indication for treatment is determined by scoring based on tumor number, size, histology, and atypia [bib_ref] Upper gastrointestinal cancer in patients with familial adenomatous polyposis, Spigelman [/bib_ref]. In this CQ, we performed a qualitative systematic review of sporadic duodenal adenomas [bib_ref] Sporadic nonampullary duodenal adenoma in the natural history of duodenal cancer: a..., Okada [/bib_ref] [bib_ref] Comparison of nonampullary duodenal adenomas in patients with familial adenomatous polyposis versus..., Cassani [/bib_ref] [bib_ref] Method and timing of resection of superficial non-ampullary duodenal epithelial tumors, Kakushima [/bib_ref] [bib_ref] Accuracy of biopsy for the preoperative diagnosis of superficial nonampullary duodenal adenocarcinoma, Kinoshita [/bib_ref] [bib_ref] Endoscopic diagnosis of superficial non-ampullary duodenal epithelial tumors in Japan: multicenter case..., Goda [/bib_ref]. We considered that histological atypia of non-ampullary duodenal adenomas increases with follow-up even if they are sporadic, and in a certain percentage of cases, the histological diagnosis after endoscopic treatment is more atypical than the biopsy diagnosis before endoscopic treatment. ## Cq2-2. how can adenoma and cancer in duodenal tumors be differentiated? - Although histological diagnosis by biopsy is the standard for differentiating adenomas from cancers, performing endoscopic diagnosis when endoscopic treatment is being considered is weakly recommended. (Recommendation: weak, 100% agreed, evidence level C) Comment: Generally, the standard method of differentiating benign from malignant tumors of the gastrointestinal tract is biopsy before treatment. Histological diagnosis is highly specific in differentiating adenomas from carcinomas in duodenal tumors, and is a standard diagnostic method as with other gastrointestinal tumors. However, several studies have shown that the correct diagnosis rate of endoscopic diagnosis, including magnifying endoscopy with narrow-band imaging, is also comparable or higher than that of biopsy diagnosis [bib_ref] A simple endoscopic scoring system to differentiate between duodenal adenoma and carcinoma, Kakushima [/bib_ref] [bib_ref] Endoscopic features of nonampullary duodenal tumors with narrow-band imaging, Yoshimura [/bib_ref] [bib_ref] Diagnostic algorithm of magnifying endoscopy with narrow band imaging for superficial non-ampullary..., Kikuchi [/bib_ref] [bib_ref] Magnifying endoscopy with narrow band imaging for superficial non-ampullary duodenal epithelial tumors..., Tsuji [/bib_ref] [bib_ref] Clinical usefulness of magnifying endoscopy for non-ampullary duodenal tumors, Mizumoto [/bib_ref] [bib_ref] Magnified endoscopy with narrow-band imaging for the differential diagnosis of superficial non-ampullary..., Kakushima [/bib_ref]. Endoscopic diagnosis can also be weakly recommended when considering endoscopic treatment, including the effects of fibrosis of the lesion caused by biopsy. CQ3-1. What is recommended to differentiate intramucosal from submucosal carcinoma? - Evaluation by endoscopic gross type and coloration is weakly recommended. (Recommendation: weak, 100% agreed, evidence level C) Comment: Endoscopic gross type and color are important to distinguish M (tumor confined to the lamina propria) from SM (tumor confined to the submucosa), and endoscopic ultrasound (EUS) may be a reference finding, as several cases of SM invasion have been reported [bib_ref] Endoscopic diagnosis of superficial nonampullary duodenal epithelial tumors, Goda [/bib_ref] [bib_ref] The actual condition of early duodenal carcinoma and the indications for endoscopic..., Hase [/bib_ref] [bib_ref] Endoscopic diagnosis and treatment of superficial non-ampullary duodenal epithelial tumors, Goda [/bib_ref]. Future case accumulation is desirable for the diagnosis using magnifying endoscopy as well as EUS. ## Cq3-2. what is recommended for diagnosis of distant metastases? - Imaging, including contrast-enhanced CT scan, is weakly recommended. (Recommendation: weak, 100% agreed, evidence level C) Comment: Only one retrospective case-control report that met the intent of the CQ was found in the literature [bib_ref] Duodenal neoplasms: predictive value of CT for determining malignancy and tumor resectability, Kazerooni [/bib_ref]. To date, computed tomography (CT) scans have been reportedly used for evaluating intramural and extramural extension of the primary tumor, vascular invasion, periduodenal adipose tissue invasion, adjacent organ invasion, lymph nodes, and other organ metastasis. The selected papers also concluded that CT examination including contrast studies can evaluate metastasis to other organs, vascular invasion, and invasion to adjacent organs, and is useful in determining whether radical resection is feasible. However, there are no reports on positron emission tomography (PET) or magnetic resonance imaging (MRI) for duodenal cancer, and we consider these imaging tests to be effective in the diagnosis of distant metastasis, although further accumulation of case reports is desirable. CQ4-1. What are the indications for various endoscopic treatments for duodenal neoplasms? - Although polypectomy, EMR, ESD, LECS, etc. have been performed, the indication criteria for various treatment methods are unclear. (Background Question) Comment: A paper on a survey of 13 Japanese institutions regarding endoscopic treatment of superficial nonampullary duodenal epithelial tumor (SNADET) is available [bib_ref] Current status of endoscopic treatment and incidental events for nonpapillary tumors of..., Ono [/bib_ref]. Although the survey has the largest number (1397) of cases in a Japanese paper, carcinoid and Brunner's adenoma/hyperplasia were included in the target lesions, and it was not possible to evaluate the outcome of SNADET alone. Furthermore, no description of lesion size or indications for each treatment (endoscopic mucosal resection; EMR, endoscopic submucosal dissection; ESD, cold polypectomy; CP, underwater EMR; U-EMR, laparoscopy and endoscopy cooperative surgery; LECS) was provided, making it difficult to compare treatment outcomes. There were no randomized controlled trials of endoscopic treatment of SNADET, and most reports were retrospective observational studies. Furthermore, the reality of endoscopic treatment differs between Japan and other countries. Outside of Japan, EMR is the treatment of choice even for large tumors, and piecemeal EMR is often used, while all ESD reports are from Japan, where larger tumors are treated compared to EMR, and high en bloc and R0 resection rates are reported. The rate of recurrence was 0% [bib_ref] Endoscopic submucosal dissection and endoscopic mucosal resection for non-ampullary superficial duodenal tumor, Hoteya [/bib_ref] [bib_ref] Outcomes of endoscopic resection for superficial duodenal epithelial neoplasia, Yahagi [/bib_ref] [bib_ref] Therapeutic outcomes of endoscopic resection for superficial non-ampullary duodenal tumor, Yamamoto [/bib_ref] [bib_ref] Efficacy of an over-thescope clip for preventing adverse events after duodenal endoscopic..., Tashima [/bib_ref]. However, the incidence of incidental adverse events was higher with ESD. The criteria for selecting EMR and ESD are currently based on the actual conditions of endoscopic treatment at each institution. Although the long-term prognosis of CP and U-EMR is unknown, it was suggested that CP and U-EMR may be effective treatment options with few complications for lesions with small tumor diameters, as there were no cases of perforation or bleeding [bib_ref] Cold polypectomy for duodenal adenomas: a prospective clinical trial, Maruoka [/bib_ref] [bib_ref] Underwater endoscopic mucosal resection for superficial nonampullary duodenal adenomas, Yamasaki [/bib_ref]. There were no observational studies of LECS and Argon plasma coagulation with more than 30 cases. From the above, it was considered difficult to establish uniform criteria for treatment methods. CQ4-2. What are the endoscopist and facility requirements for various types of endoscopic procedures? - Although there are no clear requirements for endoscopist and facilities, performance of ESD by endoscopist and facilities that are skilled in the technique is weakly recommended. (Recommendation: weak, 100% agreed, evidence level C) Comment: Although the incidence of adverse events during duodenal ESD has decreased over time, it is still higher than ESD for other organs, and there are reports of expert-led ESD in high-volume centers , but there are only few reports from small and mediumsized centers. There are no reports of LECS with a large number of cases. Although EMR has a lower incident rate compared to ESD, emergency surgery has been reported in some cases, and the procedure by novice endoscopist should be avoided. There were few reports from small and mediumsized facilities as an institutional requirement, but we judged that there was insufficient evidence to institutional requirements. Although the incidences of adverse events during cold snare polypectomy, cold forceps polypectomy, and U-EMR are low, and relatively safe procedures can be performed, discussions based on the R0 resection rate and other factors are also necessary. Therefore, there is little rationale for setting specific endoscopist and facility requirements. CQ5. Are prophylactic measures recommended after endoscopic treatment of superficial non-ampullary duodenal epithelial tumors? - Performance of prevention measures for adverse events during duodenal EMR and ESD, including mucosal suture and wound covering with PGA sheets, is weakly recommended. (Recommendation: weak, 100% agreed, evidence level C) Comment: Specific methods for the prevention of adverse events during endoscopic treatment for superficial non-ampullary duodenal tumors include clips/threaded clips or endoloops [bib_ref] Endoscopic submucosal dissection and endoscopic mucosal resection for non-ampullary superficial duodenal tumor, Hoteya [/bib_ref] [bib_ref] Clinical impact of closure of the mucosal defect after duodenal endoscopic submucosal..., Kato [/bib_ref] [bib_ref] Clinical outcomes of endoscopic resection for nonampullary duodenal high-grade dysplasia and intramucosal..., Maruoka [/bib_ref] [bib_ref] Endoscopic resection for superficial non-ampullary duodenal epithelial tumor in patients on antithrombotic..., Hosotani [/bib_ref] [bib_ref] Suitable closure for postduodenal endoscopic resection taking medical costs into consideration, Mori [/bib_ref] , suturing with an Over-The-Scope Clip (OTSC) [bib_ref] Efficacy of an over-thescope clip for preventing adverse events after duodenal endoscopic..., Tashima [/bib_ref] [bib_ref] Suitable closure for postduodenal endoscopic resection taking medical costs into consideration, Mori [/bib_ref] [bib_ref] Efficacy of endoscopic preventive procedures to reduce delayed adverse events after endoscopic..., Tsutsumi [/bib_ref] , or covering with a polyglycolic acid (PGA) sheet [bib_ref] Clinical impact of closure of the mucosal defect after duodenal endoscopic submucosal..., Kato [/bib_ref] [bib_ref] Endoscopic resection for superficial non-ampullary duodenal epithelial tumor in patients on antithrombotic..., Hosotani [/bib_ref] , and laparoscopically assisted augmentation from the serosal side (so-called D-LECS) [bib_ref] Laparoscopic and endoscopic co-operative surgery for non-ampullary duodenal tumor, Ichikawa [/bib_ref] were reported. While all these studies were retrospective, the incidence of adverse events was significantly reduced by taking various prevention measures. A quantitative systematic review by four editors [bib_ref] Endoscopic submucosal dissection and endoscopic mucosal resection for non-ampullary superficial duodenal tumor, Hoteya [/bib_ref] [bib_ref] Cold polypectomy for duodenal adenomas: a prospective clinical trial, Maruoka [/bib_ref] [bib_ref] Clinical impact of closure of the mucosal defect after duodenal endoscopic submucosal..., Kato [/bib_ref] [bib_ref] Endoscopic resection for superficial non-ampullary duodenal epithelial tumor in patients on antithrombotic..., Hosotani [/bib_ref] , in which comparisons were made with the target population, found that the risk was reduced by approximately 84%. However, OTSC, PGA sheets with fibrin glue are expensive. Fibrin glue is a blood product derived from donated blood and carries a low risk of infection. However, adverse events that occur after endoscopic treatment in the duodenum are often very serious, and from the viewpoint of the balance of benefits and harms, it is recommended that measures be taken to prevent late-onset adverse events. CQ6-1. What are the recommended criteria for surgical treatment after endoscopic treatment? - Additional surgery in cases of submucosal carcinoma and vascular invasion is weakly recommended. (Recommendation: weak, 100% agreed, evidence level C) Comment: Additional surgery is recommended for submucosal carcinoma because of the high risk of local recurrence and lymph node metastasis. Although the local recurrence rate is high in patients undergoing piecemeal resection, strict follow-up can be considered because subsequent endoscopic treatment is effective and shows a good prognosis [bib_ref] Short-and long-term outcomes of endoscopically treated superficial non-ampullary duodenal epithelial tumors, Hara [/bib_ref] [bib_ref] Endoscopic mucosal resection of non-ampullary sporadic duodenal adenomas: a retrospective analysis with..., Valerii [/bib_ref] [bib_ref] Selection of appropriate endoscopic therapies for duodenal tumors: an open-label study, single-center..., Matsumoto [/bib_ref] [bib_ref] Endoscopic submucosal dissection for nonampullary large superficial adenocarcinoma/ adenoma of the duodenum:..., Hoteya [/bib_ref] [bib_ref] Endoscopic resection of duodenal neoplasms: a single-center study, Sohn [/bib_ref] [bib_ref] Clinical outcomes of endoscopic resection for nonampullary duodenal tumor, Nonaka [/bib_ref] [bib_ref] Clinical outcome of EMR of sporadic, nonampullary, duodenal adenomas: a 10-year retrospective, Tomizawa [/bib_ref]. Although there were few reports on vascular invasion after endoscopic treatment, additional surgery was recommended based on surgical treatment cases [bib_ref] Outcomes of surgical resection for primary duodenal adenocarcinoma: a systematic review, Li [/bib_ref]. ## Cq6-2. is endoscopic surveillance recommended after endoscopic treatment for early detection of local recurrence and metachronous lesions? - Endoscopic surveillance for local recurrence after endoscopic treatment is weakly recommended. (Recommendation: weak, 100% agreed, evidence level C) Comment: In the qualitative systematic review conducted in this study, no high-quality studies such as prospective studies that followed a defined surveillance methodology were identified; only retrospective studies were identified. No evidence was found on the detection of metachronous lesions, as well as on the interval and duration of surveillance [bib_ref] Endoscopic submucosal dissection and endoscopic mucosal resection for non-ampullary superficial duodenal tumor, Hoteya [/bib_ref] [bib_ref] Short-and long-term outcomes of endoscopically treated superficial non-ampullary duodenal epithelial tumors, Hara [/bib_ref] [bib_ref] Endoscopic mucosal resection of non-ampullary sporadic duodenal adenomas: a retrospective analysis with..., Valerii [/bib_ref] [bib_ref] Clinical outcome of EMR of sporadic, nonampullary, duodenal adenomas: a 10-year retrospective, Tomizawa [/bib_ref] [bib_ref] Clinical outcome of endoscopic resection for nonampullary duodenal tumors, Nonaka [/bib_ref] [bib_ref] Nonampullary duodenal adenomas rarely recur after complete endoscopic resection: a Swiss experience..., Valli [/bib_ref] [bib_ref] Endoscopic resection of large duodenal and papillary lateral spreading lesions is clinically..., Klein [/bib_ref]. The majority of the locally recurrent lesions detected by surveillance were controlled endoscopically, and no cause specific mortality was observed. However, surveillance costs less than surgery [bib_ref] Endoscopic resection of large duodenal and papillary lateral spreading lesions is clinically..., Klein [/bib_ref] , considering the balance of benefits and harms, endoscopic surveillance for the detection of local recurrence after endoscopic treatment may be beneficial, as the mortality rate due to endoscopic complications was low at 0.001%. Furthermore, a high recurrence rate has been reported in lesions that have been treated in a piecemeal fashion, and surveillance is especially desirable. Surgical treatment CQ1. Is lymph node dissection recommended in the surgical treatment of duodenal cancer? - Lymph node dissection is weakly recommended in the surgical treatment of duodenal cancer. However, lymph node dissection may be omitted for intra-mucosal lesions. (Recommendation: weak, 96% agreed, evidence level D) Comment: In previous retrospective studies in duodenal cancer, lymph node-positive cases were associated with significantly poorer prognosis [bib_ref] A clinicopathological study on primary carcinoma of the duodenum, Sugawara [/bib_ref] [bib_ref] A clinicopathological study of our 27 cases undergone resection for primary duodenal..., Inose [/bib_ref] [bib_ref] Surgical procedure depending on the depth of tumor invasion in the duodenal..., Kato [/bib_ref] [bib_ref] Outcomes and treatment options for duodenal adenocarcinoma: a systematic review and meta-analysis, Meijer [/bib_ref]. Furthermore, numerous multivariate analyses have reported that lymph node metastasis is an independent prognostic factor along with progression, histologic differentiation, and vascular invasion [bib_ref] Surgical procedure depending on the depth of tumor invasion in the duodenal..., Kato [/bib_ref] [bib_ref] What prognostic factors important in duodenal adenocarcinoma?, Bakaeen [/bib_ref] [bib_ref] Optimal lymphadenectomy for duodenal adenocarcinoma: does the number alone matter?, Sakamoto [/bib_ref]. Although there are not many reports on the frequency of lymph node metastasis according to tumor localization in the duodenum, in the first portion of duodenum, the lymph nodes in the subpyloric region (No. 6) and the posterior pancreatic head (No. 13), and in the descending part of the duodenum, the lymph nodes in the posterior pancreatic head (No. 13) and anterior pancreatic head (No. 17) are considered to be sentinel lymph nodes [bib_ref] Sentinel node navigation surgery for early malignant tumor of the duodenum, Mitsumori [/bib_ref] , and lymphatic flow in the transvers and ascending part of the duodenum is speculated to flow from the inferior pancreatoduodenal artery and upper jejunal artery into the lymphatic system around the superior mesenteric artery [bib_ref] Four Cases of primary duodenal adenocarcinoma in the fourth portion, Mizuma [/bib_ref]. It is also possible that the preferred site of lymph node metastasis differs depending on localization [bib_ref] Optimal lymphadenectomy for duodenal adenocarcinoma: does the number alone matter?, Sakamoto [/bib_ref]. Meanwhile, a study on the relationship between tumor depth and lymph node metastasis showed that the lymph node metastasis rate for submucosal carcinoma is 5-11%, and the frequency is even higher in the intrinsic muscle layer and deeper (MP; tumor invasion of the muscularis propria: 44%, SS; tumor invasion of the sub-serosa: 41%, SE; tumor invasion that is contiguous to or penetrates the serosa and is exposed to the peritoneal cavity /Sl; tumor invasion of adjacent structures: 73%). In addition, it is often reported that lymph node metastasis is not observed in intra-mucosal lesions [bib_ref] A case of primary early carcinoma the duodenum, Hase [/bib_ref] [bib_ref] A case of early duodenal cancer, Kawaguchi [/bib_ref] [bib_ref] Case report of early duodenal cancer with segmental resection and long-term survival...., Ryu [/bib_ref] [bib_ref] Primary duodenal carcinoma: six surgically treated cases, Nishiwada [/bib_ref] [bib_ref] Surgery for advanced primary duodenal adenocarcinoma, Abe [/bib_ref]. However, the above reports only indicate the presence and frequency of lymph node metastasis. There is no evidence that shows that lymph node dissection for duodenal cancer contributes to a prolonged prognosis. There is also no evidence regarding the optimal extent of dissection or complications associated with lymph node dissection. Therefore, evidence is needed to discuss its balance of benefits and harms can be considered. Although it is necessary to mention that the body of clear evidence for this CQ is insufficient, peripheral lymph node dissection may be considered to the extent that it can be safely resected. If the lesion is deeper than the submucosa, a surgery with surrounding lymph node dissection, such as pancreatoduodenectomy, can be performed regardless of the location of the lesion in the duodenum. Only when surgical treatment is indicated and the lesion is judged to be intramucosal, a modified operation such as distal gastrectomy or partial duodenectomy may be considered, depending on the location of the lesion. Clinical indications are based on whether vital organ function is preserved, and performance status is maintained. CQ2. In consideration of the depth and site of occupancy, is performing a procedure other than pancreatoduodenectomy recommended? - In cases of duodenal cancer deeper below the submucosa, we weakly recommend that no procedure other than pancreato-duodenectomy be performed. (Recommendation: weak, 79% agreed, evidence level C) Comment: As discussed in CQ1, lymph node metastasis is reported to occur in duodenal cancer that extend deeper than the submucosal layer, and the frequency of lymph node metastasis increases as the depth of the disease progresses. For duodenal cancer in the submucosal layer or deeper, pancreato-duodenectomy is currently proposed as the standard procedure, taking tumor factors into consideration. However, several case series have reported that the 5-year postoperative survival rates of pancreato-duodenectomy and limited resection of the duodenum (including pancreas-sparing partial duodenectomy and local duodenectomy) for duodenal cancer are similar [bib_ref] Outcomes of surgical resection for primary duodenal adenocarcinoma: a systematic review, Li [/bib_ref] [bib_ref] Surgical procedure depending on the depth of tumor invasion in the duodenal..., Kato [/bib_ref] [bib_ref] Outcomes and treatment options for duodenal adenocarcinoma: a systematic review and meta-analysis, Meijer [/bib_ref] [bib_ref] What prognostic factors important in duodenal adenocarcinoma?, Bakaeen [/bib_ref] [bib_ref] Does the extent of resection impact survival for duodenal adenocarcinoma? Analysis of..., Cloyd [/bib_ref] [bib_ref] 15-year experience with surgical treatment of duodenal carcinoma: a comparison of periampullary..., Onkendi [/bib_ref] [bib_ref] Prognostic factors and clinical characteristics of patients with primary duodenal adenocarcinoma: a..., Jiang [/bib_ref] ; furthermore, the incidence of postoperative complications, such as operative mortality and pancreatic fistula, tend to be higher for pancreato-duodenectomy [bib_ref] What prognostic factors important in duodenal adenocarcinoma?, Bakaeen [/bib_ref] [bib_ref] Does the extent of resection impact survival for duodenal adenocarcinoma? Analysis of..., Cloyd [/bib_ref] [bib_ref] Surgical outcomes for duodenal adenoma and adenocarcinoma: a multicentre study in Australia..., Lee [/bib_ref] [bib_ref] Adenocarcinoma of the duodenum: factors influencing long-term survival, Sohn [/bib_ref] [bib_ref] Surgical strategy for T1 duodenal or ampullary carcinoma according to the depth..., Kohga [/bib_ref] [bib_ref] Adenocarcinoma of the third and fourth portions of the duodenum: results of..., Adriano [/bib_ref]. Considering these surgical results and the frequency of lymph node metastasis, local duodenal resection (including endoscopic treatment) without lymph node dissection can be selected for intra-mucosal cancer, regardless of the site of occupancy. In addition, the preferred site of lymph node metastasis may differ depending on the site of occupancy. Furthermore, the efficacy and safety of pancreato-duodenectomy for duodenal cancer have not been fully established. Therefore, it may be appropriate to choose a technique other than pancreato-duodenectomy, such as local resection of the duodenum with lymph node dissection proximal to the tumor, for duodenal cancers that extend deeper than the submucosa, taking tumor and patient-related factors into full consideration. CQ3. What follow-up is recommended for diagnosis of recurrence after surgical resection of duodenal cancer? - After surgical treatment of duodenal cancer, careful follow-up with various imaging tests is weakly recommended for the diagnosis of distant metastasis and local recurrence. (Recommendation: weak, 100% agreed, evidence level C) Comment: Based on the idea that early diagnosis of recurrence by periodic follow-up in other gastrointestinal cancers leads to appropriate subsequent treatment, we propose careful follow-up according to the actual situation of each case and facility. Endoscopic and surgical treatment CQ1. Is gastrointestinal anastomosis or endoscopic stenting recommended for un-resectable duodenal cancer with obstructive symptoms? - Gastrointestinal anastomosis and endoscopic stent insertion are weakly recommended when these procedures are expected to be effective. (Recommendation: weak, 100% agreed, evidence level D) Comment: Surgical gastric jejunal bypass and endoscopic stent insertion are expected to restore oral intake and improve quality of life, as well as extend survival due to the ability to endure chemotherapy and chemoradiation. However, to date, there have been no reports on these outcomes in detail in un-resectable duodenal cancer, and the evidence for this CQ is insufficient. However, based on actual clinical practice and reflecting the opinions of the guideline drafting committee members, a consensus was reached that gastrointestinal anastomosis and endoscopic stent insertion for un-resectable duodenal cancer with obstructive symptoms are weakly recommended if they are expected to be effective. Chemotherapy CQ1. Is perioperative adjuvant therapy recommended for small bowel cancer, including resectable duodenal cancer? - We weakly recommend against performing postoperative adjuvant therapy to treat resectable small bowel cancer. (Recommendation: weak, 96% agreed, evidence level D). Comment: A literature search for CQ identified 17 articles [bib_ref] Outcomes and treatment options for duodenal adenocarcinoma: a systematic review and meta-analysis, Meijer [/bib_ref] [bib_ref] What prognostic factors important in duodenal adenocarcinoma?, Bakaeen [/bib_ref] [bib_ref] Adenocarcinoma of the duodenum: factors influencing long-term survival, Sohn [/bib_ref] [bib_ref] Adjuvant concurrent chemoradiation for node-positive adenocarcinoma of the duodenum, Swartz [/bib_ref] [bib_ref] Adenocarcinoma of the small bowel at a single Korean institute: management and..., Moon [/bib_ref] [bib_ref] Is there a role for adjuvant therapy in resected adenocarcinoma of the..., Overman [/bib_ref] [bib_ref] Adjuvant chemotherapy for small bowel adenocarcinoma after curative surgery, Koo [/bib_ref] [bib_ref] Role of adjuvant chemoradiotherapy for duodenal cancer: a single center experience, Kim [/bib_ref] [bib_ref] Duodenal adenocarcinoma: clinicopathologic analysis and implications for treatment, Poultsides [/bib_ref] [bib_ref] Treatment and survival of small-bowel adenocarcinoma in the United States: a comparison..., Young [/bib_ref] [bib_ref] Efficacy of adjuvant chemotherapy for small bowel adenocarcinoma: a propensity score-matched analysis, Ecker [/bib_ref] [bib_ref] Role of adjuvant chemotherapy in T2N0M0 periampullary cancers, Ostwal [/bib_ref] [bib_ref] Evaluation of prognostic factors and adjuvant chemotherapy in patients with small bowel..., Aydin [/bib_ref] [bib_ref] Meta-analysis of adjuvant therapy following curative surgery for periampullary adenocarcinoma, Acharya [/bib_ref] [bib_ref] Role of adjuvant chemoradiotherapy for duodenal cancer: an updated analysis of long-term..., Jang [/bib_ref] [bib_ref] Effect of postoperative radiotherapy on survival in duodenal adenocarcinoma: a propensity score-adjusted..., Lim [/bib_ref] [bib_ref] Meta-analysis of postoperative adjuvant therapy for small bowel adenocarcinoma, Ye [/bib_ref]. There are no randomized controlled trials that compared surgery alone with perioperative adjuvant therapy in patients with small bowel cancer, including resectable duodenal cancer. All 17 articles are retrospective comparisons of outcomes between cases treated with surgery alone and cases treated with perioperative adjuvant therapy, using single/multicenter treatment cases or national clinical database (NCD) data, and no articles on preoperative adjuvant therapy were identified. Although three studies [bib_ref] Adenocarcinoma of the small bowel at a single Korean institute: management and..., Moon [/bib_ref] [bib_ref] Treatment and survival of small-bowel adenocarcinoma in the United States: a comparison..., Young [/bib_ref] [bib_ref] Efficacy of adjuvant chemotherapy for small bowel adenocarcinoma: a propensity score-matched analysis, Ecker [/bib_ref] showed an overall survival benefit with adjuvant therapy, the remaining 14 concluded that ''adjuvant therapy does not contribute to an overall survival benefit''. Of those showing an overall survival benefit with adjuvant therapy, only one has been studied with a sufficient sample size, and it was concluded that the benefit was particularly high in stage III patients. However, three meta-analysis articles [bib_ref] Outcomes and treatment options for duodenal adenocarcinoma: a systematic review and meta-analysis, Meijer [/bib_ref] [bib_ref] Meta-analysis of adjuvant therapy following curative surgery for periampullary adenocarcinoma, Acharya [/bib_ref] [bib_ref] Meta-analysis of postoperative adjuvant therapy for small bowel adenocarcinoma, Ye [/bib_ref] all concluded that ''adjuvant therapy does not contribute to prolonged survival''. The variability of the above results is due to the fact that this was a retrospective study, therefore, selection bias among the patients was likely, and there was a large variation in perioperative treatment among the reports of chemotherapy/radiotherapy/chemoradiotherapy. Furthermore, the chemotherapy regimens employed varied widely from report to report, which may have had an impact on the results. Randomized controlled trials using a uniform treatment regimen are needed to answer this CQ. CQ2. Are MSI, HER2, and RAS gene tests recommended for small bowel cancer, including un-resectable or recurrent duodenal cancer? - MSI testing is strongly recommended. (Recommendation: strong, 96% agreed, evidence level B) - We weakly recommend against performing HER2 and RAS gene tests. (Recommendation: weak, 100% agreed, evidence level D) Comment: Tests for mismatch-repair defects include the microsatellite instability (MSI) test, which examines differences in microsatellite length associated with abnormal repeat counts in microsatellite regions, and the mismatchrepair (MMR) proteins (MLH1, MSH2, MSH6, PMS2) for immunohistochemistry, and next-generation sequencers are available. In Japan, MSI-High should be confirmed when pembrolizumab is administered to patients with duodenal cancer. In this review, there was no difference in frequency according to the testing method . See CQ4 for information on immune checkpoint inhibitors for MSI-High cases. Since there are a certain number of MSI-High cases in duodenal cancer, and the results of the MSI-High test are expected to be effective with pembrolizumab, MSI testing is strongly recommended when tissue biopsy can be performed safely. However, no drug has been shown to be effective for HER2 and RAS gene testing, even based on test results, and the significance of these tests is not clear at this time. CQ3. Is systemic chemotherapy recommended for small bowel cancer, including un-resectable or recurrent duodenal cancer? - Systemic chemotherapy with pyrimidine fluoride and oxaliplatin is weakly recommended for small intestinal cancer, including un-resectable or recurrent duodenal cancer. (Recommendation: weak, 100% agreed, evidence level D) Comment: Only single-arm prospective [bib_ref] Chemotherapy for patients with unresectable or metastatic small bowel adenocarcinoma: a systematic..., Nishikawa [/bib_ref] and retrospective studies [bib_ref] Evaluation of prognostic factors and adjuvant chemotherapy in patients with small bowel..., Aydin [/bib_ref] [bib_ref] Chemotherapy for primary adenocarcinoma of the small bowel, Jigyasu [/bib_ref] [bib_ref] Combination chemotherapy in advanced small bowel adenocarcinoma, Locher [/bib_ref] [bib_ref] Natural history and chemotherapy effectiveness for advanced adenocarcinoma of the small bowel:..., Fishman [/bib_ref] [bib_ref] Chemotherapy in small bowel adenocarcinoma: 10-year experience of the British Columbia cancer..., Czaykowski [/bib_ref] [bib_ref] Chemotherapy with 5-fluorouracil and a platinum compound improves outcomes in metastatic small..., Overman [/bib_ref] [bib_ref] Chemotherapy for small-bowel adenocarcinoma at a single institution, Suenaga [/bib_ref] [bib_ref] Primary adenocarcinoma of the small intestine: presentation, prognostic factors, and clinical outcome, Hong [/bib_ref] [bib_ref] Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study, Zaanan [/bib_ref] [bib_ref] Treatment and outcome in small bowel cancer, Ogata [/bib_ref] [bib_ref] Efficacy of the FOLFOX/ CAPOX regimen for advanced small bowel adenocarcinoma: a..., Zhang [/bib_ref] [bib_ref] Multicenter retrospective study of 132 patients with unresectable small bowel adenocarcinoma treated..., Tsushima [/bib_ref] [bib_ref] Prognostic implications of thymidylate synthase gene polymorphisms in patients with advanced small..., Yhim [/bib_ref] [bib_ref] A retrospective review of chemotherapy for patients with small bowel adenocarcinoma in..., Duerr [/bib_ref] [bib_ref] Evaluation of prognostic factors and treatment in advanced small bowel adenocarcinoma: report..., Aydin [/bib_ref] [bib_ref] The characteristics and outcomes of small bowel adenocarcinoma: a multicentre retrospective observational..., Sakae [/bib_ref] [bib_ref] Suggestion of added value by bevacizumab to chemotherapy in patients with unresectable..., Takayoshi [/bib_ref] [bib_ref] Clinical use of molecular targeted agents for primary small bowel adenocarcinoma: a..., Hirao [/bib_ref] [bib_ref] A single institutional analysis of systemic therapy for unresectable or recurrent small..., Makino [/bib_ref] have investigated whether systemic chemotherapy improves prognosis in patients with small bowel cancer, including un-resectable or recurrent duodenal cancer. There have been no randomized comparative studies with best supportive care, and the results are still unclear. In retrospective studies of first-line treatment, combination therapy with pyrimidine fluoride and oxaliplatin is the most commonly used regimen, and cisplatin, irinotecan, and gemcitabine have also been reported. In a report that compared the efficacy of different treatment regimens, for pyrimidine fluoride plus oxaliplatin combination therapy, the response rate was 34-42%, median progression-free survival was 6.9-8.2 months, and median overall survival was 17.8-22.2 months; in combination with pyrimidine fluoride and cisplatin, response rates ranged from 31 to 38%, median progression-free survival ranged from 3.8 to 4.8 months, and median overall survival ranged from 9.3 to 12.6 months; and for irinotecan plus pyrimidine fluoride combination therapy, the response rate was 9-25%, median progression-free survival was 5.6-6.0 months, and median overall survival was 9.4-10.6 months. Although randomized controlled trials using a uniform treatment regimen are needed to answer this CQ, based on the above results, combination therapy based on pyrimidine fluoride and oxaliplatin is recommended as primary therapy when systemic chemotherapy is administered. CQ4. Are immune checkpoint inhibitors recommended for small bowel cancer, including un-resectable or recurrent duodenal cancer? - Pembrolizumab alone is strongly recommended only for previously treated un-resectable or recurrent small bowel cancer, including duodenal cancer, with MSI-High or dMMR. (Recommendation: strong, 92% agreed, evidence level B) Comment: To date, there have been no phase III trials of immune checkpoint inhibitors for small bowel cancer. Four papers [bib_ref] PD-1 blockade in tumors with mismatch-repair deficiency, Le [/bib_ref] [bib_ref] Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade, Le [/bib_ref] [bib_ref] Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer:..., Marabelle [/bib_ref] [bib_ref] First FDA approval agnostic of cancer site -when a biomarker defines the..., Lemery [/bib_ref] have reported the efficacy of pembrolizumab in small bowel cancer, including solid tumors with MSI-High overall, and the overall response rate (ORR) of pembrolizumab monotherapy ranged from 0 to 71%. A phase II trial investigating the efficacy of pembrolizumab monotherapy in 40 previously treated patients with small bowel cancer (including 24 patients with duodenal cancer) has been reported. The primary endpoint of ORR was 8% (95% CI, [bib_ref] Small intestinal cancer: a population-based study of incidence and survival patterns in..., Qubaiah [/bib_ref] [bib_ref] The epidemiology and pathogenesis of neoplasia in the small intestine, Schottenfeld [/bib_ref] [bib_ref] Incidence of phenotypes of and survival from small bowel cancer in Denmark,..., Bojesen [/bib_ref] [bib_ref] Trends in incidence, treatment, and survival of small bowel adenocarcinomas between 1999..., Legué [/bib_ref] [bib_ref] Incidence patterns of small bowel cancer in a population-based study in Sweden:..., Lu [/bib_ref] [bib_ref] The incidence of non-ampullary duodenal cancer in Japan: the first analysis of..., Yoshida [/bib_ref] [bib_ref] The risk of upper gastrointestinal cancer in familial adenomatous polyposis, Offerhaus [/bib_ref] [bib_ref] Upper gastrointestinal tumours in Japanese familial adenomatous polyposis patients, Yamaguchi [/bib_ref] [bib_ref] Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis, Bulow [/bib_ref] [bib_ref] Upper gastrointestinal cancer in patients with familial adenomatous polyposis, Spigelman [/bib_ref] [bib_ref] Spigelman stage IV duodenal polyposis does not precede most duodenal cancer cases..., Thiruvengadam [/bib_ref] [bib_ref] Sporadic nonampullary duodenal adenoma in the natural history of duodenal cancer: a..., Okada [/bib_ref] [bib_ref] Comparison of nonampullary duodenal adenomas in patients with familial adenomatous polyposis versus..., Cassani [/bib_ref] [bib_ref] Method and timing of resection of superficial non-ampullary duodenal epithelial tumors, Kakushima [/bib_ref] [bib_ref] Accuracy of biopsy for the preoperative diagnosis of superficial nonampullary duodenal adenocarcinoma, Kinoshita [/bib_ref] [bib_ref] Endoscopic diagnosis of superficial non-ampullary duodenal epithelial tumors in Japan: multicenter case..., Goda [/bib_ref] [bib_ref] A simple endoscopic scoring system to differentiate between duodenal adenoma and carcinoma, Kakushima [/bib_ref] [bib_ref] Endoscopic features of nonampullary duodenal tumors with narrow-band imaging, Yoshimura [/bib_ref] [bib_ref] Diagnostic algorithm of magnifying endoscopy with narrow band imaging for superficial non-ampullary..., Kikuchi [/bib_ref] , and the primary endpoint could not be achieved. A total of 26 patients who underwent MSI testing had an ORR of 50% in MSI-High patients (n = 4) and 10% in patients without microsatellite instability (microsatellite stable) (n = 20). The U.S. Food and Drug Administration (FDA) approved pembrolizumab for MSI-High or mismatch-repair deficient (dMMR) solid tumors in 2017 in the United States, and this drug was approved in Japan in December 2018. There are no reports of phase III trial results comparing pembrolizumab with existing chemotherapies for duodenal cancer. Although there are a small number of cases, the results suggest that pembrolizumab compares favorably with the response rate and safety of existing chemotherapy in the treatment of MSI-High or dMMR solid tumors. Considering that duodenal cancer with MSI-High or dMMR is a rare disease, pembrolizumab monotherapy is strongly recommended for duodenal cancer with MSI-High or dMMR. # Conclusion These guidelines are the most standardized guidelines at the time of their creation, and do not regulate the implementation of medical treatment methods that differ from the indications described in the guidelines. It is important to decide the treatment plan for each case based on discussions with the patient/family as well as the doctors and other medical staff involved in the treatment, while considering the actual capabilities of the facility (personnel, experience, equipment, etc.) and the characteristics of the patient (shared decision making). In duodenal cancer treatment, physicians should refer to these guidelines together with their patients and try to explain the position and details of each diagnosis and treatment method in a simple manner for the patient's understanding. If a patient is to be treated differently from the treatment recommended in the guidelines, it is necessary to explain to the patient why the treatment is being chosen and to ensure that the patient fully understands the reasons. (Department of Clinical Oncology, Aichi Cancer Center Author contributions All authors participated equally in the conception of the study. KN drafted the manuscript. MS supervised the writing of the manuscript. All authors approved the final version of the manuscript and unanimously agreed to be accountable for all aspects of the work and to ensure that any questions related to the accuracy or integrity of any part of the report are appropriately investigated and resolved. Funding Financial support for the development of this guideline was provided by a Grant-in-Aid for Scientific Research on Health, Labor and Welfare, ''Improving the quality of healthcare delivery systems through the development of guidelines for the treatment of rare cancers (Project number: H29-GANTAISAKU-IPPAN-013)'' and ''Research on Improvement of Quality of Appropriate Medical Care for Rare Cancers and Human Resource Development in the Field of Rare Cancers for the Next Generation through Cooperation with Academic Societies (Project number: 20EA1021)'' research group (Project leader: Professor Yasuhiro Kodera, Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine). Some members of the guideline development committee received support for travel expenses related to their attendance at guideline development committee meetings; however, no remuneration or manuscript fees were paid, and these supports did not influence the development of the guideline. No funds were provided by specific companies. 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://creativecommons. org/licenses/by/4.0/. # Declarations ## Conflict of interest [fig] Figure 2: Treatment algorithm of resectable duodenal cancer. Although there is no evidence for additional surgery after local resection of the duodenum, a comprehensive decision an overall decision should be made whether to perform pancreato-duodenectomy plus lymph node dissection, taking into account pathological tumor and patient factors such as vascular invasion and residual cancer. Tis tumor confined to the lamina propria, SM tumor confined to the submucosa, CQ clinical question, EMR endoscopic mucosal resection, CSP cold snare polypectomy, ESD endoscopic submucosal dissection, LECS laparoscopy and endoscopy cooperative surgery, HM horizontal margin, VM vertical margin, EGD esophagogastroduodenoscopy [/fig] [fig] Figure 3: Treatment algorithm of un-resectable duodenal cancer. CQ clinical question [/fig]	None	https://link.springer.com/content/pdf/10.1007/s00535-022-01919-y.pdf	None
f29f4b956f7571e3908c746035b3ba40d908c0c6	pubmed	National Psoriasis Foundation COVID-19 Task Force Guidance for Management of Psoriatic Disease During the Pandemic: Version 1	National Psoriasis Foundation COVID-19 Task Force Guidance for Management of Psoriatic Disease During the Pandemic: Version 1 Objective:To provide guidance about management of psoriatic disease during the coronavirus disease 2019 (COVID-19) pandemic. Study design: A task force (TF) of 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care was convened. The TF was supplemented by nonvoting members, which included fellows and National Psoriasis Foundation (NPF) staff. Clinical questions relevant to the psoriatic disease community were informed by questions received by the NPF. A Delphi process was conducted.Results: The TF approved 22 guidance statements. The average of the votes was within the category of agreement for all statements. All guidance statements proposed were recommended, 9 with high consensus and 13 with moderate consensus.Limitations: The evidence behind many guidance statements is limited in quality.Conclusion: These statements provide guidance for the management of patients with psoriatic disease on topics ranging from how the disease and its treatments impact COVID-19 risk and outcome, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with severe acute respiratory syndrome coronavirus 2 and what they should do if they develop COVID-19. ## National psoriasis foundation covid-19 Task Force Guidance for Management of Psoriatic Disease During the Pandemic: Version 1 Key words: biologics; COVID-19; psoriasis; psoriatic arthritis; SARS-CoV-2. Severe acute respiratory coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus that binds to the angiotensinconverting enzyme 2 receptor and causes the illness called coronavirus disease 2019 (COVID- , has precipitated devastating personal, economic, and societal repercussions worldwide. 1-4 SARS-CoV-2 usually causes a mild, self-limited illness, but approximately 15% of affected individuals have a more severe, sometimes lifethreatening course, with the risk of poor outcomes increasing with age and comorbidities. [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan [/bib_ref] [bib_ref] Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in..., Cummings [/bib_ref] [bib_ref] Epidemiology of COVID-19: a systematic review and meta-analysis of clinical characteristics, risk..., Li [/bib_ref] Diffuse alveolar damage and acute respiratory distress syndrome are the most common presentations in severe COVID-19. Additionally, thromboembolic events, along with direct and indirect viralinduced injury, may target the skin, gastrointestinal tract, kidney, heart, and brain, with devastating consequences. [bib_ref] Extrapulmonary manifestations of COVID-19, Gupta [/bib_ref] [bib_ref] COVID-19: the vasculature unleashed, Teuwen [/bib_ref] [bib_ref] COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection, Al-Samkari [/bib_ref] The type 1 interferon response, which is required to clear the virus, is often insufficient in the early phase of SARS-CoV-2 infection, but a delayed persistent elevation may develop as the illness progresses. [bib_ref] Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients, Hadjadj [/bib_ref] Profound dysregulation of innate and acquired immunity can occur with more severe COVID-19, including significant lymphopenia as a direct result of viral-induced apoptosis and necrosis of lymphocytes in the spleen and lymph nodes. [bib_ref] Immunology of COVID-19: current state of the science, Vabret [/bib_ref] The persistent interferon response can result in systemic hyperinflammation, also known as cytokine storm. [bib_ref] On the alert for cytokine storm: immunopathology in COVID-19, Henderson [/bib_ref] [bib_ref] In the eye of the COVID-19 cytokine storm, Vaninov [/bib_ref] Several of the cytokines elevated in severe COVID-19 patients (tumor necrosis factor [TNF], interleukin 6, and interleukin 17) are also elevated in patients with psoriatic disease. [bib_ref] New therapies for psoriasis and psoriatic arthritis, Ritchlin [/bib_ref] [bib_ref] Pathophysiology, clinical presentation, and treatment of psoriasis: a review, Armstrong [/bib_ref] [bib_ref] Psoriatic arthritis, Ritchlin [/bib_ref] The current model of COVID-19 is that immune suppression in early infection may be harmful by allowing uncontrolled SARS-CoV-2 replication and dissemination but may be helpful in severe illness by limiting organ damage from a dysregulated hyperimmune response. [bib_ref] Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered..., Catanzaro [/bib_ref] Many treatments used for psoriatic disease directly or indirectly impact immune pathways involved in COVID-19. [bib_ref] Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the..., Menter [/bib_ref] [bib_ref] Joint AAD-NPF guidelines of care for the management and treatment of psoriasis..., Menter [/bib_ref] [bib_ref] American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic..., Singh [/bib_ref] Patients and providers are concerned about the safety of immunomodulating agents in the setting of the COVID-19 pandemic. These concerns are particularly relevant given that many of the comorbidities associated with psoriasis and psoriatic arthritis, including obesity, diabetes, and cardiovascular disease, are risk factors for the development of severe COVID-19. [bib_ref] Recognizing and managing comorbidities in psoriatic arthritis, Ogdie [/bib_ref] [bib_ref] Psoriasis and comorbid diseases: epidemiology, Takeshita [/bib_ref] To address the questions posed by patients and providers, the National Psoriasis Foundation (NPF) commissioned a COVID-19 task force (TF) to develop scientifically based guidance that promotes optimal management of psoriatic disease during the pandemic. # Methods See the Online Supplement for detailed methods, available via Mendeley Data, V2, at https://doi.org/ 10.17632/x4mxnjmc76. [fig_ref] Table I: National Psoriasis Foundation COVID-19 Task Force Guidance for Management of Psoriatic Disease... [/fig_ref] Mendeley Data, V1, at https://doi.org/10.17632/ 2cbs7r7z72.1). The TF was supplemented by nonvoting members, which included 4 trainees in dermatology, rheumatology, and infectious diseases, 1 postdoctoral fellow in epidemiology, as well as senior staff from the NPF. ## Establishment of the tf ## Evidence synthesis The TF co-chairs completed weekly literature searches for COVID-19 in relation to psoriatic disease. TF members also recommended papers of broad importance to COVID-19 related to its basic biology, epidemiology, and treatment. Additional sources of data were obtained from the Centers for Disease Control and Prevention (CDC), World Health Organization, the United States Food and Drug Administration, and the National Institutes of Health. ## Development of clinical questions The TF met every 2 weeks to discuss the developments in the literature and clinical experience. Clinical questions relevant to the psoriatic disease community were iterated and informed by questions received by the NPF from the broader patient and clinical community. The questions were subdivided into 5 categories, and work groups with balanced expertise were formed. Each TF work group convened to draft responses to the clinical questions based on the available evidence. These responses were reviewed and drafted into guidance statements. ## Modified delphi process The guidance statements were presented to the 18 TF members using a modified Delphi process, including 2 rounds of voting with discussion in between. The Delphi approach was based on the RAND appropriateness method, which has been extensively validated. [bib_ref] American College of Rheumatology Guidance for the Management of Rheumatic Disease in..., Mikuls [/bib_ref] [bib_ref] The reproducibility of a method to identify the overuse and underuse of..., Shekelle [/bib_ref] [bib_ref] Assessing the predictive validity of the RAND/UCLA appropriateness method criteria for performing..., Shekelle [/bib_ref] [bib_ref] Appropriateness criteria for coronary angiography in angina: reliability and validity, Hemingway [/bib_ref] [bib_ref] Validity of criteria used for detecting underuse of coronary revascularization, Kravitz [/bib_ref] TF members were asked to report their level of agreement anonymously with each guidance statement on a scale of 1 to 9. A rating of 1 corresponded to ''complete disagreement,'' 5 corresponded to ''uncertain or neutral,'' and 9 corresponded to ''complete agreement.'' The members were able to provide anonymous written comments. Median vote ratings of 1 to 3, 4 to 6, and 7 to 9 were defined a priori as disagreement, uncertainty/neutral, and agreement, respectively. Panel consensus was determined to be ''low'' when $5 votes fell into the 1 to 3 rating range with $5 votes concurrently falling into the 7 to 9 rating range. Consensus was interpreted as ''high'' if all 18 votes fell within a single tertile, with all other combinations considered as ''moderate'' levels of consensus. The results were analyzed by the NPF along with an independent analysis of the data by a nonvoting member of the TF, which yielded identical results. # Results The NPF COVD-19 TF Delphi was completed over a 2-week period (Supplemental E- Patients with psoriatic disease appear to have similar rates of infection with SARS-CoV-2 and COVID-19 outcomes 33-37 as the general population (Guidance 1.1). However, uncertainty remains regarding this question. First, a few reports suggest that patients with psoriasis may be more prone to infection with COVID-19 or have worse outcomes. [bib_ref] Dermatological diseases presented before COVID-19: are patients with psoriasis and superficial fungal..., Kutlu [/bib_ref] [bib_ref] Factors associated with COVID-19-related death using OpenSAFELY, Williamson [/bib_ref] [bib_ref] Psoriasis and risk of the COVID-19: is there a role for angiotensin..., Shahidi-Dadras [/bib_ref] For example, a United Kingdom study with more than 17 million patients found a small but statistically increased risk of death from COVID-19 (fully adjusted hazards ratio, 1.19; 95% confidence interval, 1.11-1.27) in individuals with psoriasis, rheumatoid arthritis, or lupus. [bib_ref] Factors associated with COVID-19-related death using OpenSAFELY, Williamson [/bib_ref] It is unknown from this study the degree to which the observed finding is driven by psoriasis, its severity, or treatment. Additionally, patients with psoriatic disease may be prone to thrombotic complications that can also occur in COVID-19. [bib_ref] The risk of stroke in patients with psoriasis, Gelfand [/bib_ref] [bib_ref] Risk of myocardial infarction in patients with psoriasis, Gelfand [/bib_ref] [bib_ref] Prevalence of metabolic syndrome in patients with psoriasis: a populationbased study in..., Langan [/bib_ref] [bib_ref] Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort..., Mehta [/bib_ref] [bib_ref] Objective measures of psoriasis severity predict mortality: a prospective population-based cohort study, Noe [/bib_ref] [bib_ref] Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid..., Ogdie [/bib_ref] [bib_ref] Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and..., Ogdie [/bib_ref] [bib_ref] Risk of moderate to advanced kidney disease in patients with psoriasis: population..., Wan [/bib_ref] [bib_ref] Psoriasis and the risk of diabetes: a prospective population-based cohort study, Wan [/bib_ref] [bib_ref] Thrombosis in hospitalized patients with COVID-19 in a New York City health..., Bilaloglu [/bib_ref] [bib_ref] Cardiovascular manifestations and treatment considerations in COVID-19, Kang [/bib_ref] [bib_ref] Neutrophil subsets, platelets, and vascular disease in psoriasis, Teague [/bib_ref] [bib_ref] Platelet P-selectin reflects a state of cutaneous inflammation: possible application to monitor..., Garbaraviciene [/bib_ref] [bib_ref] Platelet activation: a link between psoriasis per se and subclinical atherosclerosisda caseecontrol..., Saleh [/bib_ref] [bib_ref] Endothelial cell-, platelet-, and monocyte/macrophage-derived microparticles are elevated in psoriasis beyond cardiometabolic..., Takeshita [/bib_ref] There was unanimous agreement that severity of COVID-19 is driven by risk factors such as older age and comorbidities (Guidance 1.2). [bib_ref] Epidemiology and outcomes of novel coronavirus 2019 in patients with immune-mediated inflammatory..., Gianfrancesco [/bib_ref] [bib_ref] Covid-19 in immunemediated inflammatory diseases-case series from New York, Haberman [/bib_ref] [bib_ref] Clinical course of COVID-19 in 41 patients with immune-mediated inflammatory diseases: experience..., Allocca [/bib_ref] [bib_ref] Factors associated with COVID-19-related death using OpenSAFELY, Williamson [/bib_ref] [bib_ref] COVID-19 and older adults: what we know, Shahid [/bib_ref] [bib_ref] Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia..., Chen [/bib_ref] [bib_ref] Clinical Characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref] Psoriatic diseasedparticularly severe psoriasisdis associated with many of the comorbidities that drive COVID-19 mortality. [bib_ref] Objective measures of psoriasis severity predict mortality: a prospective population-based cohort study, Noe [/bib_ref] [bib_ref] Psoriasis and the risk of diabetes: a prospective population-based cohort study, Wan [/bib_ref] [bib_ref] Psoriasis severity and the prevalence of major medical comorbidity: a populationbased study, Yeung [/bib_ref] Category 2: What are the effects of psoriasis or psoriatic arthritis treatment on SARS-CoV-2 infection and COVID-19 illness? The existing literature suggests that treatments for psoriasis or psoriatic arthritis, or both, do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes (Guidance 2.1). [bib_ref] Psoriasis, biological drugs and coronavirus disease 2019: real life experience of two..., Vispi [/bib_ref] [bib_ref] Covid-19 in immunemediated inflammatory diseases-case series from New York, Haberman [/bib_ref] [bib_ref] Clinical course of COVID-19 in 41 patients with immune-mediated inflammatory diseases: experience..., Allocca [/bib_ref] Cyclosporine, the most broadly immunosuppressive of psoriasis treatments, was not found to alter the risk of COVID-19 in 130 patients in Italy with psoriasis or atopic dermatitis (2 became infected with SARS-CoV-2 and recovered without hospitalization). [bib_ref] Covid-19 infection in psoriasis patients treated with cyclosporin, Lernia [/bib_ref] This study lacked a comparison group and was too small to reach definitive conclusions. One study suggested that patients with psoriasis on biologics were more likely to be hospitalized for COVID-19 but did not adjust for risk factors known to drive poor COVID-19 outcomes. [bib_ref] Biologics increase the risk of SARS-CoV-2 infection and hospitalization, but not ICU..., Damiani [/bib_ref] The rheumatology literature also suggests that treatments used for psoriatic disease, such as TNF inhibitors and methotrexate, do not negatively impact COVID-19, 87-90 with 1 large registry (600 case reports from 40 countries) finding that TNF inhibitors are associated with a reduced adjusted odds of COVID-19 hospitalization compared with patients with rheumatic conditions not treated with TNF inhibitors. [bib_ref] Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data..., Gianfrancesco [/bib_ref] Similarly, adverse effects of TNF inhibitors on COVID-19 were not observed in large registries of patients with inflammatory bowel disease. [bib_ref] but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients..., Brenner [/bib_ref] [bib_ref] Impact of anti-TNF and thiopurines medications on the development of COVID-19 in..., Khan [/bib_ref] Small case series have reported poor COVID-19 outcomes in patients on Janus kinase inhibitors for psoriatic arthritisand secukinumab for ankylosing spondylitis [bib_ref] COVID-19 in rheumatic disease patients on immunosuppressive agents, Sharmeen [/bib_ref] ; however, these isolated reports could be due to selection bias, chance, or underlying comorbidity. By contrast, an analysis of approximately 1400 patients from the It is not known with certainty whether having psoriatic disease meaningfully alters the risks of contracting SARS-CoV-2 (the virus that causes COVID-19 illness) or having a worse course of COVID-19 illness. Existing data, with some exceptions, generally suggest that patients with psoriasis and/or psoriatic arthritis have similar rates of SARS-CoV-2 infection and COVID-19 outcomes as the general population. ## Moderate ## 1.2 The likelihood of poor outcomes from COVID-19 is driven by risk factors such as older age and comorbidities, such as chronic heart, lung, or kidney disease, and metabolic disorders such as diabetes and obesity. Patients with psoriatic disease are more prone to these comorbidities, particularly in those with more severe disease. rheumatology, gastroenterology, and dermatology literature concluded that biologic or targeted synthetic disease-modifying antirheumatic drug therapy has not been associated with more severe COVID-19 outcomes. [bib_ref] Epidemiology and outcomes of novel coronavirus 2019 in patients with immune-mediated inflammatory..., Gianfrancesco [/bib_ref] Given these data, patients who are not infected with SARS-CoV-2 should continue their biologic or oral therapies for psoriasis or psoriatic arthritis in most cases (Guidance 2.2). Nevertheless, the existing literature is largely based on small case series or large registries of spontaneous reports, and therefore, shared decision-making between clinician and patient is recommended (Guidance 2.2, 2.4, and 2.5). By contrast, studies in the rheumatology and gastroenterology literature have observed that long-term use of oral corticosteroids is associated with worse COVID-19 outcomes (ie, hospitalization or a composite outcome of any or all of intensive care unit admission, ventilator use, or death). [bib_ref] Epidemiology and outcomes of novel coronavirus 2019 in patients with immune-mediated inflammatory..., Gianfrancesco [/bib_ref] [bib_ref] Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data..., Gianfrancesco [/bib_ref] [bib_ref] but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients..., Brenner [/bib_ref] Chronic systemic corticosteroids should be avoided, if possible, for the management of psoriatic arthritis (Guidance 2.3). Category 3: How should medical care be delivered to patients with psoriatic disease to lower their risk of infection with SARS-CoV-2 while still ensuring quality of care? The pandemic has disrupted the ability of patients and providers ability to meet in person due to personal protective equipment shortages, measures implemented to lower risk of SARS-CoV-2 transmission, and patients' personal and economic hardships. [bib_ref] Dermatologists and SARS-CoV-2: the impact of the pandemic on daily practice, Gisondi [/bib_ref] [bib_ref] Teledermatology in the wake of COVID-19: advantages and challenges to continued care..., Gupta [/bib_ref] [bib_ref] Critical supply shortagesthe need for ventilators and personal protective equipment during the..., Ranney [/bib_ref] Patients express concern about being exposed to SARS-CoV-2 in the clinical setting either directly or indirectly (ie, on public transportation). Telemedicine can achieve similar outcomes for psoriasis patients compared with in-person care with a dermatologist 98-100 ; however, limited information is available on the management of psoriatic arthritis with telemedicine. [bib_ref] Telerheumatology in COVID-19 era: a study from a psoriatic arthritis cohort, Costa [/bib_ref] [bib_ref] Outcomes, Satisfaction, and costs of a rheumatology telemedicine program: a longitudinal evaluation, Wood [/bib_ref] Telemedicine should be considered when pandemic conditions limit inperson visits (Guidance 3.1).However, there are limitations of telemedicine, and therefore, some patients should be evaluated in person (Guidance 3.2). Office-based phototherapy remains an important option for patients with psoriasis (Guidance 3.3, [fig_ref] Table II ,: available via Mendeley Data, V1, at https [/fig_ref]. [bib_ref] Recommendations for phototherapy during the COVID-19 pandemic, Lim [/bib_ref] [bib_ref] Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the..., Elmets [/bib_ref] Category 4: What should patients with psoriatic disease do to protect themselves from becoming infected with SARS-CoV-2? Patients should be advised to follow measures that prevent infection with SARS-CoV-2 (Guidance 4.1; E-Table VI, available via Mendeley Data, V2, at https://doi.org/10.17632/w5m8jf94m8).These prevention measures should be followed at work (Guidance 4.2) and school (Guidance 4.3). In cases where measures to prevent transmission of SARS-CoV-2 at work or school cannot be maintained, shared decision making is recommended to determine whether specific accommodations are medically necessary (Guidance 4.2 and 4.3). Psoriasis, even when involving the face or hands, is not a contraindication to face coverings and hand washing, respectively, and a variety of approaches can be applied to mitigate skin irritation (E-Table VII, available via Mendeley Data, V2, at https://doi.org/ 10.17632/w5m8jf94m8). [bib_ref] Preventing and treating occupationally induced dermatologic conditions during COVID-19. A guide to..., Thiers [/bib_ref] [bib_ref] Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis..., Elmets [/bib_ref] Patients with psoriatic disease should receive the seasonal inactivated (eg, killed) influenza vaccine, which is of special importance to individual and public health during the COVID-19 pandemic (Guidance 4.4). Providers may consider temporary discontinuation of methotrexate for 2 weeks after the influenza immunization to ## 5.7 Patients with psoriatic disease who become infected with SARS-CoV-2 should follow CDC guidance on home isolation and discuss with their health care providers when they can end home isolation. We recommend waiting a minimum of 10 days after COVID-19 symptom onset, along with fever resolution for 24 hours, without antipyretics, and improvement in other symptoms before ending home isolation and returning to work, as patients are unlikely to be infectious after this point. In patients with severe cases of COVID-19 or when patients with psoriasis are on medications with immunosuppressive effects, we recommend a case-by-case approach to determining the length of home isolation. J AM ACAD DERMATOL improve the immunogenicity of the seasonal influenza vaccine. [bib_ref] Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal..., Park [/bib_ref] Category 5: What should patients with psoriatic disease do if they become infected with SARS-CoV-2? Patients with psoriatic disease who become infected with SARS-CoV-2 should monitor their symptoms (Supplemental E- [fig_ref] Table II ,: available via Mendeley Data, V1, at https [/fig_ref] , discuss management of their psoriatic disease treatments with their health care providers, and should be prescribed and adhere to evidence-based COVID-19 treatments, if available (Guidance 5.1 and 5.2). [bib_ref] Severe COVID-19 outcomes in patients with psoriasis, Lima [/bib_ref] [bib_ref] Remdesivir for the treatment of Covid-19dpreliminary report, Beigel [/bib_ref] [bib_ref] Dexamethasone in hospitalized patients with Covid-19dpreliminary report, Recovery Collaborative Group [/bib_ref] The mortality benefit of initiation of corticosteroids in patients with severe COVID-19 outweighs the risks of potentially precipitating a psoriasis flare, and therefore, acute systemic corticosteroids are not contraindicated for the management of COVID-19 in patients with psoriatic disease (Guidance 5.3). [bib_ref] Dexamethasone in hospitalized patients with Covid-19dpreliminary report, Recovery Collaborative Group [/bib_ref] [bib_ref] Systemic steroids in the treatment of psoriasis: what is fact, what is..., Mrowietz [/bib_ref] On the basis of limited available data, and to be consistent with prescribing information, it may be prudent to hold treatments that target the immune system in the setting of suspected or confirmed SARS-CoV-2 infection, but the final decision needs to be determined on a caseby-case basis. Consistent with guidance from the Food and Drug Administration and the American College of Physicians, the use of hydroxychloroquine or chloroquine is not recommended to prevent or treat COVID-19 in patients with psoriatic disease outside of a clinical trial (guidance 5.4). [bib_ref] Infectious Diseases Society of America Guidelines on the Treatment and Management of..., Bhimraj [/bib_ref] [bib_ref] Update alert 2: should clinicians use chloroquine or hydroxychloroquine alone or in..., Qaseem [/bib_ref] [bib_ref] Hydroxychloroquine and tocilizumab therapy in COVID-19 patients-an observational study, Ip [/bib_ref] [bib_ref] Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients..., Rosenberg [/bib_ref] [bib_ref] A case of exacerbation of psoriasis after oseltamivir and hydroxychloroquine in a..., Kutlu [/bib_ref] [bib_ref] Hydroxychloroquine effects on psoriasis: a systematic review and a cautionary note for..., Sachdeva [/bib_ref] Patients with psoriatic disease should be aware that infection with SARS-CoV-2 may result in a flare of psoriasis, which may occur due to discontinuation of psoriasis treatments, treatment of COVID-19 with antimalarial drugs, or due to triggering of inflammation as part of COVID-19 illness (Guidance 5.6). [bib_ref] A case of exacerbation of psoriasis after oseltamivir and hydroxychloroquine in a..., Kutlu [/bib_ref] [bib_ref] A case of severe psoriatic erythroderma with COVID-19, Ghalamkarpour [/bib_ref] [bib_ref] Covid-19 and exacerbation of psoriasis, Ozaras [/bib_ref] [bib_ref] Guttate psoriasis secondary to COVID-19, Gananandan [/bib_ref] Patients with psoriatic disease who become infected with SARS-CoV-2 should follow CDC guidance 130-133 on home isolation and discuss with their health care providers when they can end home quarantine (Guidance 5.7; Supplemental E- [fig_ref] Table I: National Psoriasis Foundation COVID-19 Task Force Guidance for Management of Psoriatic Disease... [/fig_ref]. [bib_ref] Universal masking to prevent SARS-CoV-2 transmissiondthe time is now, Brooks [/bib_ref] In the event someone with psoriatic disease has close contact (Supplemental E- with an individual with suspected or confirmed SARS-CoV-2 infection, they should quarantine for 14 days after the last contact, according to CDC guidelines (Guidance 5.8).The decision regarding continuing or holding psoriasis treatments during a period of quarantine should be individualized on a case-by-case basis between patient and provider. Resumption of psoriasis or psoriatic arthritis treatments held during SARS-CoV-2 infection should be decided on a case-by-case basis (Guidance 5.5). The persistence of 1 or more symptoms of COVID-19, such as fatigue or joint pain, beyond the acute phase of the illness can occur 137 and may complicate the decision to restart psoriasis or psoriatic arthritis medications. Therefore, shared decision making is recommended (Guidance 2.5). # Discussion The NPF COVID-19 TF guidance statements serve to promote optimal management of psoriatic disease during the pandemic. There are several strengths to the approach taken. First, the TF assembled is a geographically diverse team that has expertise in adult and pediatric dermatology, rheumatology, critical care, infectious diseases, epidemiology, and basic and translational immunology, with experience managing surges in COVID-19. The TF also includes trainees in dermatology, rheumatology, and infectious disease, who are on the frontlines managing patients with COVID-19, as well as senior staff from the NPF who are in touch daily with patients and providers worldwide whose questions are brought to the TF. Second, we have established a robust process for staying up-to-date with the latest literature relevant to COVID-19 and the management of psoriatic disease resulting in the dissemination and evaluation of hundreds of peer reviewed publications by the TF. Third, a validated Delphi approach enabled transparency and reproducibility of our process for evaluating consensus statements. [bib_ref] American College of Rheumatology Guidance for the Management of Rheumatic Disease in..., Mikuls [/bib_ref] [bib_ref] The reproducibility of a method to identify the overuse and underuse of..., Shekelle [/bib_ref] [bib_ref] Assessing the predictive validity of the RAND/UCLA appropriateness method criteria for performing..., Shekelle [/bib_ref] [bib_ref] Appropriateness criteria for coronary angiography in angina: reliability and validity, Hemingway [/bib_ref] [bib_ref] Validity of criteria used for detecting underuse of coronary revascularization, Kravitz [/bib_ref] Several limitations are acknowledged. First, the TF did not formally grade the strength of our recommendations. [bib_ref] GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables, Guyatt [/bib_ref] With the exception of guidance statements 4.4, 5.2, and 5.4, which are based on large-scale randomized controlled trials, the evidence behind many of the guidance statements was often limited in quality. For example, studies evaluating the safety of treatments for psoriasis and psoriatic arthritis in the setting of COVID-19 involve small case series or large collections of case reports and thus should be considered preliminary. Largescale, longer-term, population-based studies with appropriate comparator groups, adjustment for relevant confounding variables, and complete ascertainment of clinically important COVID-19 outcomes are urgently needed. Second, the guidance is not intended to be proscriptive or comprehensive. The ultimate judgment regarding how these recommendations should be followed is best left with the treating clinician and the patient in light of the circumstances presented by the individual patient and the variability and biologic behavior of the disease and therapeutics. Third, the TF does not have global representation of experts or direct inclusion of patients. The guidance statements are intended to be part of a ''living'' document that will be updated and amended when necessary by the rapidly evolving science of COVID-19. Readers are encouraged to visit https://www.psoriasis.org/covid-19-resourcecenter regularly for the latest guidance from the TF in order to promote optimal care and outcomes for patients with psoriatic disease during the pandemic. [fig] Category 1: What are the effects of psoriatic disease itself on SARS-CoV-2 infection and COVID-19 illness? [/fig] [table] Table II ,: available via Mendeley Data, V1, at https://doi.org/10.17632/ 2cbs7r7z72). Five categories of questions were explored (Supplemental E-Table III, available via Mendeley Data, V1, at https://doi.org/10.17632/ 2cbs7r7z72) with 100% complete voting on 22 guidance statements(Table I 32 and Supplemental E-Table IV, available via Mendeley Data, V2, at https://doi.org/ 10.17632/n78m9f3cpr). The median was within the category of agreement for all statements, with the number of votes outside the range of agreement being only 1 or 2 for statements where agreement was not unanimous. All guidance statements were recommended, 9 with high consensus, and the remainder with moderate consensus. [/table] [table] Table I: National Psoriasis Foundation COVID-19 Task Force Guidance for Management of Psoriatic Disease During the Pandemic: Version 1 [/table]	None	None	None
4b049a49ce1e9ec0b048c6e5e311cc26b9c28d9c	pubmed	WSAVA Guidelines for the vaccination of dogs and cats	WSAVA Guidelines for the vaccination of dogs and cats # Introduction The WSAVA Vaccination Guidelines Group (VGG) was convened in 2006 with the aim of producing global vaccination guidelines for dogs and cats that would consider international differences in economic and societal factors that impact on the keeping of these small companion animals. The WSAVA guidelines are therefore intended to be much broader in scope than those produced for North America by the American Academy of Feline Practitioners [bib_ref] AAFP Feline Vaccination Advisory Panel report, Scherk [/bib_ref] and the American Animal Hospital Association [bib_ref] AAHA canine vaccination guidelines, Welborn [/bib_ref] or for Europe by the Advisory Board on Cat Diseases [bib_ref] Matrix vaccination guidelines: ABCD recommendations for indoor/outdoor cats, rescue shelter cats and..., Hosie [/bib_ref]. The first WSAVA guidelines were published in 2007 ) and these were updated in 2010 [bib_ref] Guidelines for the vaccination of dogs and cats, Day [/bib_ref] with an accompanying document written for the owners and breeders of pet dogs and cats. Between 2011 and 2013, the VGG focused on dog and cat infectious disease and vaccinology on the Asian continent and produced regional recommendations on aspects of vaccination for Asian practitioners. In 2014 and 2015, the VGG has worked on updating the global canine and feline vaccination guidelines as now presented in this document. The format and much of the content of this 2015 revision remain similar to the guidelines published in 2010; however, specific changes in the current document include: of mortality in small animals. Although it is difficult to obtain accurate figures, even in developed countries it is estimated that only 30-50% of the pet animal population is vaccinated, and this is significantly less in developing nations. The global economic recession post-2008 has had further impact on the uptake of preventive healthcare by pet owners in developed countries and survey data suggests a recent decline in vaccination [bib_ref] Survey suggests many pets do not receive preventive healthcare, Anon [/bib_ref]. In small animal medicine, we have been slow to grasp the concept of 'herd immunity' -that vaccination of individual pet animals is important, not only to protect the individual, but to reduce the number of susceptible animals in the regional population, and thus the prevalence of disease. Herd immunity related to use of core vaccines that provide a long (many years) DOI is highly dependent on the percentage of animals in the population vaccinated and not the number of vaccinations that occur annually. Therefore, every effort should be made to vaccinate a higher percentage of cats and dogs with the core vaccines. It is simply not possible to induce 'better' immunity in an individual animal by giving repeated vaccinations, i.e. a dog receiving a core MLV vaccine every 3 years will be equally well protected compared with one receiving the same vaccine annually [bib_ref] Serum antibody titres to canine parvovirus, adenovirus and distemper virus in dogs..., Bohm [/bib_ref] [bib_ref] Duration of serologic response to five viral antigens in dogs, Mouzin [/bib_ref] [bib_ref] Duration of serological response to canine parvovirus-type 2, canine distemper virus, canine..., Mitchell [/bib_ref] [EB1], but this may not necessarily be the case for feline core vaccines (see below). In recent years the re-emerging concept of 'One Health' has also impacted on the field of vaccinology. The management of infectious diseases through the collaborative interaction of human medical, animal and environmental healthcare professionals provides a rational and cost-effective goal at a time when the majority of newly emergent human infectious diseases is proposed to derive from wild or domestic animal sources [bib_ref] The evolution of One Health: a decade of progress and challenges for..., Gibbs [/bib_ref]. The WSAVA has embraced the One Health concept with establishment of a One Health Committee in 2010 [bib_ref] Guidelines for the vaccination of dogs and cats, Day [/bib_ref] , the work of which overlaps with that of the VGG when tackling the major small companion animal zoonoses of canine rabies and leishmaniosis. A second major concept regarding vaccination of dogs and cats has been the recognition that we should aim to reduce the 'vaccine load' on individual animals in order to minimize the potential for adverse reactions to vaccine products and reduce the time and financial burden on clients and veterinarians of unjustified veterinary medical procedures. For these reasons we have seen the development of vaccination guidelines based on a rational analysis of the vaccine requirements for each pet, and the proposal that vaccines be considered 'core' and 'non-core' in nature. To an extent this categorization of products has been based on available scientific evidence and personal experience -but concerted effort to introduce effective companion animal disease surveillance on a global scale would provide a more definitive basis on which to recommend vaccine usage [bib_ref] Surveillance of zoonotic infectious diseases transmitted by small companion animals, Day [/bib_ref]. In parallel with the categorization of vaccines has been the push towards marketing products with extended DOI, to reduce the unnecessary administration of vaccines and thereby further improve vaccine safety. Both of these changes have necessitated a frame-shift in the mind-set of veterinary practitioners, which is now becoming the accepted norm in many countries. The following VGG guidelines are prepared when considering the optimum model of committed pet owners, willing and able to bring their animals to the veterinarian, for the full recommended course of vaccination. The VGG is aware that there are less committed or able pet owners in every country and there are countries where severe financial or societal constraints often determine the nature of the vaccine course that can be administered. In situations where, for example, a decision must be made that an individual pet may have to receive only a single core vaccination during its lifetime, the VGG would emphasise that this should optimally be given at a time when that animal is most capable of responding immunologically, i.e. at greater than 16 weeks of age. The VGG has additionally considered vaccination in the shelter situation. The guidelines that we have proposed are those that we consider provide the optimum level of protection for these highly susceptible animals. The VGG also recognises that many shelters run with limited financial support which may constrain the extent of vaccination used. The minimum vaccination protocol in this situation would be a single administration of core vaccines at or before the time of admission to the shelter. This document seeks to address these current issues in canine and feline vaccinology, and to suggest practical measures by which the veterinary profession may move further towards more rational use of vaccines in these species. The most important message of the VGG is therefore encapsulated in the following statement: We should aim to vaccinate every animal with core vaccines. Non-core vaccines should be given no more frequently than is deemed necessary. ## Types of vaccine Before discussing specific vaccination guidelines, a brief review of the types of small companion animal vaccine available is justified. Vaccines may be considered simply as either 'infectious' or 'non-infectious' in nature. Most infectious vaccines used in dogs and cats contain organisms that are attenuated to reduce virulence (i.e. 'modified live virus' or attenuated vaccines), but the organisms are intact and viable and induce immunity by inducing low-level infection and replicating within the animal, without producing significant tissue pathology or clinical signs of infectious disease. Infectious vaccines have the advantage of more effectively inducing immunity at relevant anatomical sites when administered parenterally and are more likely to induce robust cell-mediated and humoral (antibody-mediated) immunity. Some infectious vaccines are administered Journal of Small Animal Practice - Vol 57 - January 2016 - © 2016 WSAVA E7 directly to mucosal sites (i.e. intranasal or oral vaccines) where they are even more effective at inducing relevant protective mucosal immunity. Some recombinant vectored vaccines (i.e. a live vector organism carrying genetic material encoding an antigen from the target pathogen) may also be considered 'infectious'; however, the vector organism is not relevant to, or pathogenic in, the dog or cat. When administered to an animal that lacks maternally-derived antibody (MDA) an infectious vaccine will generally induce protection with a single dose. Non-infectious vaccines (also known as killed or inactivated vaccines and including subunit and naked DNA vaccines) contain an inactivated but antigenically intact virus or organism, or a natural or synthetic antigen derived from that virus or organism, or the DNA that can encode such an antigen. Non-infectious agents are unable to infect, replicate or induce pathology or clinical signs of infectious disease. They generally require an adjuvant to increase their potency and usually require multiple doses (even in an adult animal) to induce protection. Non-infectious vaccines are administered parenterally and may be less likely to induce both cellmediated and humoral immunity and generally have a shorter DOI compared with infectious vaccines. ## Canine vaccination guidelines ## Vaccination of individual dogs The Basic Immunization Schedule Guidelines and recommendations for core (recommended), non-core (optional) and not recommended vaccines for the general veterinary practice are given in . The VGG considers that a core vaccine is one that all dogs throughout the world must receive, at recommended intervals, in order to provide life-long protection against infectious diseases of global significance. The core vaccines for the dog are those that confer protection against infection by canine distemper virus (CDV), canine adenovirus (CAV; types 1 and 2) and canine parvovirus type 2 (CPV-2) and its variants. The VGG recognizes that particular countries will identify additional vaccines that they consider core. A particular example of a vaccine that may be considered core in only some countries is that against rabies virus. In a geographical area in which this infection is endemic, all dogs should be vaccinated routinely for the protection of both the pet and human populations. The VGG strongly endorses the joint statement of the WSAVA One Health Committee and the International Organisation for Animal Health (OIE) which sets a target for global elimination of canine rabies by 2030 [bib_ref] WSAVA and OIE call for action on rabies, Anon [/bib_ref]. In many countries, rabies vaccination is a legal requirement, and is generally also required for international pet travel. Non-core vaccines are those for which use is determined on the basis of the geographical and lifestyle exposure risks of the individual and an assessment of risk-benefit ratios (i.e. the risk of being unvaccinated and susceptible or the risk of being vaccinated and developing an adverse reaction versus the benefit of being protected against the infection in question). Not recommended vaccines are those for which there is little scientific justification (insufficient evidence base) for their use. Puppy Vaccination and the 6-or 12-Month Booster Most puppies are protected by MDA in the first weeks of life. In most puppies, passive immunity will have waned by 8-12 weeks of age to a level that allows active immunization. Puppies with poor MDA may be vulnerable (and capable of responding to vaccination) at an earlier age, while others may possess MDA at such high titres that they are incapable of responding to vaccination until ≥12 weeks of age [bib_ref] Untersuchung der wirksamkeit von parvovirussimpfstoffen und der effektivitat zweier impfschemata, Friedrich [/bib_ref]. No single primary vaccination policy will therefore cover all possible situations. The recommendation of the VGG is for initial core vaccination at 6-8 weeks of age, then every 2-4 weeks until 16 weeks of age or older. Therefore the number of puppy primary core vaccinations will be determined by the age at which vaccination is started and the selected interval between vaccinations. Possible schedules are outlined in [fig_ref] Table 5: weeks, 13 weeks, 17 weeks then 26 or 52 weeks [/fig_ref]. By this recommendation, when vaccination is started at 6 or 7 weeks of age, a course of four primary core vaccines would be administered with a 4-week interval, but only three would be required with an 8-or 9-week start and a similar 4-week interval. In contrast, many vaccine datasheets continue to recommend an initial course of two injections of core vaccine. Some products are also licensed with a '10 week finish' designed such that the second of two core vaccinations is given at 10 weeks of age. The rationale behind this protocol is to permit 'early socialization' of puppies while diminishing the risk of infectious diseases. The VGG recognizes that early socialization is essential to the behavioural development of dogs [bib_ref] Comparison of early socialization practices used for litters of small-scale registered dog..., Korbelik [/bib_ref] [EB1]. Where such protocols (i.e. 'puppy classes') are adopted, vigilance should still be maintained by the owner -allowing restricted exposure of their puppy to controlled areas and only to other puppies and adults that appear healthy and are fully vaccinated. In particular 'puppy classes' should be held in venues away from the veterinary practice. Alternatively, if it is decided that veterinary premises must be used, the floors should be cleaned and disinfected before each class and the classes held in an area not highly trafficked by dogs of unknown vaccination or disease status. A recent US study has shown the minimal risk for CPV-2 amongst vaccinated puppies attending socialization classes [bib_ref] Frequency of CPV infection in vaccinated puppies that attended puppy socialization classes, Stepita [/bib_ref]. The VGG recommends that whenever possible the last of the puppy primary series of core vaccines be given at 16 weeks of age or older . An integral part of core vaccination of puppies is the 'booster' vaccine that has traditionally been given either at 12 months of age or 12 months after the last of the primary series of puppy vaccines. The main aim of this vaccine is to ensure that a protective immune response develops in any dog that may have failed to respond to any of the vaccines in the primary core series, rather than necessarily 'boosting' the immune response. The delivery of this vaccine at 12 months of age is likely to have been chosen historically as a convenient time to request the owner to attend the practice for a first annual health check. This therefore implies that should an individual puppy fail to respond to any of the primary core vaccinations, that puppy may be unprotected until it receives this 12-month vaccine. This might account for occurrences of infectious disease (e.g. canine parvoviral enteritis) in a proportion of vaccinated puppies at less than 12 months of age. The VGG has re-evaluated this practice and now suggests that veterinarians might wish to reduce this possible window of susceptibility by bringing forward this vaccine from 52 weeks to 26 weeks of age (or indeed at any time point between 26 and 52 weeks of age; however, 26 weeks of age provides a convenient timing). This practice will require that pet owners clearly understand why this is recommended, because as indicated in [fig_ref] Table 5: weeks, 13 weeks, 17 weeks then 26 or 52 weeks [/fig_ref] , adopting such a protocol will mean that vaccination started in a 6 or 7 week old puppy, might now entail up to five vaccine visits in the first 6 months of life. For core vaccines, after a 26 week 'booster', another core vaccine would not be required for at least another 3 years. This new recommendation for vaccination at 6 months of age as an alternative to vaccination at about 1 year of age is certainly not mutually exclusive to, and does not preclude, a 1-year or 16-month 'first annual health check'. Many veterinarians are understandably keen to check the animals under their care at around the time they reach skeletal maturity. ## Revaccination of adult dogs Dogs that have responded to vaccination with MLV core vaccines maintain a solid immunity (immunological memory) for many years in the absence of any repeat vaccination [bib_ref] Serum antibody titres to canine parvovirus, adenovirus and distemper virus in dogs..., Bohm [/bib_ref] [bib_ref] Duration of serologic response to five viral antigens in dogs, Mouzin [/bib_ref] [bib_ref] Duration of immunity for canine and feline vaccines: a review, Schultz [/bib_ref] [bib_ref] Duration of serological response to canine parvovirus-type 2, canine distemper virus, canine..., Mitchell [/bib_ref] [EB1]. Following the 26 or 52 week booster, subsequent revaccinations are given at intervals of 3 years or longer. It should be emphasized that triennial adult revaccination does not generally apply to killed core vaccines (except for rabies) nor to the non-core vaccines, and particularly not to vaccines containing bacterial antigens. Thus Leptospira, Bordetella and Borrelia (Lyme disease) products, but also parainfluenza virus components, require more frequent boosters for reliable protection [bib_ref] A review of canine parainfluenza virus infection in dogs, Ellis [/bib_ref] [bib_ref] A new tetravalent canine leptospirosis vaccine provides at least 12 months immunity..., Klaasen [/bib_ref] [bib_ref] How well do vaccines for Bordetella bronchiseptica work in dogs? A critical..., Ellis [/bib_ref] [bib_ref] European consensus statement on leptospirosis in dogs and cats, Schuller [/bib_ref]. Therefore an adult dog may, according to these guidelines, still be revaccinated annually, but the components of these vaccinations may differ each year. Typically, core vaccines are currently administered triennially, with chosen non-core products being given annually. The VGG is aware that in some countries only multi-component products containing core and non-core combinations are available. The VGG would encourage manufacturers to make a full range of reduced-component vaccines (or at least separate core and non-core vaccines [bib_ref] Duration of serological response to canine parvovirus-type 2, canine distemper virus, canine..., Mitchell [/bib_ref] available wherever possible. An adult dog that had received a complete course of core vaccinations as a puppy, including a 26 or 52 week booster, but that may not have been vaccinated regularly as an adult, requires only a single dose of MLV core vaccine to boost immunity [bib_ref] Duration of serologic response to five viral antigens in dogs, Mouzin [/bib_ref] [bib_ref] Duration of serological response to canine parvovirus-type 2, canine distemper virus, canine..., Mitchell [/bib_ref]. Similarly, an adopted adult dog (or puppy over 16 weeks of age) of unknown vaccination history requires only a single dose of MLV core vaccine to engender a protective immune response. Many vaccine datasheets will advise in these circumstances that the dog requires two vaccinations (as for a puppy), but this practice is unjustified and contrary to fundamental immunological principles . Note again, that this does not apply to non-core vaccines, many of which will require two doses in an adult dog. Particular mention should be made of canine rabies vaccines. The VGG recommends that in any country in which canine rabies is endemic, vaccination of dogs should be strongly recommended to clients by veterinarians, even if not required by law. Revaccination intervals for canine rabies are often mandated by law. Internationally available killed rabies vaccines were initially produced with a licensed 1-year DOI and so statutes required annual revaccination. These same products now carry a 3-year DOI in many countries, where laws have been modified to incorporate this change. However, in some countries the legal requirement is at odds with the vaccine license and in others neither the vaccine license, nor the law, has been changed. Finally, some countries also have locally-manufactured rabies vaccines with a 1-year DOI that most likely cannot safely be extended to 3 years. Veterinarians should be mindful of the law, but where they have access to a product that confers a minimum of 3-years immunity, national associations might lobby to have the laws changed to match the current scientific evidence. Serological Testing to Monitor Immunity to Canine Vaccines Since publication of the 2010 guidelines there have been advances in the availability of rapid and simple in-practice serological test kits that can detect the presence of protective antibody specific for CDV, CAV and CPV-2 in individual dogs. These test kits complement the traditional laboratory-based modalities (i.e. virus neutralization and haemagglutination inhibition test) that remain the 'gold standards' for serological testing. Two commercially produced test kits are available and have been applied and validated in the practice and shelter setting [bib_ref] Comparison of two assays for detection of antibodies against canine parvovirus and..., Gray [/bib_ref] [bib_ref] Prevalence of positive antibody test results for canine parvovirus (CPV) and canine..., Litster [/bib_ref]. These test kits have proven popular with veterinarians who wish to be able to offer their clients an alternative to routine core revaccination at 3-yearly intervals, but the kits remain relatively expensive and unfortunately, at present, testing costs more than a dose of vaccine. A negative test result indicates that the dog has little or no antibody, and that revaccination is recommended. Some seronegative dogs are in fact immune (false-negative) and their revaccination would be unnecessary because they would make a rapid and substantial anamnestic response to vaccination [bib_ref] Duration of serologic response to five viral antigens in dogs, Mouzin [/bib_ref]. However, such dogs cannot be detected readily and an animal with a negative result, regardless of the test used, should be considered as having no antibody and potentially susceptible to infection. In contrast, a positive test result would lead to the conclusion that revaccination is not required. Monitoring serum antibody specific for canine rabies is not generally used in the same manner for determining revaccination requirements as these are mandated by law. Laboratory testing for a protective rabies antibody titre (considered as more than 0·5 IU/ml) is required for international pet travel. Rabies serology is only performed by recognized reference laboratories. Serological testing for CDV, CAV and CPV-2 has application for determining protective immunity in the puppy, for informing revaccination intervals in adult dogs and in management of infectious disease outbreaks in shelters. A dedicated owner may wish to confirm that a puppy is protected after the course of primary vaccinations when these are completed at 16 weeks or older . A serum sample taken at least 4 weeks after the final vaccination may be tested. This interval will ensure that MDA is no longer present and that even 'slow responder' puppies have seroconverted. A seropositive puppy would not require a 26 or 52 week booster and could next receive core vaccine 3 years later. Seronegative puppies should be revaccinated and retested. If the pup again tests negative, it should be considered a non-responder that is possibly incapable of developing protective immunity. Testing for antibody is presently the only practical way to ensure that a puppy's immune system has recognized the vaccinal antigen. Vaccines may fail to induce protective immunity in a puppy for various reasons: (1) MDA neutralizes the vaccine virus This is the most common reason for vaccination failure. However, when the last vaccine dose is given 16 weeks of age or older, MDA should have decreased to a low level [bib_ref] Untersuchung der wirksamkeit von parvovirussimpfstoffen und der effektivitat zweier impfschemata, Friedrich [/bib_ref] [EB1], and active immunization will succeed in most puppies. (2) The vaccine is poorly immunogenic Poor immunogenicity may reflect a range of factors from the stage of vaccine design and manufacture to administration to the animal. For example, the virus strain, its passage history or production errors in the manufacture of a particular batch of product may be a cause of vaccine failure. In reality, such effects rarely affect vaccines produced by large, well-established manufacturers that market their vaccines internationally. These manufacturers have strict requirements from government regulatory agencies for batch potency testing before release. Post-manufacture factors such as incorrect storage or transportation (interrupted cold chain) and handling (disinfectant use) of the vaccine in the veterinary practice, may result in inactivation of an MLV product. The VGG has recognized that such 'vaccine husbandry' remains an issue in many countries and has included some simple guidelines in . (3) The animal is a poor responder (its immune system intrinsically fails to recognize the vaccinal antigens) If an animal fails to develop an antibody response after repeated revaccination, it should be considered a genetic non-responder. Because immunological non-responsiveness is genetically controlled in other species, certain breeds of dogs have been suspected to be poor-responders. It is believed (but unproven) that the high susceptibility to CPV-2 recognized in certain Rottweilers and Dobermanns during the 1980s (regardless of their vaccination history) relates in part to a high prevalence of non-responders [EB4]. In the USA today, these two breeds seem to have no greater numbers of non-responders to CPV-2 than other breeds, possibly because carriers of the genetic trait may have died from CPV-2 infection. Some dogs of these breeds may be low or non-responders to other antigens. For example, in the UK and Germany, the non-responder phenotype remains prevalent amongst Rottweilers [EB3] for CPV-2 and recent studies have shown this breed to have a higher proportion of animals failing to achieve the titre of rabies antibody required for pet travel [bib_ref] Factors influencing the antibody response of dogs vaccinated against rabies, Kennedy [/bib_ref] [EB1]. Some broad estimates have been made of the proportion of genetic non-responders in the canine population, these being: 1 in every 5,000 dogs for CDV, 1 in every 100,000 dogs for CAV and 1 in every 1,000 dogs for CPV-2 [EB4]. Serological Testing to Determine the Duration of Immunity (DOI) Antibody tests can be used to demonstrate the DOI after vaccination with core vaccines. It is known that a large majority of dogs maintain protective antibody against CDV, CPV-2, CAV-1 and CAV-2 for many years and numerous experimental studies support this observation [bib_ref] Serum antibody titres to canine parvovirus, adenovirus and distemper virus in dogs..., Bohm [/bib_ref] [bib_ref] Duration of serologic response to five viral antigens in dogs, Mouzin [/bib_ref] [bib_ref] Duration of immunity for canine and feline vaccines: a review, Schultz [/bib_ref] [bib_ref] Duration of serological response to canine parvovirus-type 2, canine distemper virus, canine..., Mitchell [/bib_ref] [EB1]. Therefore, when antibody is absent (irrespective of the serological test used) the dog should be revaccinated unless there is a medical reason for not so doing, even though some will be protected by immunological memory. Antibody determinations to other vaccine components are of limited or no value because of the short time period these antibodies persist (e.g. Leptospira products) or the lack of correlation between serum antibody and protection (e.g. Leptospira and canine parainfluenza) [bib_ref] Humoral immune response of dogs after vaccination against leptospirosis measured by an..., Hartman [/bib_ref] [bib_ref] Duration of immunity in dogs vaccinated against leptospirosis with a bivalent inactivated..., Klaasen [/bib_ref] [bib_ref] A review of canine parainfluenza virus infection in dogs, Ellis [/bib_ref] [formula] [EB1]. [/formula] The VGG recognizes that at present such serological testing might be relatively expensive. However, the principles of 'evidencebased veterinary medicine' suggest that testing for antibody status (for either puppies or adult dogs) should be better practice than simply administering a vaccine booster on the basis that this would be 'safe and cost less'. ## Passive immunization While vaccination (i.e. active immunization) dominates infectious disease prevention, passive immunization continues to be used in the treatment of infectious disease in many countries. Although virus infections trigger both cellular and humoral immunity, it is mainly the antibody response that contributes to the reduction of viral load and recovery. In many virus infections, antibody levels are therefore taken as correlates of protection. During viraemia, pre-existing or injected antibodies directed against surface structures of virions bind to the particles, neutralize their infectivity and prepare them for removal. Therapeutically, most serum or immunoglobulin preparations used in passive immunization are injected subcutaneously (because they are from a different animal species) and quickly reach the circulation. Not unexpectedly, intravenous infusions of plasma or serum (from the same species) have been found to work as well. In local infections, such as those initiated by the bite of a rabid carnivore, post-exposure antibody prophylaxis has also proven invaluable in human medicine. Human rabies immune globulin provides rapid protection when given on the first day of the post-exposure prophylaxis regimen. As much as possible of the preparation is infiltrated into and around the wound, and may be given intramuscularly at a site distant from the rabies vaccine, which is applied simultaneously. In companion animal practice, preventive active immunization is so commonplace that serum prophylaxis/therapy is considered only under exceptional circumstances (e.g. when a dog is presented with distemper or a cat is presented with panleukopenia, or during a disease outbreak in a kennel/cattery). There is still a market for serum and immunoglobulin products, and companies producing them exist in the USA, Germany, the Czech Republic, Slovakia, Russia and Brazil. The preparations are either of homologous or heterologous (e.g. horse) origin, are polyvalent (directed against several viruses) and consist of sera or their immunoglobulin fraction. Despite the availability of such products, the VGG recommends that they be used conservatively, and only after careful consideration. In the case of an outbreak of CDV infection in a kennel, it is much safer and more effective to vaccinate all dogs with CDV vaccine rather than give immune serum (see below and [fig_ref] Table 7: Use of Serological Testing in a Shelter Infectious Disease Outbreak [/fig_ref] [bib_ref] Effect of vaccination with recombinant canine distemper virus vaccine immediately before exposure..., Larson [/bib_ref] [EB1]. In such a situation it has previously been recommended that MLV vaccines be administered intravenously (off-label) rather than subcutaneously or intramuscularly, but there is little evidence that this practice provides more effective or rapid protection than subcutaneous or intramuscular injection. Administration of CDV vaccines by any of those routes will provide protection from severe disease and death immediately or very Journal of Small Animal Practice - Vol 57 - January 2016 - © 2016 WSAVA E11 shortly after vaccination. In this instance the vaccine does not prevent infection, but instead it protects from severe disease (especially from neurological disease) so the animal will survive and will subsequently be immune for life. In the case of a cattery outbreak of FPV infection, or a kennel outbreak of CPV-2 infection, a recent study has shown that if immune plasma is given after clinical signs appear, there is no benefit in reduction of morbidity or mortality [bib_ref] Clinical evaluation of a single dose of immune plasma for treatment of..., Bragg [/bib_ref] [EB1]. However, this work has been criticised because only a small volume (12 ml) of immune plasma was given to each puppy in this study. Much larger volumes (6·6-11 ml/kg) are routinely used by researchers and practitioners and these large doses are believed by some experienced clinicians and investigators to have efficacy [bib_ref] Immune plasma for treatment of parvoviral gastroenteritis, Dodds [/bib_ref] [EB4]. In order to have a maximal beneficial effect, immune serum or plasma must be given after infection, but prior to the onset of clinical signs. In this case administration of immune serum or plasma is best provided within 24-48 hours after infection and a large amount of high titred serum or plasma is required. The serum or plasma must be given parenterally (e.g. subcutaneously, intravenously or intraperitoneally) and not orally. There is no benefit from oral administration even when treatment is started prior to infection. An important consideration in a shelter situation is the relative cost of these commercial products. An alternative practice that is sometimes used in a shelter situation is to collect serum or plasma from animals in the shelter that have survived disease or have been recently vaccinated. However, this practice carries risk as the serum will not necessarily have been screened for transmissible pathogens (e.g. haemoparasites or feline retroviruses). Serological testing provides a more effective approach to controlling disease outbreaks in a shelter situation (see below and [fig_ref] Table 7: Use of Serological Testing in a Shelter Infectious Disease Outbreak [/fig_ref]. ## An update on new canine vaccines Since publication of the 2010 WSAVA guidelines, newly introduced vaccines include a Bordetella bronchiseptica vaccine for oral administration [bib_ref] Evaluation of efficacy of oral administration of Bordetella intranasal vaccine when used..., Hess [/bib_ref] [bib_ref] How well do vaccines for Bordetella bronchiseptica work in dogs? A critical..., Ellis [/bib_ref] and, globally, an increased range of Leptospira vaccines containing multiple, geographically relevant serogroups [bib_ref] The evolution of One Health: a decade of progress and challenges for..., Gibbs [/bib_ref] [bib_ref] European consensus statement on leptospirosis in dogs and cats, Schuller [/bib_ref]. These products are described in . A vaccine against canine influenza virus (CIV) infection is licensed only in the USA [bib_ref] Evaluation of the efficacy of a canine influenza virus (H3N8) vaccine in..., Deshpande [/bib_ref] [bib_ref] Efficacy of the canine influenza virus H3N8 vaccine to decrease severity of..., Larson [/bib_ref]. The influenza A subtype H3N8 has been well recognized as a cause of respiratory disease in North American dogs that are housed together [bib_ref] Transmission of equine influenza virus to dogs, Crawford [/bib_ref] [bib_ref] Influenza A virus (H3N8) in dogs with respiratory disease, Payungporn [/bib_ref] [bib_ref] Canine H3N8 influenza virus infection in dogs and mice, Castleman [/bib_ref] , but to date only sporadic outbreaks have been recognized and reported elsewhere [bib_ref] Transmission of equine influenza virus to dogs, Crawford [/bib_ref] [bib_ref] Transmission of equine influenza virus to English foxhounds, Daly [/bib_ref] [bib_ref] Influenza virus transmission from horses to dogs, Kirkland [/bib_ref] [bib_ref] A population prevalence study on influenza infection in dogs in Southern Italy, Pratelli [/bib_ref] [bib_ref] Prevalence of canine influenza virus A (H3N8) in dogs in Germany, Schulz [/bib_ref]. The CIV vaccine contains inactivated virus and is administered to pups from 6 weeks of age with a second dose 2-4 weeks later and then annual revaccination. Immunity develops approximately 7 days after the second dose. The vaccine is considered non-core and is recommended only for at-risk dogs in North America that are likely to be exposed as part of their lifestyle [bib_ref] Prevalence of and exposure factors for seropositivity to H3N8 canine influenza virus..., Anderson [/bib_ref] [EB1]. At the time of writing, a local outbreak of canine influenza attributed to virus of the H3N2 subtype was reported from the Chicago and Wisconsin region of the USA and a conditionally licensed vaccine against this subtype has been released. The first canine immunotherapeutic vaccine for malignant melanoma was licensed in 2010. This product comprises the human tyrosinase gene incorporated into a plasmid (a 'naked DNA' vaccine) that is repeatedly delivered by use of a high-pressure transdermal injection device. The vaccine is used as an adjunctive treatment in dogs with oral melanomas and induces an immune response to this melanoma target antigen. Initial studies showed that the median survival time of dogs with grade II-IV melanoma increased to 389 days (from an expected survival of 90 days) [bib_ref] Development of a xenogeneic DNA vaccine program for canine malignant melanoma at..., Bergman [/bib_ref] , but more recent studies have shown a lesser effect [bib_ref] Safety and efficacy of a xenogeneic DNA vaccine encoding for human tyrosinase..., Grosenbaugh [/bib_ref] [bib_ref] A retrospective analysis of the efficacy of Oncept vaccine for the adjunct..., Ottnod [/bib_ref] [EB1]. The vaccine is also available in Europe and, as in the USA, is limited to use by recognized veterinary oncology specialists. Two licensed vaccines for canine leishmaniosis were until recently available in Brazil, where leishmaniosis is a disease of major importance to the canine and human populations. The first of these is a subunit product containing GP63 of Leishmania donovani (also known as the 'fucose mannose ligand'; FML) in saponin adjuvant. It is considered to induce antibody that blocks the transmission of the organism from the dog to the sandfly vector by preventing binding of Leishmania to the midgut of the sand fly and has been extensively evaluated in immunological and epidemiological field studies [bib_ref] Decrease of the incidence of human and canine visceral leishmaniasis after dog..., Palatnik-De-Sousa [/bib_ref] [bib_ref] One health: the global challenge of epidemic and endemic leishmaniasis, Palatnik-De-Sousa [/bib_ref] [EB1]. However, this product has been recently withdrawn from the Brazilian market. The second Brazilian vaccine contains the A2 antigen from L. donovani in saponin adjuvant. This vaccine is reported to induce similar protective effects in vaccinated dogs (i.e. with respect to seroconversion, prevention of infection and clinical signs and transmission to the vector) to the FML vaccine, when both were compared in a natural exposure field trial in an endemic area over an 11 month period. Dogs vaccinated with the A2 vaccine developed a lesser humoral immune response but showed a greater frequency of adverse events post vaccination . A European Leishmania vaccine for dogs was introduced in 2011 [bib_ref] Vaccination with LiESP/QA-21 (CaniLeish®) reduces the intensity of infection in Phlebotomus perniciosus..., Bongiorno [/bib_ref]. This vaccine contains excretory-secretory antigens of Leishmania infantum in adjuvant. The vaccine is used in seronegative dogs from 6 months of age as three primary doses administered 3 weeks apart with an annual booster. Vaccinated dogs will seroconvert, but the product datasheet describes a discriminatory serological test. Evidence for a cell-mediated immune response is also suggested. The vaccine claims to reduce the likelihood of infection and reduce the severity of clinical signs in infected dogs, but makes no public health claim for an effect on human disease prevalence [EB2]. ## Feline vaccination guidelines ## Vaccination of individual cats The Basic Immunization Schedule Guidelines and recommendations for core (recommended), non-core (optional) and not recommended vaccines for cats visiting the general veterinary practice are given in [fig_ref] Table 3: WSAVA Feline Vaccination Guidelines Core [/fig_ref]. The core vaccines for the cat are those that protect against feline panleukopenia (FPV), FHV-1 and FCV. A particular example of a vaccine that may be considered core in only some countries is that against rabies virus. In a geographical area in which this infection is endemic, the VGG recommends that all cats should be routinely vaccinated for the protection of both the pet and human populations. In some countries, mandatory rabies vaccination is a legal requirement (although this does not always include cats) and rabies vaccination is also required for international pet travel. In terms of feline core vaccines it is important to realize that the protection afforded by the FCV and FHV-1 vaccines will not match the immunity provided by FPV vaccines. Thus the feline core respiratory disease vaccines should not be expected to give the same robust protection, nor the duration of immunity, that is seen with canine core vaccines. FCV vaccines have been designed to produce cross-protective immunity against multiple strains of FCV; however, it is still possible for infection and disease to occur in vaccinated adult animals [bib_ref] An isolated epizootic of hemorrhagic-like fever in cats caused by a novel..., Pedersen [/bib_ref] [bib_ref] An epizootic of highly virulent feline calicivirus disease in a hospital setting..., Schorr-Evans [/bib_ref] [EB1]. There is no FHV-1 vaccine that can protect against infection with virulent virus and infection may lead to the virulent virus becoming latent with the possibility of reactivation during periods of severe stress [bib_ref] Clinical, virological, and immunological parameters associated with superinfection of latently with FeHV-1..., Richter [/bib_ref] [EB1]. The reactivated virus may cause clinical signs in the vaccinated animal or the virus can be shed to susceptible animals and cause disease in them. The VGG recommends triennial revaccination of low-risk cats for FHV-1 and FCV on the basis of a published study showing a minimum duration of partial, but clinically significant, immunity of 7.5 years for these core vaccines [bib_ref] Long-term immunity in cats vaccinated with an inactivated trivalent vaccine, Scott [/bib_ref]. A more recent study of a MLV FHV-1/FCV vaccine seemed to show much less substantial, partial protection against FHV-1 at 3 years post vaccination; although the FCV partial protection was comparable to that shown by Scott and Geissinger in1999 [bib_ref] Three-year duration of immunity for feline herpesvirus and calicivirus evaluated in a..., Jas [/bib_ref]. . The VGG recommends that annual revaccination of cats against FHV-1/FCV be carried out in higher-risk situations. A low-risk cat might be defined as a solitary, indoor animal that does not visit a boarding cattery. A higher-risk cat might be defined as an animal that regularly visits a boarding cattery or that lives in a multicat, indoor-outdoor household. Moreover, the VGG encourages practitioners to consider the timing of administration of FHV-1/FCV vaccines to higher-risk, regularly boarding cats. The most robust immunity conferred by these vaccines occurs within the 3-month period after vaccination [bib_ref] Feline herpesvirus, Gaskell [/bib_ref] [EB1], and so administration of these vaccines might best be timed for immediately before a regularly boarded cat is due to make an annual visit to the cattery. Vaccination against feline leukaemia virus (FeLV) is also often a point of debate amongst experts. The VGG regards FeLV as a noncore vaccine [fig_ref] Table 3: WSAVA Feline Vaccination Guidelines Core [/fig_ref] , but fully appreciates that use of this product must be determined by the lifestyle and perceived exposure risk of individual cats and the prevalence of infection in the local environment. Many feline experts believe that even though the prevalence of FeLV infection is now markedly reduced in many parts of the world due to successful control programmes [bib_ref] The presence of leukaemia (lymphosarcoma) and feline leukaemia virus (FeLV) in cats..., Weijer [/bib_ref] [bib_ref] Control of feline leukaemia virus infection by a removal programme, Weijer [/bib_ref] [bib_ref] Changes in prevalence of progressive feline leukaemia virus infection in cats with..., Meichner [/bib_ref] [EB1], in geographical areas in which FeLV infection remains prevalent, any cat less than 1 year old with an element of outdoor lifestyle (e.g. even living with a cat that goes outdoors) should receive the benefit of protection by routine vaccination with two doses of vaccine given 2-4 weeks apart starting not earlier than 8 weeks of age. This 'risk-benefit' analysis for FeLV should form a routine part of the feline vaccination interview and only FeLV-negative cats should be vaccinated. The VGG has also reconsidered the FIV vaccine, which in previous iterations of these guidelines has been categorized as 'not recommended'. The basis for this categorization was: (1) questions over the cross-protection between subtypes of virus included in the vaccine and those subtypes and recombinants in the field in different geographical areas [bib_ref] Protection against homologous but not heterologous challenge induced by inactivated feline immunodeficiency..., Hosie [/bib_ref] [bib_ref] Limited efficacy of an inactivated feline immunodeficiency virus vaccine, Dunham [/bib_ref] [bib_ref] Feline immunodeficiency virus pathogenesis and development of a dual-subtype feline-immunodeficiency-virus vaccine, Yamamoto [/bib_ref] [bib_ref] Feline immunodeficiency virus (FIV) vaccine efficacy and FIV neutralizing antibodies, Coleman [/bib_ref] [bib_ref] Neutralising antibody response in domestic cats immunised with a commercial feline immunodeficiency..., Beczkowski [/bib_ref] [EB1], (2) the interference of the vaccine with antibody testing used for diagnosis of FIV infection [bib_ref] Vaccine protection against feline immunodeficiency virus: setting the challenge, Hosie [/bib_ref] [EB1], and (3) the fact that this is an adjuvanted vaccine that must be given repeatedly (a primary course of three injections and annual revaccination) to a species susceptible to injection site sarcoma. The VGG is aware that in some parts of the world, there remains a significant prevalence of FIV seropositivity and/or infection [bib_ref] Prevalence of antibody to feline immunodeficiency virus in some cat populations, Bennett [/bib_ref] [bib_ref] Prevalence of feline leukaemia virus and antibodies to feline immunodeficiency virus in..., Hosie [/bib_ref] [bib_ref] Feline immunodeficiency virus: prevalence, disease associations and isolation, Friend [/bib_ref] [bib_ref] Prevalence of feline immunodeficiency virus and feline leukemia virus infections in random-source..., Glennon [/bib_ref] [bib_ref] Prevalence of feline immunodeficiency virus and other retroviral infections in sick cats..., Bandecchi [/bib_ref] [bib_ref] Prevalence of feline immunodeficiency virus in submissions of feline serum to a..., Hitt [/bib_ref] [bib_ref] Prevalence of feline leukemia virus and antibodies to feline immunodeficiency virus in..., Ueland [/bib_ref] [bib_ref] The prevalence of feline immunodeficiency virus infection in hyperthyroid cats, Jones [/bib_ref] [bib_ref] Prevalence of antibodies to feline parvovirus, calicivirus, herpesvirus, coronavirus, and immunodeficiency virus..., Hofmann-Lehmann [/bib_ref] [bib_ref] Prevalence of FIV and FeLV infections in cats in Istanbul, Yilmaz [/bib_ref] [bib_ref] Prevalence of feline leukemia virus infection and serum antibodies against feline immunodeficiency..., Lee [/bib_ref] [bib_ref] Prevalence of feline leukaemia virus and antibodies to feline immunodeficiency virus and..., Muirden [/bib_ref] [bib_ref] Prevalence of feline immunodeficiency virus infection in domesticated and feral cats in..., Norris [/bib_ref] [bib_ref] Prevalence of feline immunodeficiency virus and feline leukaemia virus among client-owned cats..., Gleich [/bib_ref] [bib_ref] Naturally acquired feline immunodeficiency virus (FIV) infection in cats from western Canada:..., Ravi [/bib_ref] [bib_ref] Prevalence and risk factors of feline leukaemia virus and feline immunodeficiency virus..., Bande [/bib_ref] [bib_ref] A door-to-door prevalence study of feline immunodeficiency virus in Australia, Fung Martel [/bib_ref] [bib_ref] Prevalence of viral infections in cats in southwestern Poland in the years, Rypula [/bib_ref] [EB1]. There are now discriminatory serological tests [bib_ref] Serological differentiation of FIV-infected cats from dual-subtype feline immunodeficiency virus vaccine (Fel-O-Vax..., Kusuhara [/bib_ref] [bib_ref] Differentiation of feline immunodeficiency virus vaccination, infection, or vaccination and infection in..., Levy [/bib_ref] [bib_ref] Determining the feline immunodeficiency virus (FIV) status of FIV-vaccinated cats using point-of-care..., Westman [/bib_ref] and more robust polymerase chain reaction (PCR) testing for the diagnosis of FIV infection [bib_ref] Evaluation of a novel nested PCR for the routine diagnosis of feline..., Arjona [/bib_ref] [bib_ref] Dual-emission fluorescence resonance energy transfer (FRET) real-time PCR differentiates feline immunodeficiency virus..., Wang [/bib_ref] [bib_ref] Validation of real-time polymerase chain reaction tests for diagnosing feline immunodeficiency virus..., Morton [/bib_ref] [EB1]. In many countries, it is most unlikely that cat owners will be persuaded to keep their cats indoors, away from the major risk of FIV transmission (bites by infected cats). Disease progression in FIV-infected cats has recently been shown to be impacted by housing conditions and number of cats in the household [bib_ref] Contrasting clinical outcomes in two cohorts of cats naturally infected with feline..., Beczkowski [/bib_ref]. Given that this vaccine has been shown to have efficacy in some studies, but not in others, and might benefit some at-risk populations of cats, the VGG has reclassified the product as a non-core vaccine. Kitten Vaccination and the 6-or 12-Month Booster As discussed for puppies, most kittens are protected by MDA in the first weeks of life. However, without serological testing, the level of protection and the point at which the kitten will become susceptible to infection and can respond immunologically to vaccination are unknown. This is related to the level of maternal antibody and variation in uptake of MDA between litters and individuals. In general, MDA will have waned by 8-12 weeks of age to a level that allows an active immunological response; however, kittens with poor MDA may be vulnerable (and capable of responding to vaccination) at an earlier age, while others may possess MDA at such high titres that they are incapable of responding to vaccination until sometime after 12 weeks of age. The VGG has reviewed recent studies suggesting that up to one third of kittens may fail to respond to a final core vaccine given at 16 weeks of age and that a proportion of kittens may still have blocking MDA at 20 weeks of age [bib_ref] Prevalence of serum antibody titers against feline panleukopenia virus, feline herpesvirus 1,..., Digangi [/bib_ref] [bib_ref] Vaccination against feline panleukopenia: implications from a field study in kittens, Jakel [/bib_ref]. The VGG notes that one of these studies was of a relatively low number of animals, dominated by one breed, within a cattery setting, and suggests that the data may not be fully applicable to the wider feline population. Nevertheless, the VGG has increased the recommended age for the final vaccination in the series of primary core vaccinations from 14-16 weeks of age to 16 weeks or older . The VGG recommendation for the core vaccination of kittens is therefore in line with the schedules proposed for puppies above: beginning at 6-8 weeks of age and then repeating vaccination every 2-4 weeks until 16 weeks of age or older. Therefore the number of kitten primary core vaccinations will be determined by the age at which vaccination is started and the chosen revaccination interval. Possible schedules are outlined in [fig_ref] Table 5: weeks, 13 weeks, 17 weeks then 26 or 52 weeks [/fig_ref]. By this recommendation, when vaccination is started at 6 or 7 weeks of age, a course of four primary core vaccines would be administered, but only three would be required with an 8-or 9-week start. An integral part of core vaccination of kittens is the 'booster' vaccine that has traditionally been given either at 12 months of age or 12 months after the last of the primary series of kitten vaccines. The main aim of this vaccine is to ensure that a protective immune response develops in any cat that may have failed to respond to any of the three vaccines in the primary core series, rather than necessarily 'boosting' the immune response. The delivery of this vaccine at 12 months of age is likely to have been chosen historically as a convenient time to request the owner to attend the practice for a first annual health check. This therefore implies that should an individual kitten fail to respond to any of the three primary core vaccinations, that kitten may be unprotected until it receives this 12-month vaccine. This might account for occurrences of infectious disease in a proportion of vaccinated kittens at less than 12 months of age. The VGG has re-evaluated this practice and now suggests that veterinarians might wish to reduce this possible window of susceptibility by bringing forward this vaccine from 52 weeks to 26 weeks of age (or indeed at any time point between 26 and 52 weeks of age; however, 26 weeks of age provides a convenient timing). This practice will require that pet owners clearly understand why this is recommended, because as indicated in [fig_ref] Table 5: weeks, 13 weeks, 17 weeks then 26 or 52 weeks [/fig_ref] , adopting such a protocol will mean that vaccination started in a 6 or 7 week old kitten, might now entail up to five vaccine visits in the first 6 months of life. For core vaccines, after a 26 week 'booster', another core vaccine would not be required for at least another 3 years (for a low-risk cat). As for puppies, adoption of the 26 week vaccination approach would not preclude a first annual health check at 12 or 16 months of age. ## Revaccination of adult cats Cats that have responded to vaccination with MLV core vaccines maintain a solid immunity (immunological memory) against FPV for many years in the absence of any repeat vaccination. Immunity against FCV and FHV-1 is only partial . The VGG recommendation for adult 'low-risk' cats is for revaccination with MLV core vaccines at intervals of 3 years or longer. For 'higher-risk' cats (see definitions above) the veterinarian might consider administering FPV vaccine no more frequently than every 3 years, but giving FCV and FHV-1 vaccines annually, with these latter products timed for administration shortly before any regular annual visit to a boarding cattery [EB1]. These recommendations do not generally apply to killed core vaccines (except for rabies) nor to the non-core vaccines, and particularly not to vaccines containing bacterial antigens. Thus Chlamydia (formerly Chlamydophila; [bib_ref] Emendation of the family Chlamydiaceae: proposal of a single genus, Chlamydia to..., Sachse [/bib_ref] and Bordetella products, if their use is deemed necessary, require annual boosters for the limited protection afforded by these products . Therefore, according to these guidelines, an adult cat may still receive an annual vaccination; however, the components of that vaccination may differ from year to year. Typically, core vaccines (especially FPV) are currently administered triennially with respiratory virus vaccines given according to risk and chosen non-core products being given annually. The VGG is aware that in some countries only multi-component products containing core and non-core combinations are available. The VGG would encourage manufacturers to make a full range of vaccines available wherever possible or, at the very least, make a core-only combination for those not wanting to give any of the non-core vaccines. An adult cat that received a complete course of vaccination for FPV, FHV-1 and FCV as a kitten (including the 6-or 12-month booster), but may not have been regularly vaccinated as an adult requires only a single dose of MLV core vaccine to boost immunity . An adopted adult cat (or kitten over 16 weeks of age) of unknown vaccination history requires only a single dose of MLV FPV core vaccine to engender a protective immune response to that virus. In contrast, an adopted adult cat of unknown vaccination history should receive two doses of MLV FHV-1/FCV vaccine (2-4 weeks apart) to establish an adequate immune response [EB2]. ## Sites of vaccination for cats Vaccines (of any type) are one class of injectable product that has been linked to the pathogenesis of the feline injection site sarcoma (FISS) and particular attention has focused on the administration of adjuvanted FeLV and rabies vaccines [bib_ref] Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in..., Kass [/bib_ref]. FISS has been the subject of much research and there are a number of recent reviews on the subject [bib_ref] Feline injection-site sarcoma: past, present and future perspectives, Martano [/bib_ref] [bib_ref] Comparative vaccine-specific and other injectable-specific risks of injection-site sarcomas in cats, Srivastav [/bib_ref] [bib_ref] Injection site-associated sarcoma in the cat: treatment recommendations and results to date, Ladlow [/bib_ref]. Although the pathogenesis of FISS remains unproven, current belief is that a localized chronic inflammatory reaction initiates malignant transformation of mesenchymal cells and that this process has some genetic basis. Most subcutaneous injections (including of vaccines) have traditionally been given into the interscapular region of the cat, which remains a common site for formation of a FISS. The infiltrative nature of these tumours means that radical surgical resection is often necessary to attempt removal of these lesions although adjunctive treatment modalities are also used [bib_ref] Feline injection-site sarcoma: past, present and future perspectives, Martano [/bib_ref] [bib_ref] Injection site-associated sarcoma in the cat: treatment recommendations and results to date, Ladlow [/bib_ref]. In North America the response to this issue was the recommendation of a protocol whereby the two perceived high-risk adjuvanted vaccines would be administered into distinct anatomical sites that would be more amenable to surgical removal of any FISS that might develop. Accordingly the recommendation 'left leg leukaemia, right leg rabies' suggested that FeLV vaccine should be given as far distal as possible into the left hindlimb, whilst rabies vaccine should be given as far distal as possible into the right hindlimb. This recommendation remains in the current AAFP guidelines [bib_ref] AAFP Feline Vaccination Advisory Panel report, Scherk [/bib_ref] , which also specify administration of the three feline core vaccines into a distal forelimb. One study evaluated the effect of this practice by comparing the anatomical distribution of FISS in cats before the recommendation was made and after the practice was adopted [bib_ref] Temporal changes in characteristics of injection-site sarcomas in cats: 392 cases (1990-2006), Shaw [/bib_ref]. The data showed a significant decrease in the prevalence of interscapular FISS and an increase in prevalence of tumours in the right (but not left) forelimb. More notably, there was also an increase in the number of tumours reported arising in the combined regions of the right hindlimb with right lateral aspect of the abdomen (12.5% to 25.0%) and the left hindlimb with left lateral aspect of the abdomen (11.4% to 13.8%). This was attributed to the difficultly of injecting into the distal hindlimb and these abdominal sites being accidentally injected. This practice has not been widely adopted outside of North America. Recently, one publication has shown the efficacy of administering FPV and rabies vaccines into the tail of cats [bib_ref] Tail vaccination in cats: a pilot study, Hendricks [/bib_ref]. Adult cats from a community trap-neuter-return programme were given trivalent MLV core vaccine (FPV, FHV-1, FCV) into the distal third of the dorsal tail with inactivated rabies vaccine administered 2 cm distal to the site of the trivalent vaccination. Seroconversion occurred in all cats to FPV and all but one cat for rabies virus. Tail vaccination was reported to be well tolerated by the cats in this small study. In the 2010 WSAVA vaccination guidelines, the VGG proposed the alternative of delivering vaccine into the skin of the lateral thorax, or better, the lateral abdomen [bib_ref] Guidelines for the vaccination of dogs and cats, Day [/bib_ref]. Tail injection may prove to be a safer alternative than distal limb injections or lateral body wall injections, but further studies of tail vaccination will be required. This remains a confusing and contentious area and individual practitioners must decide for themselves which approach is practical for their own practice setting. However, the following principles should still be applied: - Any risk of FISS is outweighed by the benefit of protective immunity conferred by vaccines. Current estimates of the prevalence of FISS are 1 in every 5,000 to 12,500 cats vaccinated [bib_ref] World Wide Web-based survey of vaccination practices, postvaccinal reactions, and vaccine site-associated..., Gobar [/bib_ref]. - Non-adjuvanted vaccines should be administered to cats wherever possible. - Vaccines (particularly adjuvanted products) or other injectables should not be administered into the interscapular region. - Vaccines (particularly adjuvanted products) should be administered into other subcutaneous (and not intramuscular) sites. The choice of these sites should be based on a balance between the ease of surgical resection of any FISS that might develop and acceptable safety for the vaccinator (i.e. to avoid accidental self-injection during difficult restraint of the animal). - Vaccines should be administered into a different site on each occasion. This site should be recorded in the patient's record or on the vaccination card by use of a diagram indicating which products were administered on any one occasion. The sites should be 'rotated' on each occasion. Alternatively, a practice might develop a group policy that all feline vaccinations are administered to a specific site during one calendar year and this site is then rotated during the following year. - The VGG encourages all cases of suspected FISS to be notified via the appropriate national reporting route for suspected adverse reactions or to the vaccine manufacturer. ## Serological testing Since the publication of the 2010 guidelines, one commercial in-practice rapid test for determination of serum antibody to FPV, FCV and FHV-1 has become available. This test has now been validated and applied in a series of published investigations [bib_ref] Evaluation of an in-house dot enzyme-linked immunosorbent assay to detect antibodies against..., Mende [/bib_ref]. This test kit may be used for the determination of the presence of protective antibody against FPV as there is excellent correlation between the presence of such antibody and resistance to infection [bib_ref] Use of serologic tests to predict resistance to feline herpesvirus 1, feline..., Lappin [/bib_ref] [EB1]. The FPV test kit is reported to have 89% specificity and 79% sensitivity [bib_ref] Evaluation of an in-house dot enzyme-linked immunosorbent assay to detect antibodies against..., Mende [/bib_ref] The correlation between circulating serum antibody and protection against FCV and FHV-1 infection is less robust than the presence of adequate local mucosal immunity and cell-mediated immunity, respectively. For that reason, a negative test result for FCV or FHV-1 antibody would not necessarily indicate lack of protection in a particular cat [bib_ref] Use of serologic tests to predict resistance to feline herpesvirus 1, feline..., Lappin [/bib_ref] [EB1]. These tests can be applied in practice as described above for the dog: for determination of protection of kittens following FPV vaccination, for determination of protection against FPV in adult cats (in order to inform decisions about revaccination) and for use in the shelter situation in the control of outbreaks of FPV infection. It should be emphasized that antibody testing for FIV is used to diagnose disease and is of no value in determining immunity to FIV, but as discussed above, where FIV vaccine is used and FIV infection is suspected, diagnosis should be made using a discriminatory serological test or, preferably, a validated PCR test. ## Vaccination of dogs and cats in the shelter environment An animal shelter is a holding facility for animals usually awaiting adoption, rescue or reclamation by owners. In general, animal shelters are characterized by a random source population with a mostly unknown vaccination history, high population turnover and high infectious disease risk. The term 'shelter' encompasses situations ranging from sanctuaries that possess a stable population, to facilities that admit hundreds of animals per day, to rescue and foster homes that care for multiple individuals or litters at any given time. Just as vaccination strategy varies with each individual pet, there is no one-size-fits-all strategy for vaccinating shelter animals. The likelihood of exposure and the potentially devastating consequences of infection necessitate a clearly defined shelter vaccination program. Shelter medicine differs from individual care in that clinicians have to practice in an environment where eradication of infectious disease cannot be attained. It is possible, however, to minimize the spread of infections within a high-density, high-risk population and maintain the health of not-yet-infected individuals. When the overall purpose is to place healthy pets into welcoming homes, the time and effort dedicated to controlling infectious disease is only one of many variables in the complex shelter medicine and husbandry equation. The recommendations provided here attempt to address some shelter-unique issues as they pertain to vaccination and disease control. Guidelines and recommendations for vaccines to be used in shelters are given in Tables 2 and 4. In these updated guidelines, we have standardized the recommendations for puppies and kittens entering a shelter to indicate that core vaccination may be started as early as 4-6 weeks of age, and (where funding permits) revaccination should be every 2 weeks until the animal reaches 20 weeks of age, if it remains in the shelter until that time . Recent US studies have shown that cats entering shelters may be seropositive for vaccine-preventable infectious disease agents. [bib_ref] Prevalence of serum antibody titers against feline panleukopenia virus, feline herpesvirus 1,..., Digangi [/bib_ref] reported seropositivity for FPV (60.2%), FHV-1 (89%) and FCV (63.4%) and [bib_ref] Response of feral cats to vaccination at the time of neutering, Fischer [/bib_ref] reported seropositivity for FPV (33%), FHV-1 (21%), FCV (64%) and rabies virus (3%). Seropositivity to CDV (41.2%) was less than for CPV (84.3%) in dogs entering one US shelter [bib_ref] Prevalence of positive antibody test results for canine parvovirus (CPV) and canine..., Litster [/bib_ref] and in another study 35.5% of dogs were seropositive to both CDV and CPV, 7.7% to CDV only, 31.5% to CPV only and 25.3% to neither virus [bib_ref] Prevalence of protective antibody titers for canine distemper virus and canine parvovirus..., Lechner [/bib_ref]. If unambiguous documentation of vaccination is provided for an adult animal at the time of admission to a shelter, there is no reason to revaccinate with canine core vaccines, but feline core vaccines, specifically FCV and FHV-1, may be of value in boosting immunity. The VGG discriminates between a shelter and a boarding kennel/cattery. The latter are facilities where fully vaccinated animals may be temporarily boarded for relatively short periods of time (e.g. when owners are on vacation). It should be a requirement of entry to any such facility that the individual dog or cat is fully vaccinated with core products given according to the guidelines presented herein. In dogs, the use of non-core vaccines against respiratory infections is also appropriate under these circumstances. The VGG is aware that in some countries vaccination protocols for animals entering a boarding kennel/cattery are formulated by local authorities and may be contrary to current guidelines (e.g. insistence on annual revaccination). The VGG encourages such authorities to reconsider these recommendations in light of current scientific thinking and product availability and encourages the veterinary profession and national associations to lobby for such change. Since publication of the 2010 guidelines, the availability of rapid in-house serological test kits has had major impact on the management of outbreaks of CDV, CPV or FPV in animal shelters . The approach to use of these kits in such situations is outlined in [fig_ref] Table 7: Use of Serological Testing in a Shelter Infectious Disease Outbreak [/fig_ref]. ## General considerations comprehensive individual care beyond vaccination In the past, veterinary practice has benefited from the annual administration of vaccines. By encouraging owners to bring their pets yearly for vaccination, veterinarians were able to recognize and treat disease earlier than might otherwise have been the case. In addition, the annual visit provided an opportunity to inform clients of important aspects of canine and feline health care. Unfortunately, many clients have come to believe that vaccination is the most important reason for annual veterinary visits. Veterinarians have been concerned that a reduction in vaccination frequency will cause clients to forgo the annual visits and that the E16 Journal of Small Animal Practice - Vol 57 - January 2016 - © 2016 WSAVA quality of care will diminish. It is therefore essential that veterinarians stress the importance of all aspects of a comprehensive individualized health care program. Emphasis should be placed on detailed history taking; thorough physical examination performed in the presence of the client, and individualized patient care. The importance of dental care, proper nutrition, appropriate diagnostic testing and the control of parasites and of zoonotic diseases should be addressed during evaluation of each pet. Behavioural concerns should be discussed, as well as the necessity for more frequent, tailored examination of young and geriatric animals and animals of particular breeds with well characterized disease predispositions. Discussion of vaccination is simply one part of the annual health check visit. During regular (usually annual) health checks, clinicians should assess the need for core and non-core vaccines for that particular year. The practitioner should explain to the client the types of vaccines available, their potential benefits and risks, and their applicability to the particular animal, given its lifestyle and risk of exposure. While an animal might not receive core vaccination every year, most non-core vaccines require annual administration -so owners will continue to see their animal vaccinated annually. The regional incidence and risk factors for various infectious diseases should also be discussed. Ways to reduce the impact of acquired disease (e.g. avoiding overcrowding, improving nutrition, and restricting access to infected animals) should also be reviewed. Vaccinations should be considered as only one component of a comprehensive preventive health care plan individualized based on the age, breed, health status, environment (potential exposure to harmful agents), lifestyle (contact with other animals) and travel habits of the pet. Age has a significant effect on the preventive health care needs of any given individual. Puppy/kitten programs have traditionally focused on vaccinations, parasite control and neutering. Today, opportunity exists to incorporate behaviour counselling and zoonotic disease management. For the ageing pet, senior care programs are becoming increasingly popular. Nutritional, dental disease and parasite control assessment and counselling should take place on an individualized basis throughout the life of the pet. There is no evidence that older dogs and cats, which have been fully vaccinated as pups or kittens, require a specialized programme of core vaccination [bib_ref] Guidelines for the vaccination of dogs and cats, Day [/bib_ref] [bib_ref] Vaccination protocols for companion animals: the veterinarian's perspective, Horzinek [/bib_ref]. Experimental evidence shows that older dogs and cats have persisting immunological memory to core vaccines, as detected by measurement of serum antibody, and that this may be readily boosted by administration of a single vaccine dose [bib_ref] Guidelines for the vaccination of dogs and cats, Day [/bib_ref] [EB1]. In adult animals, decisions about revaccination with most core products (CDV, CAV and CPV and FPV) may be made via serological testing. Practitioners who offer this alternative to vaccination report that it is greatly appreciated by owners who may have concerns about vaccination frequency and offering this alternative acts as a 'practice builder'. By contrast, aged animals may not be as efficient at mounting primary immune responses to novel antigens that they have not previously encountered [bib_ref] Guidelines for the vaccination of dogs and cats, Day [/bib_ref] [EB1]. Studies of UK dogs and cats vaccinated for the first time against rabies for pet travel have clearly shown that more aged animals fail to achieve the legally required antibody titre [bib_ref] Factors influencing the antibody response of dogs vaccinated against rabies, Kennedy [/bib_ref] [EB1]. The environment in which a pet resides can profoundly affect its health status and should be assessed during annual health care visits in order to define risk factors and develop appropriate preventive measures. By estimating the extent to which dogs and cats come into contact with other animals in unobserved circumstances, veterinarians can assess the need for non-core vaccinations. Dogs that visit kennels, grooming salons, common areas and wooded, tick-infested areas are potentially at greater risk from certain infectious diseases than dogs that do not frequent these areas. Just as the human population has become more mobile, so has the pet population, resulting in potential exposure to infectious agents, parasites and environmental hazards not found where the animal normally lives. Determining past and anticipated future travel during each visit allows for greater individualization of preventive care and diagnostic testing plans. ## Medical record documentation At the time of vaccine administration, the following information should be recorded in the patient's permanent medical record: - date of vaccine administration - identity (name, initials or code) of the person administering the vaccine - vaccine name, lot or serial number, expiry date and manufacturer - site and route of vaccine administration. The use of peel-off vaccine labels and stamps that imprint the medical record with the outline of a pet facilitates this type of record keeping which is mandatory in some countries. Adverse events should be recorded in a manner that will alert all staff members during future visits. Informed consent should be documented in the medical record in order to demonstrate that relevant information was provided to the client and that the client authorized the procedure (e.g. 'off-label' use of products as discussed above). At the very least, this notation should indicate that a discussion of risks and benefits took place prior to vaccination. VGG recommends that vaccination certificates be designed to include not just the dates on which vaccines were administered, but also a field for the veterinarian to state the date on which vaccination is next recommended. This will help diminish confusion in the minds of pet owners and kennel/cattery proprietors. Annually or more often in very high-risk animals not protected by annual booster. Non-core. B. bronchiseptica is available as a single product or in combination with CPiV or with both CPiV and CAV2. Transient (3-10 days) coughing, sneezing, or nasal discharge may occur in a small percentage of vaccinates. Intranasal or oral vaccines MUST NOT be delivered by parenteral injection as this may lead to severe adverse reactions, including death. Bordetella bronchiseptica (killed bacterin, parenteral Bordetella bronchiseptica (cell wall antigen extract, parenteral) Administer one dose at 6-8 weeks and one dose at 10-12 weeks of age. Two doses 2-4 weeks apart. Annually or more often in very high-risk animals not protected by annual booster. Non-core. Intranasal or oral products are preferred to the killed parenteral to provide local protection [EB4]; however, a review published at the time of compilation questions this advantage [bib_ref] How well do vaccines for Bordetella bronchiseptica work in dogs? A critical..., Ellis [/bib_ref] In Australia there is a monovalent vaccine containing serogroup australis and in New Zealand monovalent serogroup icterohaemorrhagiae vaccines are available. Initial dose at 8 weeks of age or older. A second dose is given 2-4 weeks later. Two doses 2-4 weeks apart. Annually. Non-core. Leptospira vaccines have been developed to account for the known circulating pathogenic serogroups in different geographical areas. Note that Leptospira serogroups may include multiple serovars. There is often confusion with the use of the terms 'serogroup' and 'serovar'. Vaccination should be restricted to use in geographical areas where a risk of exposure has been established or for dogs whose lifestyle places them at risk. This vaccine is known to provide protection that is less robust and may be of shorter duration, and therefore these products must be administered annually [EB1]. In the past, Leptospira bacterin vaccines have been suggested to be linked to a higher prevalence of allergic adverse events -particularly in small breed dogs. Administer one dose at time of admission (from 6-8 weeks of age) and a second dose 2 weeks later. Two doses 2 weeks apart are recommended. Parenteral vaccination is recommended only when it is not possible to administer an intranasal or oral vaccine. Canine respiratory disease complex ('kennel cough') is not a vaccine-preventable disease and the vaccine should only be used to help manage the disease. ## Rabies A single dose should be administered at the time of discharge from the facility. A single dose should be administered at the time of discharge from the facility. The administration of rabies vaccine will be determined by whether the shelter is in a country in which the disease is endemic, and by local statute. In the USA, the CIV vaccine is often used in the shelter situation when two doses can be given 2 weeks apart. Many of the recommendations for shelters are different for use of the same vaccines for owned pet dogs in the practice situation. These recommendations take into account the potential for high infectious disease pressure in the shelter environment. ## E20 Journal of Small Animal Practice - Vol 57 - January 2016 - © 2016 WSAVA MLV preparations are preferable. Use of intranasal FPV vaccines is not recommended in the shelter environment [bib_ref] A commentary on parvovirus vaccination, Schultz [/bib_ref]. Use of intranasal FCV/FHV-1 MLV vaccines may be preferable when rapid onset (48 hrs) of immunity is important. Post-vaccinal sneezing, more commonly seen following administration of intranasal FCV/FHV-1 vaccine is impossible to distinguish from active infection. ## Rabies A single dose should be administered at the time of discharge from the facility. A single dose should be administered at the time of discharge from the facility. The administration of rabies vaccine will be determined by whether the shelter is in a country in which the disease is endemic and vaccination is required by law. The VGG does not recommend the use of other feline vaccines in the shelter situation. provides examples of possible vaccination schedules for puppies and kittens where vaccines are given either every 3 or 4 weeks, as would normally be done in veterinary practice for owned pet animals. Although revaccination every 2 weeks might be used in areas of high infectious disease pressure in some geographical areas, such a protocol is not shown for simplicity of presentation. After the 26 or 52 week booster vaccine; vaccinate with core products no more frequently than every 3 years (with the exception of feline respiratory virus vaccines for higher risk cats). ## Table 6. vaccine husbandry: key points for veterinary practitioners - Vaccines have an optimum storage temperature that is usually between 2-8°C (domestic refrigerators should be maintained at 4°C). These products should not be frozen or positioned adjacent to the freezer compartment of the refrigerator, and refrigerator temperature should be monitored regularly. Vaccines transported into the field should also be subject to continuation of the 'cold chain'. - Freeze-dried vaccines should be reconstituted immediately before use with appropriate diluent or liquid vaccine given simultaneously (as per manufacturer's recommendations). It is bad practice and contraindicated to make up the vaccines anticipated to be used during the day first thing in the morning. Some vaccine components (e.g. CDV, FHV-1) are particularly labile in this regard and so these vaccines may not induce adequate immunity if not reconstituted just before use. - Vaccines should only be mixed together in the same syringe if this is specified as acceptable in the manufacturer's data sheets. - Syringes and needles for vaccines should not be re-utilized. - Vaccine injection sites should not be sterilized with alcohol or other disinfectant as this may inactivate infectious (MLV) vaccines. - Vaccines should be 'in date' and precise details of batch numbers, components and site of injection should be noted in the animal's medical record. [From]. Seropositive animals These are protected and will not become infected or die. These should be separated from the non-or low-responder animals. Seronegative animals These should be separated from the seropositive animals. These animals are susceptible and should not be adopted out of the shelter until after the incubation period for the infection (i.e. at least 2 weeks for CPV, at least 6 weeks for CDV). These animals should be vaccinated and retested to confirm seropositivity after the incubation periods above. Animals outside of a shelter needing to be admitted in the face of a disease outbreak in the shelter Seropositive animals These may safely enter the shelter as they are protected from disease. ## Seronegative animals These animals should be vaccinated and sent to foster homes until after they have seroconverted. They should not be allowed to enter the shelter until they are seropositive. ## Adverse events Adverse events are defined as any side effects or unintended consequences (including lack of protection) associated with the administration of a vaccine product. They include any injury, toxicity or hypersensitivity reaction associated with vaccination, whether or not the event can be directly attributed to the vaccine. Adverse events should be reported, whether their association with vaccination is recognized or only suspected. A vaccine adverse event report should identify the product(s) and animal(s) involved in the event(s) and the individual submitting the report. Reporting field observations of unexpected vaccine performance is the most important means by which the manufacturer and the regulatory agency are alerted to potential vaccine safety or efficacy problems that may warrant further investigation. The purpose of pre-licensure safety studies is to detect relatively common adverse events. Rare or delayed adverse events will be detected only by postmarketing surveillance through analysis of reported adverse events. Adverse events should be reported to the manufacturer and/or the local regulatory authority. In many countries governmental surveillance schemes are not available and reactions should therefore be notified to the manufacturer. The VGG recognizes that there is gross under-reporting of vaccine-associated adverse events, because of the passive nature of reporting schemes, which impedes knowledge of the ongoing safety of these products . The VGG would actively encourage all veterinarians to participate in such surveillance schemes. If a particular adverse event is well documented, reporting serves to provide a baseline against which future reports can be compared. In addition, reported adverse events can lead to detection of previously unrecognized reactions, detection of increases in known reactions, recognition of risk factors associated with reactions, identification of vaccine lots with unusual events or higher numbers of adverse events, and can further stimulate clinical, epidemiological or laboratory studies. Therefore, veterinarians are encouraged to report any clinically significant adverse event occurring during or after administration of any licensed vaccine. Reporting a vaccine adverse event is not an indictment against a particular vaccine; it facilitates review of temporally associated conditions and adds to the safety database of the product. # Acknowledgments The work of the Vaccination Guidelines Group has been generously sponsored by MSD Animal Health and the WSAVA. The VGG is an independent group of academic experts who have formulated these guidelines without consultation with industry. Representatives of the sponsoring company do not attend VGG meetings and the company does not have the right of veto over VGG recommendations. The VGG again acknowledges the important work undertaken by the American Animal Hospital Association (AAHA) Canine Vaccine Task Force, the American Association of Feline Practitioners (AAFP) Feline Vaccine Advisory Panel in developing recommendations for the vaccination of dogs and cats (respectively) in North America. The VGG also acknowledges the work of the European Advisory Board on Cat Diseases (ABCD) in formulating recommendations for feline vaccination from the European perspective. E27 APPENDICES FACT SHEET: CANINE PARVOVIRUS TYPE 2 (CPV-2) VACCINES Types of Vaccines Available Modified Live Virus (MLV) Vaccines: There are three contemporary variants of CPV-2, which are referred to as CPV-2a, CPV-2b and CPV-2c. The original CPV-2 variant is rarely isolated nowadays, although it is still present in some modified live vaccines and can be shed from vaccine recipients. The most recent variant to emerge is CPV-2c and this genotype is recognized in North and South America, Europe, Africa and Asia [bib_ref] Canine parvoviruses in New Zealand form a monophyletic group distinct from the..., Ohneiser [/bib_ref]. All genotypes are antigenically related; challenge studies have shown that vaccination of dogs with current CPV vaccines containing either CPV-2 or CPV-2b will provide protective immunity against all the other variants, including CPV-2c [bib_ref] Canine parvovirus type 2 vaccine protects against virulent challenge with type 2c..., Spibey [/bib_ref] [bib_ref] Canine parvovirus -a review of epidemiological and diagnostic aspects with emphasis on..., Decaro [/bib_ref]. Conversely, there is one report of an outbreak of CPV-2c infection in vaccinated adult dogs [bib_ref] Evidence for immunisation failure in vaccinated adult dogs infected with canine parvovirus..., Decaro [/bib_ref]. These dogs had been vaccinated at 42, 57 and 90 days of age and the adults had received annual boosters. Inactivated (Killed) Vaccines: Only a few killed CPV-2 vaccines are available; they are less effective and take much longer to induce an immune response when compared with the MLV vaccines [bib_ref] Dog response to inactivated canine parvovirus and feline panleukopenia virus vaccines, Pollock [/bib_ref]. They are not recommended for routine use. Killed vaccines may provide some benefit in wild and exotic species or pregnant bitches, where some MLV vaccines are not recommended. However, killed CPV-2 vaccines have not been tested for safety or efficacy in these situations. ## Mechanisms and duration of immunity (doi) - DOI after natural infection/disease is thought to be life-long in the majority of dogs. - DOI after vaccination with MLV vaccines is 9 years or longer, based on challenge and serological studies ). - DOI after vaccination with killed vaccines is 3 years or longer. - MDA interferes with active immunization for varying periods of time in the puppy, depending on the titre of colostral antibody and the amount of antibody absorbed after birth, as well as the specific vaccine [bib_ref] Maternally derived immunity to canine parvovirus infection: transfer, decline, and interference with..., Pollock [/bib_ref]. - The 'window of susceptibility' is defined as the period of time during which a pup can be infected by field virus, but vaccines cannot immunize. For highly effective MLV vaccines (i.e. high titre, low passage) the 'window of susceptibility' is as short as 2 weeks or less, while for less effective MLV vaccines, the window of susceptibility is as long as 10-12 weeks [bib_ref] Immuonogenicity of a low-passage, high-titer modified live canine parvovirus vaccine in pups..., Hoare [/bib_ref]. - After completing the puppy series at 16 weeks or older and vaccinating again at 26 or 52 months of age, revaccination need not be done more often than every 3 years. - In the absence of MDA, MLV vaccines provide immunity as early as 3 days after vaccination. - The presence of serum antibody, regardless of titre, in an actively immunized dog over the age of 20 weeks is correlated with protection. ## Precautions - MLV vaccines should not be used in wildlife species. - MLV vaccines should not be used in pregnant bitches unless specifically indicated. - Puppies younger than 4-6 weeks of age should not be vaccinated with MLV products. ## Disease facts - After infection, it takes 3-7 days for signs of disease to appear. - CPV-2 faecal shedding rarely persists for >2 weeks. - Dogs persistently infected for >4 weeks have not been reported and one can expect the animal to die or clear the virus in that period of time. - In the environment, the virus can remain infectious for 1 year or more. Therefore, all facilities where infected animals have been present must be considered infected. tory disease associated with CAV-2 infection. They are exceptionally effective and will not cause the adverse reaction commonly seen with CAV-1 vaccines known as allergic uveitis or 'blue eye' [bib_ref] The 'blue eye' phenomenon, Curtis [/bib_ref]. In addition to parenteral MLV CAV-2 vaccine preparations there are combination or monovalent products to protect against the canine infectious respiratory disease complex (CIRDC), which includes Bordetella bronchiseptica and canine parainfluenza virus (CPiV) and CAV-2. The intranasal product that contains CAV-2, CPiV and Bordetella can be used to decrease the severity of CIRDC, but should not be used as the only vaccine to prevent ICH; for this purpose, the parenteral MLV-CAV-2 should also be given. Inactivated (Killed) Vaccines: Inactivated (killed) CAV-1 and CAV-2 vaccines are sold in some countries, but they are not recommended when MLV products are available, as they are less effective. ## Mechanisms and duration of immunity (doi) - DOI after naturally-acquired canine infectious hepatitis is thought to be life-long in the majority of dogs. - DOI after vaccination with MLV vaccines is 9 years or longer in the majority of dogs, based on challenge and serological studies ). - DOI for protection from ICH with killed CAV-1 or CAV-2 vaccines is likely to be shorter than for MLV products. - MDA will block immunization after vaccination with the parenteral product and so the last dose should be given along with the other core viral vaccines (e.g. CDV, CPV-2) when the puppy is 16 weeks of age or older. - After completing the puppy series at 16 weeks or older and vaccinating again at 26 or 52 weeks of age, revaccination need not be done more often than every 3 years. - In the absence of MDA, MLV vaccines protect against ICH as early as 5 days after vaccination. - The presence of serum antibody, regardless of titre, in an actively immunized dog over the age of 20 weeks is correlated with protection. ## Precautions - Intranasal CAV-2 vaccine is intended as an aid in the prevention of upper respiratory disease caused by CAV-2 and is not intended to protect against CAV-1 infection. ## Disease facts - CAV-1 is transmitted primarily through contaminated secretions/excretions such as saliva and urine. - CAV-1 and CAV-2 are moderately stable, surviving for several days to weeks in the environment. - After experimental infection with CAV-1, it takes 5 days or longer for signs of ICH to appear. - The 'window of susceptibility' is defined as the period of time during which a puppy can be infected by field virus, but vaccines cannot immunize. Unlike CPV-2 vaccines, there generally is not a prolonged 'window' for CAV-2 vaccines (i.e. <2 weeks). - CAV-2 is transmitted primarily through the air. - CIRDC has complex pathogenesis involving stress, poor ventilation, dust, ammonia gas in unsanitary facilities and infections with Streptococcus spp., Bordetella bronchiseptica, Mycoplasma spp., CAV-2, CPiV, CIV, canine pneumovirus and canine respiratory coronavirus. - CAV-2 combined with other agents associated with CIRDC can cause respiratory disease in 3-4 days. - As a multifactorial disease CIRDC is not vaccine-preventable. The current vaccines only help in reducing disease severity. ## Fact sheet: canine distemper virus (cdv) vaccines ## Types of vaccines available modified live virus (mlv) vaccines: These are the most common products. They generally contain the CDV strains Rockborn, Snyder Hill, Onderstepoort, Lederle or others at various titres. There are many pathotypes of CDV [bib_ref] Canine distemper virus strains circulating among North American dogs, Kapil [/bib_ref] [bib_ref] Phylogenetic evidence of a new canine distemper virus lineage among domestic dogs..., Espinal [/bib_ref] which can cause varying clinical signs in a wide variety of species. However, serological differences among the many isolates are insignificant, and vaccination with any one of the current vaccines should provide protective immunity against any pathotype. MLV vaccines must not be used in wildlife species unless there is specific evidence that shows them to be safe. Vectored Recombinant (rCDV) Vaccines: A canarypox virus recombinant product is available in the USA and a few other countries. A specific canarypox vectored recombinant product has also been used in wildlife and exotic species [bib_ref] Comparison of oral and intramuscular recombinant canine distemper vaccination in African wild..., Connolly [/bib_ref]. ## Precautions - The MLV preparations are attenuated (modified and safe) for use in the domestic dog, not for use in wild and exotic species. These vaccines are highly virulent (e.g. in the black-footed ferret and grey fox), causing disease and death [bib_ref] Fatal vaccine-induced canine distemper virus infection in black-footed ferrets, Carpenter [/bib_ref] [bib_ref] Vaccine-induced canine distemper virus in black-footed ferrets, Pearson [/bib_ref] [bib_ref] Vaccine-associated canine distemper infection in a litter of African hunting dogs (Lycaon..., Durchfeld [/bib_ref]. Vaccination of these species with MLV vaccines should not be performed unless there is evidence to support the safety of a specific product. - Puppies younger than 4-6 weeks of age should not be vaccinated with MLV vaccines. ## Disease facts - Signs of disease appear between 2-6 weeks after infection. - During the incubation period, CDV causes immunosuppression, making the animal more susceptible to microbial infections. These secondary infections may lead to respiratory disease, pneumonia and death, before the more typical signs of distemper virus infection appear. - In the environment, the virus quickly loses infectivity. ## Fact sheet: feline parvovirus (fpv) vaccines ## Types of vaccines available Modified Live Virus (MLV) Vaccines: These preparations contain attenuated (avirulent) feline parvovirus (feline panleukopenia virus) at various titres, without adjuvant. There are injectable preparations and others for intranasal application, in combination with other vaccinal antigens (e.g. FCV and FHV-1). MLV vaccines are advantageous for their faster onset of action, greater efficacy at overcoming maternal antibody and greater likelihood of conferring sufficient immunity [bib_ref] Feline panleukopenia virus, feline herpesvirus-1 and feline calicivirus antibody responses in seronegative..., Lappin [/bib_ref]. Intranasal FPV combination vaccines should not be used in the shelter environment or if used for FCV/FHV-1 immunity, they should be given simultaneously with an MLV-FPV parenteral product [bib_ref] A commentary on parvovirus vaccination, Schultz [/bib_ref]. Inactivated (Killed) Vaccines: Killed adjuvanted FPV vaccines are available; a single injected dose of some products may induce good antibody responses in naïve cats within a relatively short time span. However, all killed FPV products require two doses 2-4 weeks apart and immunity is present only after the second dose. Killed vaccines may be beneficial in wild and exotic species, pregnant queens or retrovirally-infected cats, where MLV vaccines are not recommended. ## Mechanisms and duration of immunity (doi) - DOI after natural infection/disease is life-long. - DOI after vaccination with MLV vaccines is 7 years or longer, based on challenge and serological studies. - DOI after vaccination with a killed panleukopenia vaccine was demonstrated to last for a minimum of 7.5 years [bib_ref] Long-term immunity in cats vaccinated with an inactivated trivalent vaccine, Scott [/bib_ref]. - While most cases of feline panleukopenia are caused by infection with FPV, variants of canine parvovirus (CPV-2a, CPV-2b and CPV-2c) have emerged that infect cats and may cause disease [bib_ref] Canine parvovirus -a review of epidemiological and diagnostic aspects with emphasis on..., Decaro [/bib_ref]. Certain current FPV vaccines afford some protection against these CPV variants. - Maternally derived antibody (MDA) interferes with active immunization for varying periods of time in the kitten, depending on the titre of colostral antibody and the amount of antibody absorbed during the first hours after birth. - The 'window of susceptibility' is defined as the period of time during which a kitten can be infected by field virus, but vaccines cannot immunize. By analogy with canine parvovirus, an immunity gap is assumed to exist, when antibody levels are too low to protect against natural infection, but still high enough to interfere with vaccination. ## E30 Journal of Small Animal Practice - Vol 57 - January 2016 - © 2016 WSAVA - After completing the kitten series at 16 weeks or older and vaccinating again at 26 or 52 weeks of age, revaccination need not be done more often than every 3 years. - The presence of serum antibody, regardless of titre, in an actively immunized cat over the age of 20 weeks is correlated with protection. - When vaccination is being used to control disease in the face of an outbreak in a shelter situation, the more rapid induction of immunity induced by MLV vaccines is of clinical advantage. - There is a very early onset of protection after vaccination with MLV products [bib_ref] Immunisation against panleukopenia: early development of immunity, Brun [/bib_ref]. ## Precautions - MLV FPV vaccines should not be used in wild animal species unless there is evidence to show that they are safe. - MLV FPV vaccines should never be used in pregnant queens because of the risk of transfer of virus to the fetus and fetal damage. In some countries, inactivated FPV vaccines are licensed for use in pregnant queens, but in general, unnecessary administration of products to pregnant queens should be avoided. - MLV FPV vaccines should never be administered to kittens less than 4-6 weeks of age, to avoid damage to the cerebellum which is still developing in neonates. - MLV FPV vaccines should not be used in severely immunosuppressed individuals -although the risk appears small, with severe immunosuppression (for example with clinical FIV or FeLV infection or with the use of highly immunosuppressive drugs) failure to control viral replication could potentially lead to clinical signs after vaccination. ## Disease facts - After infection, it takes 2-7 days for signs of disease to appear. - Vomiting usually develops 1-2 days after the onset of fever. Diarrhoea may begin later, but is not always present. Dehydration develops rapidly, and an affected cat may sit at a water bowl, obviously thirsty, but without drinking. Terminal cases are hypothermic and may develop septic shock and disseminated intravascular coagulation. - In the environment, the virus can remain infectious for 1 year or more [bib_ref] Canine parvovirus: environmental effects on infectivity, Gordon [/bib_ref] so all facilities where infected animals have been present must be considered contaminated. Mechanisms and Duration of Immunity (DOI) - Protection afforded by FHV-1 (as well as FCV) vaccines is not as complete as that seen with the FPV vaccines. The other two feline core vaccines (FHV-1 and FCV) should not be expected to provide the same robust degree and duration of immunity as seen with the canine core vaccines or FPV. - Assessment of the DOI is difficult. Complete clinical protection is seen only shortly after vaccination, and the degree of protection decreases with time [bib_ref] Feline herpesvirus, Gaskell [/bib_ref]. - Immunity is far from solid after natural infection/disease and is of variable duration. - Persistence of antibody titre after vaccination with a killed FHV-1 vaccine was demonstrated for 3 years [bib_ref] Duration of immunity in cats vaccinated with an inactivated feline panleukopenia, herpesvirus..., Scott [/bib_ref] , but antibody titre for FHV-1 does not correlate well with protection [bib_ref] Feline herpesvirus, Gaskell [/bib_ref]. - Protection from challenge with virulent FHV-1 7.5 years after vaccination with two doses of killed vaccines was not complete, but was similar to protection after 1 year with the killed product [bib_ref] Long-term immunity in cats vaccinated with an inactivated trivalent vaccine, Scott [/bib_ref]. - After completing the kitten series at 16 weeks or older and vaccinating again at 26 or 52 weeks of age, revaccination need not be done more often than every 3 years in cats at low risk; however, cats at higher risk (e.g. those that regularly attend boarding catteries) should be revaccinated more frequently. - If booster vaccinations have lapsed in a previously well-vaccinated cat, a single injection is considered adequate to boost immunological memory. - No herpesvirus vaccine can protect against infection with virulent virus; FHV-1 will become latent and may be reactivated during periods of severe stress. The reactivated virus may cause clinical signs in vaccinated animals [bib_ref] Feline herpesvirus, Gaskell [/bib_ref] ; the virus may be shed, transmitted to susceptible animals and cause disease in susceptible kittens and cats [bib_ref] Feline herpesvirus, Gaskell [/bib_ref]. ## E31 - Cell-mediated immunity plays an important role in protection, since the absence of detectable serum antibody levels in vaccinated cats does not necessarily indicate that cats are susceptible to disease. - MDA interferes with active immunization for varying periods of time in the kitten, depending on the titre of colostral antibody and the amount of antibody absorbed after birth. The primary course of vaccination is usually started at around 6-8 weeks of age. MDA interferes less with MLV intranasal (IN) vaccines than parenterally administered MLV products. It would be expected that the IN vaccines will immunize earlier than the parenteral vaccines in kittens with MDA. - In breeding catteries, infections mostly appear in kittens prior to weaning, typically between 4-8 weeks of age, as MDA wanes. In most cases, the source of infection is the queen, whose latent virus is reactivated due to the stress of parturition and lactation. ## Precautions - Modified live parenteral FHV-1 and FCV vaccines retain some pathogenic potential and may induce disease if administered incorrectly (i.e. when accidentally aerosolized or ingested or inhaled from vaccine deposited on the skin/hair). - Upper respiratory disease signs are sometimes seen following intranasal vaccination. ## Disease facts - Viral excretion starts as soon as 24 hours after infection and lasts for 1-3 weeks. - Acute disease appears after 2-6 days and resolves within 10-14 days. - The virus spreads along the sensory nerves and reaches neuronal cell bodies, particularly in the trigeminal ganglia, which are the main sites of latency. Most cats become lifelong latent carriers, shedding the virus periodically, upon stressful events [bib_ref] Feline herpesvirus, Gaskell [/bib_ref]. In contrast, shedding of FCV is continuous for a period of months after infection. Herpesvirus genomic DNA persists in the nucleus of infected neurons without replication. - In the environment, the virus is labile and inactivated by commonly used disinfectants. ## Mechanisms and duration of immunity (doi) - There is considerable antigenic variability amongst FCV strains. Prior infection with one strain can significantly reduce the acute clinical signs upon exposure to a heterologous strain, and also oral virus shedding. In general, the level of heterologous protection depends on the pair of virus strains examined. - Virus neutralizing antibodies first appear approximately 7 days after infection; their titre correlates well with protection against homologous challenge. Cats may also be protected in the absence of serum antibody, since local secretory IgA antibody and cellular responses have been demonstrated to provide protection in vaccinated cats. - After vaccination with a killed and adjuvanted FCV vaccine, antibody was shown to persist for at least 4 years [bib_ref] Duration of immunity in cats vaccinated with an inactivated feline panleukopenia, herpesvirus..., Scott [/bib_ref]. - Protection from challenge with virulent FCV 7.5 years after vaccination with two doses of killed adjuvanted vaccine was incomplete, but was similar to protection after 1 year with the killed product [bib_ref] Long-term immunity in cats vaccinated with an inactivated trivalent vaccine, Scott [/bib_ref]. - Protection afforded by FCV (as well as by FHV-1) vaccines is not as complete as that seen with the FPV vaccines. The two core respiratory vaccines should not be expected to provide the same robust degree and duration of immunity as seen with FPV or the canine core vaccines. Reinfection with FCV of differing strains is possible in vaccinated cats. - After completing the kitten series at 16 weeks or older and vaccinating again at 26 or 52 weeks of age, revaccination need not be done more often than every 3 years in cats at low risk; however, cats at higher risk (e.g. those that regularly attend boarding catteries) may be revaccinated more frequently. - It is recommended that vaccines that contain the same virus strains be used in the kitten series. - MDA is important for protection during the first weeks of life and may interfere with vaccination. The average half-life of MDA was determined to be 15 days with persistence for 10-14 weeks [bib_ref] Transfer and decline of maternal antibody to feline calicivirus, Johnson [/bib_ref]. In a field study, about 20% of kittens at 6 weeks of age had no detectable antibodies against a widely used vaccine strain [bib_ref] A field trial to assess the effect of vaccination against feline herpesvirus,..., Dawson [/bib_ref]. MDA interferes less with MLV given intranasally than with parenterally administered MLV products. It would be expected that the IN vaccines will immunize earlier than the parenteral vaccines in kittens with MDA. ## Precautions - Upper respiratory disease signs may be seen occasionally as a complication of intranasal vaccination [bib_ref] Effects of a single dose of an intranasal feline herpesvirus 1, calicivirus,..., Lappin [/bib_ref] [bib_ref] Feline panleukopenia virus, feline herpesvirus-1, and feline calicivirus antibody responses in seronegative..., Lappin [/bib_ref]. - Because of the multitude of antigenically differing viruses circulating in the field, vaccine strain combinations have been chosen to cross-protect against severe clinical disease, but mild disease may still occur in vaccinated cats. - In contrast to FHV-1, which is shed intermittently after stressful events, shedding of FCV is continuous, but usually ceases after several months [bib_ref] Long-term analysis of feline calicivirus prevalence and viral shedding patterns in naturally..., Coyne [/bib_ref]. The impact of vaccination on shedding is controversial, with observations ranging from moderate reduction to extension of the period of virus shedding post infection. Live parenteral FCV vaccine strains can be shed, although infrequently. ## Disease facts - FCV infection can cause acute oral and upper respiratory signs, but has also been associated with chronic gingivostomatitis, which may be immune-mediated. - The incubation period is 2-10 days. Oral ulceration (particularly of the margins of the tongue), sneezing and serous nasal discharge are the main signs. Acute oral and upper respiratory disease signs are mainly seen in kittens. - A distinct syndrome, the 'virulent systemic feline calicivirus (VS-FCV) disease' is occasionally described [bib_ref] Lethal outbreak of disease associated with feline calicivirus infection in cats, Coyne [/bib_ref]. The incubation period for this infection in cats exposed in shelters and hospitals is 1-5 days; in the home environment it may be up to 12 days. This disease appears to be more severe in adults than kittens. Vaccination with current vaccines does not protect cats against field infections, but some protection has been shown experimentally [bib_ref] Efficacy of a bivalent inactivated non-adjuvanted feline calicivirus vaccine: relation between in..., Poulet [/bib_ref] [bib_ref] A dual-strain feline calicivirus vaccine stimulates broader cross-neutralization antibodies than a single-strain..., Huang [/bib_ref]. This might be due to the inherent characteristics of the hypervirulent strains. There is a killed VS-FCV strain in a vaccine available in the USA that contains both 'traditional' and VS-FCV isolates and is reported to provide protection against homologous VS-FCV [bib_ref] A dual-strain feline calicivirus vaccine stimulates broader cross-neutralization antibodies than a single-strain..., Huang [/bib_ref]. It is not known if this strain of VS-FCV will provide protection against heterologous VS-FCV strains. ## Fact sheet: rabies vaccines ## Inactivated (killed) vaccines: The use of killed vaccines is the rule for individual dog and cat protection and mass canine vaccination programmes. The killed vaccines are easier to manage than live preparations because of their stability at ambient temperatures, and accidents of self-inoculation do not represent a risk, as would be the case for MLV vaccines. ## Mechanisms and duration of immunity (doi) - Canine and feline rabies is controlled mostly by the use of inactivated vaccines. However, in the USA and Europe recombinant canary pox vectored rabies vaccine is licensed and widely used in cats because it is not associated with the inflammation at the injection site caused by adjuvanted rabies vaccines ). All initial rabies vaccinations must be followed 1 year later by revaccination. Only after that second vaccination can the interval for revaccination be extended legally to 3 years with a product that has a 3-year DOI label. - DOI after natural infection cannot be assessed, because disease following street virus infection is fatal in the dog and cat. - DOI after vaccination with commercially available inactivated and recombinant products is 3 years, based on challenge and serological studies [bib_ref] Three-year duration of immunity in cats vaccinated with a canarypox-vectored recombinant rabies..., Jas [/bib_ref]. - First vaccination is not earlier than 12 weeks of age with revaccination 1 year later; antibody titres generally reach protective levels 4 weeks after vaccination. Where serological testing is required for legal purposes the interval between vaccination and testing is crucial and may be product-dependent. The product datasheet and legal requirements should be consulted. - Some vaccines are proven to protect against virulent rabies virus challenge for 3 years, but national or local legislation may call for annual boosters. The VGG encourages all legislators to consider scientific advances when formulating policy. Some vaccines (e.g. nationally produced products) may not reliably protect for more than 1 year. - The presence of serum antibody of ≥0.5 IU/ml in an actively immunized dog over the age of 16 weeks is correlated with protection. Achieving this concentration (≥0.5 IU/ml) is also considered a legal requirement for pet travel to some countries which include serological testing post-vaccination in their protocol for movement of pets. Disease Facts - Signs of disease appear between 2 weeks and several months after infection, depending upon the site of infection (transmission is generally by bite or scratch). Any unexplained aggressive behaviour or sudden behavioural change must be considered suspicious. - The disease manifests itself as a 'furious' or a 'dumb' form. Signs of the classical 'furious' form of rabies include reduced palpebral, corneal and pupillary reflexes, strabismus, dropped jaw, salivation, pica, seizures, twitching, tremors, disorientation, aimless pacing, aimless snapping and biting, exaggerated emotional responses (irritability, rage, fear), photophobia, as well as ataxia and paralysis, ultimately followed by coma and death from respiratory arrest. The 'dumb' form of rabies is more common in dogs than cats and presents as lower motor neuron paralysis that progresses from the site of the bite injury to involve the entire central nervous system. The paralysis rapidly leads to coma and death from respiratory failure. - In the environment, the virus quickly loses infectivity, and is readily inactivated using detergent-based disinfectants. ## Frequently asked questions (faqs) QUESTIONS RELATED TO VACCINE PRODUCTS 1. May I give a MLV product to a wild, exotic species or to a domestic species other than to the ones which the vaccine was licensed to protect? No, never give MLV vaccines unless they have been shown to be safe in that species. Many MLV vaccines have caused disease in animal species other than those for which they had been licensed. Even worse, the vaccine could be shed from the wild animals, regain virulence through multiple passages and cause disease even in the target species for which it had been developed. A safe and effective vaccine for species that are susceptible to CDV is the canarypox virus-vectored recombinant CDV vaccine that is available as a monovalent product for ferrets or a combination product for dogs. The monovalent vaccine is used in many wild and exotic species susceptible to CDV, but is only available in certain countries. ## May i vaccinate a puppy that is at high risk of getting cdv with a human measles vaccine? No. Due to an insufficient amount of virus, the human MV vaccine is not immunogenic in the puppy. Measles virus vaccines made specifically for the dog (sometimes combined with CDV and additional viral components) may give temporary protection at an earlier age than a CDV vaccine. At 16 weeks or older, the puppy must be vaccinated with a CDV vaccine, to achieve permanent immunity. ## Can certain vaccines immunize pups having maternally derived antibody (mda) against cdv at an earlier age? Yes. The heterotypic measles vaccine for dogs will immunize pups about 4 weeks earlier than the MLV-CDV vaccines. Similarly, the canarypox vectored recombinant CDV vaccine will immunize approximately 4 weeks earlier than some MLV vaccines and there are some high titre MLV vaccines (i.e. vaccines containing a greater mass of virus in the vaccine ampoule) which also immunize at an earlier age in puppies with MDA. ## I know that maternally derived antibodies (mda) can prevent active immunization with mlv vaccines -but can they also block immunity to killed vaccines? Yes. MDA can block certain killed vaccines. If the killed product requires two doses, as is often the case, and the first dose is blocked by MDA, then the second dose will not immunize. In this circumstance, the second dose will prime (if not blocked), and a third dose is required to immunize and boost. This is not true for MLV vaccines, where in the absence of MDA it only takes a single dose to prime, immunize, and boost. Nevertheless two doses are often recommended, particularly in young animals, to be sure one is given when MDA has waned and cannot block. That is why in the puppy or kitten series, the last dose should be given at 16 weeks of age or older. 5. I have been told that certain canine MLV combination core products need only be given twice, with the last dose at an age as young as 10 weeks. Is that accurate? The VGG is aware that certain canine vaccines are licensed for such an 'early finish' in order to allow pups the benefit of early socialization. The VGG accepts the importance of puppy socialization, but has reservations about the immunological validity of this approach to vaccination. No combination core product currently available will immunize an acceptable percentage of puppies (particularly not against CPV-2) when the last dose is given at 10 weeks of age. The VGG advises that wherever possible the last dose should be given at 16 weeks of age or older, regardless of the number of doses given earlier. The VGG recommends that owners of pups that have not completed a full puppy vaccination series carefully control the exposure of their pup to environments outside of the home and only permit contact with healthy and fully vaccinated dogs. ## For how long can a reconstituted mlv vaccine sit at room temperature without losing activity? At room temperature, some of the more sensitive vaccines (e.g. CDV, FHV-1) will lose their ability to immunize in 2-3 hours, whereas other components will remain immunogenic for several days (e.g. CPV, FPV). The VGG recommends that MLV vaccines, after reconstitution, should be used within 1 to 2 hrs. ## 67. If an animal has gone beyond the time that is generally considered to be the minimum DOI for the core vaccine (7 to 9 years for CDV, CPV-2, CAV-2; 7 years for FPV), do I have to start the series of vaccinations again (multiple doses 2-4 weeks apart)? No. For MLV vaccines, multiple doses are only required for puppies or kittens which have MDA. The VGG is aware that many data sheets do advise re-starting a vaccination series, but does not endorse this practice which is inconsistent with fundamental immune system function and the principles of immunological memory. ## Should i vaccinate a cat infected with felv and/or fiv infection? A FeLV or FIV positive cat that is clinically well would ideally be housed indoors away from other cats to minimize the risk of exposure to infectious disease. However, if it were deemed necessary to vaccinate with core components (FPV, FCV and FHV-1) expert groups currently recommend that this should be with killed (not MLV) vaccines. Such cats should not be vaccinated against FeLV or FIV. A FeLV or FIV positive cat with clinical illness should not be vaccinated. In some countries there is a legal requirement for rabies vaccination that would also include retrovirus-infected cats. ## Where should i inject vaccine into a cat? Feline vaccines (particularly adjuvanted products) should not be given into the inter-scapular region. In the USA the practice of giving separate injections of rabies vaccine into the distal right hind limb, FeLV vaccine into the distal left hind limb and core FPV/FCV/ FHV-1 vaccines into a distal forelimb is practiced. Alternative sites for subcutaneous injection are into the distal tail or over the lateral thoracic or abdominal wall. These options are discussed further in the main text of this document. Whichever site is chosen, the vaccine must be administered subcutaneously and not intramuscularly. Importantly, the anatomical site of feline vaccination should be rotated so that vaccines are not given repeatedly to one location. This may be achieved by recording the site of vaccination for each individual on each occasion and rotating between these, or by adopting a practice policy to use one anatomical location each year. ## Does severe nutritional deficiency affect the immune response to vaccines? Yes. It has been shown that certain severe deficiencies of vitamins and trace minerals (e.g. Vitamin E/Selenium) can interfere with the development of a protective immune response in puppies. Known or suspected nutritional deficiencies should be corrected by appropriate nutritional supplementation and the animals should be revaccinated to ensure there is adequate protective immunity. ## If a puppy or kitten fails to receive colostrum will it have any passive antibody protection from the dam? Depending on the antibody titre of the dam they will have little or, most likely, no protection as approximately 95% or more of the passive antibody for the newborn puppy and kitten is obtained from the colostrum which is absorbed via the intestine into systemic circulation for up to 24 hours after birth. 72. Should a puppy or kitten that fails to receive colostrum be vaccinated during the first few weeks of life since they will not have maternally derived antibody to block active immunization? No. Puppies and kittens less than 4-6 weeks of age should not be vaccinated with the MLV core vaccines. Certain of the modified live vaccine viruses when given to puppies/kittens less than 2 weeks of age and without MDA can infect the central nervous system and/or cause disease and possibly death of the animal. This occurs because there is little or no thermoregulatory control of body temperature during the first week or more after birth, thus innate and adaptive immunity is significantly impaired. ## How can these colostrum-deprived young animals be protected from the core diseases? Artificial colostrum can be fed if the puppy or kitten is less than 1 day old. Artificial colostrum is 50% milk replacer (e.g. Esbilac TM or other similar product) and 50% immune serum (preferably from the dam or other well vaccinated animal living in the same environment as the dam). If pups or kittens are older and 1 day of age, serum from a well immunized adult animal (free of infectious disease) can be given subcutaneously or intraperitoneally or citrated plasma can be given intravenously. Depending on size of the animal, approximately 3 to 10 ml of serum or plasma should be administered twice daily for up to 3 days. ## At what age can one stop vaccinating dogs? For core vaccines, the current recommendation is for lifelong revaccination no more frequently than every 3 years and if non-core vaccines are chosen for use, these are generally given annually. One can use serological testing in any adult dog to confirm protection Journal of Small Animal Practice - Vol 57 - January 2016 - © 2016 WSAVA E41 against core diseases (i.e. CDV, CAV and CPV-2) and elect not to revaccinate that animal. Current advice is that serological assessment is performed every 3 years, but in dogs older than 10 years, this should be done annually. In many countries there is also a legal requirement to vaccinate against rabies at particular intervals. ## What protocol is recommended for an unvaccinated adult dog? Core vaccination with a single dose of MLV vaccine (CDV, CAV-2, CPV-2) plus rabies in endemic areas. There is no need to give two doses. Revaccination (or serological testing for CDV, CAV and CPV-2) no more frequently than every 3 years thereafter. Non-core vaccines should be selected based on a risk:benefit analysis for that individual animal. Non-core vaccines would require two doses given 2-4 weeks apart and then an annual booster. ## For an adult dog with an unknown leptospira vaccination history, what's the recommended vaccination protocol? is it still two doses 2-4 weeks apart as in puppies? Yes, this dog would require two doses of vaccine given 2-4 weeks apart and then annual revaccination thereafter. ## What protocol is recommended for an unvaccinated adult cat? For an adult cat that has never been vaccinated, the VGG recommends core vaccination with two doses of MLV vaccine (FPV, FCV, FHV-1) plus one dose of rabies vaccine in endemic areas. Revaccination (or serological testing for FPV) no more frequently than every thereafter for a low-risk cat, or revaccination no more frequently than every 3 years for FPV and annually for FHV-1 and FCV for a high-risk cat. Non-core vaccines should be selected based on a risk:benefit analysis for that individual animal. ## Should a cat be vaccinated if it already has signs of upper respiratory disease? A cat with current clinical disease should not be vaccinated. Once it has recovered, the cat should have some natural immunity to FCV or FHV (or both if both agents were involved in causing the respiratory disease), but such immunity is never sterilizing (even after vaccination). There is no indication NOT to vaccinate a cat that has recovered from a respiratory viral infection. A trivalent vaccine will protect against FPV and also against the respiratory virus (FHV-1 or FCV) that was not involved in causing the earlier respiratory disease. 79. Power cuts are not uncommon in parts of our country and they can last for 2-3 days. What should one do as regards any vaccine in the fridge at the time -is it OK to use? MLV vaccine that has not been stored at appropriate temperature for 2-3 days should not be used. Some of the components of these vaccines (e.g. CDV) are temperature sensitive and there may have been inactivation of the virus. If you are in any doubt, you should contact the manufacturer for advice. ## Questions about the use of serological testing ## Are serum antibody titres useful in determining vaccine-induced immunity? Yes. This is particularly the case for CDV, CPV-2 and CAV-1 in the dog, FPV in the cat and (for legal purposes) rabies virus in the cat and dog. Serum antibody titres are of limited or no value for the other vaccines. Assays for CMI are of little or no value for any of the vaccines for various technical and biological reasons. Such factors are less of an issue for serological tests where it is much easier to control many of the variables. However, discrepant results are still obtained, depending on the quality assurance program of the given laboratory. ## How long after cpv-2/cdv vaccination should you wait before measuring protective antibody concentrations using inclinic tests? This question is most relevant for puppies, because adult dogs are likely already to have serum antibodies present at the time of booster vaccination, regardless of how long an interval there has been since they were last vaccinated. If a puppy receives its final primary vaccine at 16 weeks of age, then it may be tested from 20 weeks of age onwards. Any antibody present at that stage cannot be of passive, maternal origin and therefore indicates that the puppy is actively protected. ## Why don't the vgg recommend routine rabies antibody testing? For many veterinarians, this question may be of little practical consequence, as regular rabies vaccination of dogs and cats is a legal requirement in many countries, irrespective of any titre results. Rabies antibody testing is only required in certain situations related to international pet travel. The international rabies vaccines are highly efficacious and it is generally considered that there is no need to demonstrate immunity post vaccination. [fig] FACT: SHEET: FELINE HERPESVIRUS (FHV)-1 VACCINES Types of Vaccines Available Modified Live Virus (MLV) Vaccines: These preparations contain attenuated FHV-1 (feline rhinotracheitis virus, occurring as a single serotype) at various titres, without adjuvant. There are injectable preparations and others for intranasal application, alone or in combination with other vaccinal antigens (always with FCV). Inactivated (Killed) Vaccines: Adjuvanted killed vaccines are available. [/fig] [table] E17 Table 1: Journal of Small Animal Practice • Vol 57 • January 2016 • © 2016 WSAVA WSAVA Canine Vaccination Guidelines Non-core. Use of CPiV (MLV-intranasal) is preferred to the parenteral product as the primary site of infection is the upper respiratory tract. [/table] [table] Table 2: Where the recommendations in this table are not consistent with those on datasheets [EB2] the level of evidence supporting the recommendation is given.The VGG did not consider the following products that have restricted geographical availability: Crotalus atrox (western rattlesnake vaccine) and Crotalux adamanteus (eastern rattlesnake vaccine) -Conditional USDA License Babesia vaccine (soluble parasite antigen from B. canis in saponin) -EU Licensed Canine herpesvirus vaccine -EU Licensed Leishmania vaccines -licensed in Brazil and the EU WSAVA Guidelines on Canine Vaccination for the Shelter Environment Intranasal or oral vaccine is strongly recommended in the shelter situation. Intranasal or oral vaccines MUST NOT be administered parenterally as this may lead to severe adverse reactions or death. [/table] [table] Table 3: WSAVA Feline Vaccination Guidelines Core. Only FeLV-negative cats should be vaccinated. FeLV testing must be performed prior to vaccine administration to avoid unnecessary administration of vaccine. Core. Only FeLV-negative cats should be vaccinated. FeLV testing must be performed prior to vaccine administration Journal of Small Animal Practice • Vol 57 • January 2016 • © 2016 WSAVA Core. Vaccination is most appropriately used as part of a control regime for animals in multicat environments where infections associated with clinical disease have been confirmed. Inadvertent conjunctival inoculation of vaccine has been reported to cause clinical signs of infection. Where the recommendations in this table are not consistent with those on datasheets [EB2] the level of evidence supporting the recommendation is given. [/table] [table] Table 4: WSAVA Guidelines on Feline Vaccination for the Shelter Environment [/table] [table] Table 5: weeks, 13 weeks, 17 weeks then 26 or 52 weeks [/table] [table] Table 7: Use of Serological Testing in a Shelter Infectious Disease Outbreak [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/jsap.2_12431	None
a53534f547301a4339304341f349f2a9f364ba4e	pubmed	Telehealth in rheumatology: the 2021 Arab League of Rheumatology Best Practice Guidelines	Telehealth in rheumatology: the 2021 Arab League of Rheumatology Best Practice Guidelines To develop Best Practice Guidelines (BPG) for the use of Telehealth in Rheumatology in the Arab region, to identify the main barriers and facilitators of telehealth, and to provide rheumatologists with a practical toolkit for the implementation of telehealth. Guidelines were drafted by a core steering committee from the Arab League of Associations for Rheumatology (ArLAR) after performing a literature search. A multidisciplinary task force (TF), including 18 rheumatologists, 2 patients, and 2 regulators from 15 Arab countries, assessed the BPG using 3 rounds of anonymous online voting by modified Delphi process. The statements were included in the final BPG without further voting if ≥ 80% of TF members indicated high agreement. The voting on barriers and facilitators was performed through one voting round. The toolkit was developed based on available literature and discussions during the Delphi rounds. Four General Principles and twelve Statements were formulated. A teleconsultation was specifically defined for the purpose of these guidelines. The concept of choice in telehealth was highlighted, emphasizing patient confidentiality, medical information security, rheumatologist's clinical judgment, and local jurisdictional regulations. The top barrier for telehealth was the concern about the quality of care. The toolkit emphasized technical aspects of teleconsultation and proposed a triage system. The ArLAR BPG provide rheumatologists with a series of strategies about the most reliable, productive, and rational approaches to apply telehealth. # Introduction Telehealth services were projected to light with the emergence of the Coronavirus Disease 19 pandemic in 2020, as the demand for telehealth largely exceeded the supply [bib_ref] Impact of COVID-19 on vulnerable patients with rheumatic disease: results of a..., Mehta [/bib_ref] [bib_ref] Influence of COVID-19 pandemic on decisions for the management of people with..., Dejaco [/bib_ref] [bib_ref] Impact of the COVID-19 pandemic on patients with chronic rheumatic diseases: a..., Ziadé [/bib_ref]. Even though this high demand may decline once the pandemic has ended, the need for telehealth services will most likely persist in the future. The clinical applications of telehealth are diverse. It is currently available in various settings, including emergency departments, inpatient hospital wards, intensive care units, and pharmacies [bib_ref] Barriers and facilitators to the implementation of eHealth services: systematic literature analysis, Schreiweis [/bib_ref]. In addition, significant advancements in technology have established telehealth as a feasible option for managing patients with rheumatic diseases. Studies indicate how the use of telerheumatology in certain settings has successfully increased patient access to specialty care, with good patient and provider satisfaction [bib_ref] Telemedicine in pediatric rheumatology: this is the time for the community to..., Shenoi [/bib_ref] [bib_ref] Telerheumatology: a technology appropriate for virtually all, Kulcsar [/bib_ref]. Surveys were conducted by the Arab League of Associations for Rheumatology (ArLAR) to study the impact of the COVID-19 pandemic on patients with chronic rheumatic diseases and on rheumatologists in 16 Arab countries. These surveys identified telehealth as a significant unmet need in patient management [bib_ref] Impact of the COVID-19 pandemic on patients with chronic rheumatic diseases: a..., Ziadé [/bib_ref] [bib_ref] The impact of COVID-19 pandemic on rheumatology practice: a cross-sectional multinational study, Ziadé [/bib_ref]. The successful implementation of telehealth can assist rheumatologists in providing continuity of care for patients who face obstacles that restrict their access to in-person treatment. However, the lack of a structural framework for telerheumatology has been identified as a barrier to the effective implementation of telehealth in the rheumatology clinic [bib_ref] Acceptance of telerheumatology by rheumatologists and general practitioners in Germany: Nationwide cross-sectional..., Muehlensiepen [/bib_ref]. Best Practice Guidelines (BPG) for telerheumatology can provide the necessary framework to facilitate teleconsultation as they add credibility, standardize approaches, decrease liability and facilitate reimbursement of this novel health service. Nevertheless, BPG for performing telehealth services in rheumatology (and practical advice for their implementation) are lacking. The primary objective of this study was to develop BPG for the use of Telehealth In RheumatOLogy (TIROL study) in the Arab region. The secondary objectives were to identify the main barriers to telehealth and the key facilitators of telehealth in the ArLAR countries, and to provide rheumatologists with a practical toolkit for the implementation of telehealth services in the rheumatology clinic. # Methods The BPG were developed under the umbrella of the ArLAR, in line with the Appraisal of Guidelines for REsearch & Evaluation (AGREE II) instrument [bib_ref] AGREE II: Advancing guideline development, reporting and evaluation in health care, Brouwers [/bib_ref]. A core steering committee (SC), comprising of seven authors, performed a computerized literature search of four sources that were available in the central study site (PubMED, American College of Rheumatology (ACR), American Telemedicine Association, and World Health Organization websites) to identify available guidelines and studies using keywords "telerheumatology", "telemedicine" and "guidelines". The literature search was conducted in November 2020, covered articles published in the English language, between 2001 and 2020, and identified 1494 potentially eligible studies [fig_ref] Figure 1: Study [/fig_ref]. Of these, 50 relevant articles were included. Information from these articles provided guidance in formulating the guideline statements. Based on the available published rheumatology guidelines (as well as those in other specialties), general principles (GP) and best practice statements (BPS) were drafted by two authors (NZ and MD). Four GPs and 12 BPS were formulated; levels of evidence were indicated according to the Oxford Centre for Evidence-Based Medicine. The draft was validated by the core SC and reviewed and edited by the ArLAR scientific committee, a law firm advisor, and an ACR telemedicine expert. Thereafter, a multidisciplinary task force (TF) (representing 16 Arab countries) comprising of 18 rheumatologists (16 from the Arab Adult Arthritis Awareness (AAAA) group, a special interest group from ArLAR and two ArLAR advisors), two patients with rheumatic diseases), two regulators/ payers (one from the public sector and the other from the private sector) convened online to assess the BPG using three rounds of voting by a modified Delphi process (www. calib rum. com) [fig_ref] Figure 1: Study [/fig_ref]. The levels of evidence and the decision rules were explained to the TF during a briefing meeting 2 weeks prior to the first round of voting. Taskforce members reported their level of agreement during each round of voting using a numerical rating scale:one (complete disagreement) to nine (complete agreement). Participants were able to give qualitative comments. Revisions to the GP and BPS were made by the SC through an iterative process until consensus was reached. The criteria for moving from one Delphi round to another, and for selecting the final statement, were guided by the OMERACT recommendations. GP and BPS were included in the final BPG without further voting if ≥ 80% of TF members indicated high agreement [bib_ref] Acceptance of telerheumatology by rheumatologists and general practitioners in Germany: Nationwide cross-sectional..., Muehlensiepen [/bib_ref]. All GP and BPS that scored ≥ 50% high agreement [bib_ref] Acceptance of telerheumatology by rheumatologists and general practitioners in Germany: Nationwide cross-sectional..., Muehlensiepen [/bib_ref] and ≤ 15% low agreement [bib_ref] Influence of COVID-19 pandemic on decisions for the management of people with..., Dejaco [/bib_ref] [bib_ref] Impact of the COVID-19 pandemic on patients with chronic rheumatic diseases: a..., Ziadé [/bib_ref] and all items that required rephrasing were included in the next round of voting. The criteria to select a GP and BPS in the final round were ≥ 70% high agreement (7-9) and ≤ 15% low agreement (1-3). All of the 22 TF members participated in each of the 3 rounds of voting. All votes were anonymous and weighted equally. Information from the literature review supported the SC in identifying the main physician and patient-related barriers to telehealth and the key facilitators. These items were adapted to the Arab region and formulated into short statements. Before evaluating the BPG, TF members were asked to rank the barriers and facilitators of telerheumatology in the Arab region from one (most important barrier or facilitator) to five (least important barrier or facilitator). One round of anonymous voting on barriers and facilitators was conducted through the Surveylet platform. Based on the literature review and discussions with the TF during the voting rounds, the SC proposed a practical toolkit for the possible implementation of telehealth services in the rheumatology clinic. # Results The final BPG are presented in [fig_ref] Table 1: General principles and best practice guidelines statements for telehealth in rheumatology ... [/fig_ref] , with the accompanying level of evidence (LoE), consensus, and agreement (LoA) for each round of voting. All GP and BPS reached ≥ 80% consensus by the end of the third round (Supplementary [fig_ref] Table 1: General principles and best practice guidelines statements for telehealth in rheumatology ... [/fig_ref]. ## General principles General principle A: definition of a teleconsultation (LoE 5; LoA 8.14; Consensus 100%) Adapted from the American Telemedicine Association's definition of "telemedicine" [bib_ref] Barriers and facilitators to the implementation of eHealth services: systematic literature analysis, Schreiweis [/bib_ref] ] the definition of a teleconsultation was established specifically for these guidelines as: "A rheumatology teleconsultation is a synchronous exchange of medical information between a patient and a rheumatologist via audio or audiovisual electronic communication, to improve the patient's health status", where "medical information" includes medical history, physical exam, review of test results and the final prescription and "synchronous" refers to a real-time exchange between the patient and the physician via video, audio or text [bib_ref] Telerheumatology: a systematic review, Mcdougall [/bib_ref]. The TF is aware that the definition of teleconsultation may vary in each country. Notably, teleconsultation is differentiated from e-consultation, which is an exchange of medical information between two healthcare providers via electronic audiovisual communication to improve a patient's health status. Therefore, e-consultations are not within the scope of the current BPG. Telehealth may improve the access and continuity of care for patients with rheumatic diseases who are home-bound, live in remote areas or under-served communities, or who need to adhere to social distancing restrictions This principle is supported by the ACR Position statement on telemedicineand is especially true in the era of COVID-19. Studies have shown that measures related to the containment of the COVID-19 pandemic, like national lockdowns and social distancing restrictions, led to a perceived delay between symptom onset and a first rheumatological visit [bib_ref] Influence of COVID-19 pandemic on decisions for the management of people with..., Dejaco [/bib_ref]. Several international surveys also found that, during the COVID-19 pandemic, 10% to 25% of patients with rheumatic diseases stopped their chronic medication, thus compromising the treat-to-target strategies. This emphasizes the need for an alternative to in-clinic visits [bib_ref] Impact of COVID-19 on vulnerable patients with rheumatic disease: results of a..., Mehta [/bib_ref] [bib_ref] Influence of COVID-19 pandemic on decisions for the management of people with..., Dejaco [/bib_ref] [bib_ref] Impact of the COVID-19 pandemic on patients with chronic rheumatic diseases: a..., Ziadé [/bib_ref] [bib_ref] Biologics, spondylitis and COVID-19, Rosenbaum [/bib_ref]. This principle is also supported by the results from a survey conducted with 75 rheumatologists in the Netherlands during the COVID-19 pandemic, which found that continuity of care was guaranteed through telephone and video consultations by 99% and 9% of the respondents, respectively [bib_ref] Telemedicine for patients with rheumatic and musculoskeletal diseases during the COVID-19 pandemic;..., Bos [/bib_ref]. Another survey conducted with 426 established patients and 74 physicians found that virtual video visits (VVVs) were vastly preferred to office visits by patients for convenience and travel time, while the majority (52.5%) of clinicians reported higher efficiency of a VVV appointment [bib_ref] Patient and clinician experiences with telehealth for patient follow-up care, Donelan [/bib_ref]. General principle C: Improving disease outcomes (LoE 2; LoA 7.86; Consensus 86.36%) Telehealth can help some patients adhere to the management plan, and this is likely to improve disease outcomes in some selected disease states Using a proper triage system for telehealth in rheumatology, early detection and early referral may improve disease outcomes, especially in diseases like rheumatoid arthritis (RA) where there is a limited window of opportunity for early management. By facilitating the application of the treat-to-target strategy in RA and other chronic diseases (e.g., gout), telehealth is likely to support adherence to therapy and maintaining treatment tar- gets [bib_ref] Telerheumatology: a technology appropriate for virtually all, Kulcsar [/bib_ref] [bib_ref] Telerheumatology: an idea whose time has come, Roberts [/bib_ref]. However, higher-quality randomized controlled trials are needed to demonstrate the effectiveness of different telerheumatology interventions in improving disease outcomes [bib_ref] Telemedicine for patients with rheumatic diseases: systematic review and proposal for research..., Piga [/bib_ref]. General principle D: Quality of medical care (LoE 5; LoA 8.14; Consensus 95.45%) Rheumatologists need to use professional experience and judgement to assess whether telehealth is suitable in each situation Rheumatologists should use their judgement to decide whether a teleconsultation is appropriate in each case. They should ensure that the quality of care provided remotely via telehealth services is consistent with related in-person services while ensuring that the provided services are in alignment with the local laws and regulations where the rheumatologist is based. A guide for a triage system is proposed in the Toolkit section of this document [fig_ref] BPS 2: Confidentiality [/fig_ref] Before the teleconsultation visit, an informed consent should be obtained from the patient, in writing or verbally; it should include an explanation, in a simple language, of the benefits and risks of telehealth encounters, as well as the conditions under which telehealth services may be terminated and a referral made to in-person care Some tel-ehealth providers may argue that when a patient electively chooses to visit a physician (whether it is a face-to-face visit or a teleconsultation) there is inherent informed consent and that official informed consent would only be required where the patient needs to undergo a procedure, or where patients are included in research trials. However, it should be emphasized that teleconsultation is a novel way of engaging with patients, and patients should be appropriately informed about the limitations and drawbacks of telehealth (e.g., misdiagnosis). The information provided to the patient should include the nature of the telehealth encounter, including any technical limitations or potential for disruption and contingency plans, the protection of patient identifiable information, and billing information(if appropriate). The patient should also be informed that there may be a possibility of the physician requesting the patient to attend an in-person visit where the physician considers such a visit to be more appropriate. The patient should be informed that they may withdraw consent from telehealth services at any point (before, during, or after the teleconsultation). While the standards and requirements of informed patient consent may vary depending on the jurisdiction, it is recommended to keep electronic records of informed consent. both the patient's and the provider's environment. Unless both parties explicitly agree upon it, the teleconsultation should not be recorded, neither by the patient nor by the physician. ## Bps 3: documentation (loe 5; loa 8.77; consensus 100%) The provision of telehealth services should be well documented in the patient's file, similarly to any in-person medical visit. The decision to assess the patient remotely should be justified and recorded in the patient's file It is recommended that providers of telehealth services have access to the patient's medical records, especially when the patient is unknown to them. Furthermore, the reasoning behind whether or not to assess the patient via teleconsultation should be clearly documented, and the patient's records should be updated accordingly [bib_ref] The rules for online clinical engagement in the COVID era, Howgego [/bib_ref]. ## Bps 4: shared decision and choice (loe 5; loa 8.36; consensus 100%) ## The choice of using telehealth services should be based on a shared decision between the patient and the physician. patients should have a choice of their provider of medical teleconsultation The patients should be allowed to choose whether or not they want to engage with their rheumatologist via teleconsultation, and to choose their telehealth provider without payers mandating the use of specified telehealth platforms or preferred providers with restrictive policies. Some parts of the physical exam might be performed remotely, e.g., inspection and evaluation of the range of motion. The patient should be instructed on how to be prepared for a remote physical exam using appropriate educational material Physical examination is one of the pillars of medical reasoning in rheumatology; the inability to examine a patient might be viewed as a major obstacle. While physical attendance of the patient is preferable in some cases (e.g., a patient's first consultation where an accurate examination and diagnosis is essential) some parts of the physical exam might be performed via teleconsultation and can be facilitated by the appropriate instructions to the patient with regards to what clothing to wear, the position of the camera, and the proper use of furniture. In some instances, assistance from a proxy person (e.g., a family member) can be requested for the physical exam. Physicians can also send a brochure or video tutorial regarding the maneuvers that will be performed for the physical examination to the patient, before the teleconsultation [bib_ref] Development of an educational video for self-assessment of patients with RA: steps,..., Ziade [/bib_ref] [bib_ref] The telemedicine musculoskeletal examination, Laskowski [/bib_ref] [bib_ref] Is self-assessment by patients of disease activity acceptable over the long term..., Gossec [/bib_ref] [bib_ref] Self-assessment of 28-joint disease activity scores by patients with rheumatoid arthritis on..., Shaffu [/bib_ref] [bib_ref] Telemedicine during COVID-19 and beyond: a practical guide and best practices multidisciplinary..., Wahezi [/bib_ref]. It is recommended to translate and validate such tutorials in Arabic, with adaptation to local dialects where appropriate [bib_ref] Development of an educational video for self-assessment of patients with RA: steps,..., Ziade [/bib_ref] [bib_ref] Perceptions of patients with rheumatoid arthritis about self-assessment of disease activity after..., Ziadé [/bib_ref]. ## Bps 6: patient-reported outcomes (loe 3; loa 7.73; consensus 100%) In some chronic rheumatic diseases, the use of patient-reported outcomes (PROs) by means of self-completed questionnaires adapted for telehealth can help the physician make informed clinical decisions and improve the quality of care In patients with an established disease, such as RA and spondyloarthritis, disease activity and functional status measures can be assessed before the teleconsultation using self-completed questionnaires of PROs [bib_ref] Brief report: adaptation of american college of rheumatology rheumatoid arthritis disease activity..., England [/bib_ref] [bib_ref] Adopting PROs in virtual and outpatient management of RA, Taylor [/bib_ref]. Studies have shown that among RA patients with low disease activity (LDA) or remission, a PROs-based telehealth follow-up for tight control of disease activity in RA can achieve similar disease control as a conventional outpatient follow-up [bib_ref] A tele-health follow-up strategy for tight control of disease activity in rheumatoid..., De Thurah [/bib_ref]. RA Impact of Disease (RAID) score, in particular, has been shown to function well as a PRO in routine care, where patients with RAID < 2 have a high likelihood of being in remission/ LDA (as per the disease activity score) and, if pre-screened, could avoid a clinic visit [bib_ref] Use of rheumatoid arthritis impact of disease (RAID) in routine care; identification..., Mistry [/bib_ref]. However, the validity of PROs measures needs to be evaluated in dedicated studies. In addition, several PROs measures should be translated and validated in Arabic and adapted to the cultural level of the patient where possible. The prescription should be transmitted in a safe and confidential manner to the patient with a particular attention to avoiding abuse (of opioids and narcotics prescriptions in particular) The risk of prescription abuse may be increased in a telehealth setting [bib_ref] Comparing telemedicine to in-person buprenorphine treatment in US veterans with opioid use..., Lin [/bib_ref] [bib_ref] Telemedicine increases access to buprenorphine initiation during the COVID-19 pandemic, Wang [/bib_ref]. Therefore, an efficient tracking system of prescriptions should be applied in an electronic health record system, in accordance with the legal framework of the country in which the rheumatologist is based. One such option is to have an electronic medical record allowing the physician to write the prescription electronically. However, some countries do not allow electronic signatures for prescriptions, especially for opioids and narcotics.. ## Bps 8: fees and reimbursement (loe 5; loa 8.45; consensus 100%) The teleconsultation is subject to medical fees and reimbursement similar to an in-person visit. Fees should be set before the teleconsultation The lack of a consensual reimbursement policy may be a significant deterrent to the adoption of telehealth. Therefore the physician and the legislator in the physician's country of practice should agree on a fair and transparent fee for a teleconsultation; these fees should be communicated to the patient before the visit. Physicians should be aware of the fact that some patients might be unwilling to pay for an audio-only consultation, while some payers might be inclined to pay only a percentage of the conventional fee for teleconsultations that do not utilize video, e.g., 33% in UAE, 50% in Jordan, 80% in Bahrain (data were provided by the TF during the Delphi rounds and were limited to the country where it was available at the time of the study). Aside from the patient/payer perspective, some physicians might argue that teleconsultation can be more time-consuming than an in-person visit and that reimbursement should reflect the time spent with the patient. From an economic perspective, telehealth may decrease the indirect cost for the patient (e.g., saving on travel costs, time taken off from work) [bib_ref] Telerheumatology: an idea whose time has come, Roberts [/bib_ref] and for the physician (by reducing the number of no-shows and appointment cancellations) [bib_ref] Telemedicine: is it really worth it? A perspective from evidence and experience, Freed [/bib_ref] [bib_ref] Decreasing patient cost and travel time through pediatric rheumatology telemedicine visits, Kessler [/bib_ref]. By helping to maintain patients in remission or LDA through telemonitoring, the cost of managing chronic diseases would be substantially reduced [bib_ref] Direct cost-modeling of rheumatoid arthritis according to disease activity categories in France, Beresniak [/bib_ref]. ## Bps 9: ethical considerations (loe 5; loa 8.59; consensus 100%) Telehealth practice should conform to the same professional ethics that govern in-person care and comply with local jurisdictional laws and regulations of the physician's location Advancements in technology have facilitated the use of telehealth and Information Technology in the treatment or rehabilitation of diseases. However, increased use of technology is accompanied by threats to patients' personal information. Therefore, special consideration to the ethical issues involved in telehealth practice, including confidentiality and security, doctor-patient relationship, and informed consent, are crucial to guarantee safe use while maintaining the quality of healthcare services [bib_ref] Application of ethics for providing telemedicine services and information technology, Langarizadeh [/bib_ref]. The rheumatologists are encouraged to receive proper training through seminars, workshops, and conferences to familiarize with the advantages and disadvantages of telehealth and to acquire strategies about the most productive approach to remote medical care A lack of adequate training and familiarity with telehealth can be a barrier to the successful adoption thereof [bib_ref] Telemedicine in Middle Eastern countries: progress, barriers, and policy recommendations, Al-Samarraie [/bib_ref]. Therefore, it is recommended that rheumatologists and their staff educate themselves on all aspects of telehealth through continued professional development [bib_ref] Telemedicine in Middle Eastern countries: progress, barriers, and policy recommendations, Al-Samarraie [/bib_ref]. Although professional development and training can be of value to the physician, its effectiveness on the outcomes of teleconsultations needs to be further evaluated. ## Bps 11: improve infrastructure and promote equity (loe 5; loa 8.41; consensus 100%) The technical infrastructure should be improved for patients and physicians, to enable efficient and equitable access to telehealth services across the countries and in vulnerable populations. Studies in the Middle East have shown that poor infrastructure was associated with low adoption of telehealth in the region [bib_ref] Rheumatology clinicians' perceptions of telerheumatology within the veterans health administration: a national..., Matsumoto [/bib_ref]. This is especially true for patients living below the poverty line, as research indicates that access to telehealth is challenging for these vulnerable populations [bib_ref] Impact of COVID-19 on vulnerable patients with rheumatic disease: results of a..., Mehta [/bib_ref]. On the other hand, telehealth can decrease inequities by offering easier access to care for patients living in rural or remote areas, and supporting continuity of care. Rheumatologists should therefore identify limitations of the technical infrastructure in their region and take appropriate steps to attempt to overcome such limitations, where feasible. Consideration should be given to implementing a secure platform that would allow the patient to make an appointment with their physician of choice, engage in teleconsultation, obtain the required prescription and diagnostic tests and pay the fees to the physician. ## Bps 12: support research projects in telehealth in the arab Region (LoE 5; LoA 8.32; Consensus 95.45%) Local and regional research projects to assess the implementation of telehealth and the resulting disease outcomes in the Arab region are strongly encouraged Recommendations from the Middle East also highlight the need for health initiatives to focus on health education and promotion, to raise awareness of the benefits of telehealth services in the region [bib_ref] Telemedicine in Middle Eastern countries: progress, barriers, and policy recommendations, Al-Samarraie [/bib_ref]. ## Top barriers and facilitators to telehealth Voting on the top physician and patient-related barriers and facilitators to Telehealth in Rheumatology in the Arab region [bib_ref] Impact of COVID-19 on vulnerable patients with rheumatic disease: results of a..., Mehta [/bib_ref] [bib_ref] Telemedicine in pediatric rheumatology: this is the time for the community to..., Shenoi [/bib_ref] [bib_ref] Patient and clinician experiences with telehealth for patient follow-up care, Donelan [/bib_ref] [bib_ref] Telerheumatology: an idea whose time has come, Roberts [/bib_ref] [bib_ref] Development of an educational video for self-assessment of patients with RA: steps,..., Ziade [/bib_ref] [bib_ref] A tele-health follow-up strategy for tight control of disease activity in rheumatoid..., De Thurah [/bib_ref] [bib_ref] Telemedicine: is it really worth it? A perspective from evidence and experience, Freed [/bib_ref] [bib_ref] Telemedicine in Middle Eastern countries: progress, barriers, and policy recommendations, Al-Samarraie [/bib_ref] [bib_ref] Rheumatology clinicians' perceptions of telerheumatology within the veterans health administration: a national..., Matsumoto [/bib_ref] [bib_ref] Implementation guide for rapid integration of an outpatient telemedicine program during the..., Smith [/bib_ref] [bib_ref] Mobile health usage, preferences, barriers, and ehealth literacy in rheumatology: patient survey..., Knitza [/bib_ref] [bib_ref] Telerheumatology-breaking barriers to access care in rheumatology, Teixeira [/bib_ref] [bib_ref] State of telehealth, Dorsey [/bib_ref] [bib_ref] Virtual rheumatology appointments during the COVID-19 pandemic: an international survey of perspectives..., Howren [/bib_ref] revealed that concern about the quality of care and proper communication, and internal and external technical difficulties, were regarded as the top patient and physician-related barriers. Lack of alternatives when social distancing is required, and increased access to care, were voted as the top physician and patient-related facilitators to telehealth, respectively [fig_ref] Table 2: Top Physician-and Patient-related Barriers-and Facilitators to Telehealth in Rheumatology in the Arab... [/fig_ref]. ## Practical toolkit for the implementation of telehealth A Triage System for a Teleconsultation in Rheumatology [fig_ref] BPS 2: Confidentiality [/fig_ref] was developed to assist rheumatologists in assessing whether telehealth is suitable in each situation, based on the complexity of the diagnosis, the patient's clinical status, and disease prognosis. Rheumatologists need to use their professional experience and judgement to assess whether telehealth is suitable in each situation while ensuring that the services provided comply with the laws and regulations of their respective countries. In addition, a practical toolkit for the possible implementation of teleconsultation in rheumatology was developed to provide guidance on how to translate theory into practice, highlighting the activities to perform before, during, and after the teleconsultation [fig_ref] Figure 3: Toolkit for the implementation of telehealth in the rheumatology clinic [/fig_ref]. # Discussion The ArLAR BPG for telehealth were developed to inform rheumatologists about the advantages and limitations of telehealth and to provide them with a series of strategies to practice telehealth in the rheumatology clinic. The need for practical ways to provide remote health care has been highlighted during the COVID-19 pandemic, where social distancing and potential risks to patient safety have prohibited regular in-person consultations. In that setting, telehealth can be a valuable tool for managing patients with rheumatic disease, especially more vulnerable patients with co-morbidities and other risk factors [bib_ref] Telerheumatology in COVID-19 era: a study from a psoriatic arthritis cohort, Costa [/bib_ref]. In addition, recent studies suggest that telehealth services could positively impact on disease activity, medication adherence, physical activity, and self-efficacy levels in patients with RA, External technical difficulties such as poor internet connection or suitable equipment 3 Internal technical difficulties such as lack of familiarity with e-Health, and lack of trained staff 4 Lack of motivation (lack of reimbursement) 5 Absence of legal framework: inter-country licensure laws, need for credentialing at multiple sites, and liability concerns Choice rank Top physician-related facilitators to telehealth in rheumatology in the Arab region Concern about the quality of care or proper communication 2 Internal technical difficulties such as lack of familiarity with technology 3 External technical difficulties such as poor internet connection or unsuitable equipment 4 Resistance to change 5 Lack of motivation or unclear benefit (patient lives near the healthcare facility, elderly patient with more spare time) Choice rank Top patient-related facilitators to telehealth in rheumatology in the Arab region 1 Increased access to care and/or possibility to obtain specialist medical opinion from remotely based expert physicians 2 Lack of alternatives when social distancing measures are needed 3 Less travel costs 4 Quick communication and reassurance from the physician 5 Better time management provided these interventions are well-designed, versatile, and adaptive [bib_ref] Tele-health interventions to support self-management in adults with rheumatoid arthritis: a systematic..., Maciver [/bib_ref]. While some studies have found telehealth to be generally effective for the diagnosis and self-management of rheumatic disease (with mostly positive patient and provider satisfaction) [bib_ref] Telerheumatology: a systematic review, Mcdougall [/bib_ref] [bib_ref] Tele-health interventions to support self-management in adults with rheumatoid arthritis: a systematic..., Maciver [/bib_ref] , others have found that it was associated with diagnostic delay, reduced likelihood of changing existing immunosuppressive therapy, earlier requirement for review and a lower likelihood of discharge, even though it led to improved appointment attendance [bib_ref] The impact of telerheumatology and COVID-19 on outcomes in a tertiary rheumatology..., Zhu [/bib_ref]. This highlights the notion that the appropriateness of telerheumatology in patients' care may vary widely, differing by age, phase of illness, severity of symptoms, and rheumatic disease type. Furthermore, the effects of telerheumatology on patient access and the outcome of rheumatic disease across race, ethnicity, or socioeconomic status have not been explicitly studied in literature and may be difficult to predict [bib_ref] Leveraging telemedicine as an approach to address rheumatic disease health disparities, Mcdougall [/bib_ref]. In a study evaluating the patient's feelings about changing from a face-to-face consultation to a virtual one, only 76% of patients had the means to access a teleconsultation. The proportion of internet access and the agreement for a teleconsultation decreased in patients over 70 years old. The factors associated with an acceptance for teleconsultation were the significant distance from the consultation site and a higher level of education. The TIROL Steering Committee acknowledges the significant disparity between countries in terms of available laws and legislation that manage telehealth and that any guidelines will always be subject to compliance with the applicable laws and regulations of each ArLAR country. Rheumatologists are encouraged to actively participate in the effort to sensitize legislators to the interest and benefit of telerheumatology. Focusing on the patient-and physicianrelated barriers in the Arab region can assist authorities in establishing appropriate strategies for promoting telehealth. Moreover, the committee acknowledges the disparity in internet accessibility, electricity stability, and technology skills across the Arab countries, which are critical to consider when deciding whether telehealth is an appropriate method of providing health care. In the absence of clear evidence, rheumatologists should use their professional experience and judgment to assess whether telehealth is suitable in each situation while always prioritizing security and confidentiality considerations. In summary, the ArLAR BPG provide a conceptual framework for the application of telehealth in rheumatology practice. Most of the statements were based on a low level of evidence and expert opinion, highlighting the need for further dedicated research to recognize the advantages and limitations of telehealth in rheumatology and for a subsequent update of these BPG in the future. The ArLAR BPG for telehealth are not intended to compel the use of telehealth in the same manner for every patient in every case; but are rather designed to provide the rheumatologists with a series of strategies about the most reliable, productive, and rational approaches to apply telehealth in the rheumatology programs before the visit to improve speed/connectivity. *Environment checklist: Set up your workspace so that you are front-lit, the camera view covers approximately your head and shoulders, and the camera is at eye height. Make sure the background is not distracting. You might consider using a virtual background with your hospital logo or design. Dress professionally setting, and principally in the context of pressing pandemic restrictions. ## Supplementary information The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s00296-021-05078-w. [fig] Figure 1: Study [/fig] [fig] BPS 2: Confidentiality (LoE 5; LoA 8.82; Consensus 100%)The use of telehealth services must ensure the patient's information security and confidentiality This should include proper and mandatory measures to ensure online information security (e.g., anti-hacking measures, password-protected access) and visual and auditory privacy, in [/fig] [fig] Figure 2: Triage system for a teleconsultation in rheumatology. Provided that the patient accepts teleconsultation 1 3 [/fig] [fig] BPS 5: Patient's physical examination (LoE 2; LoA 7.77; Consensus 90.91%) [/fig] [fig] BPS 7: Safe Prescription (LoE 5; LoA 8.05; Consensus 95.45%) [/fig] [fig] BPS 10: Training of rheumatologists (LoE 5; LoA 8.18; Consensus 95.45%) [/fig] [fig] Figure 3: Toolkit for the implementation of telehealth in the rheumatology clinic. Technical checklist: Check if your device and browser support the telehealth platform. Check if your internet is stable. Check sound and webcam on your device. Have a backup plan if the connection fails. Take time to familiarize yourself with the telehealth platform and its functions. Ensure all your devices are charged and have the chargers handy in case your battery drain; Close other apps/ [/fig] [table] Table 1: General principles and best practice guidelines statements for telehealth in rheumatology LoE: Level of Evidence according to the Oxford Centre for Evidence-Based Medicine Consensus: % of votes with a score from 7 to 9 * LoA: Level of agreement from 1 to 9, with 9 being the highest agreement ‡ Exchange of medical information includes medical history, physical exam, review of test results and final prescription Shared decision and choiceThe choice of using telehealth services should be based on a shared decision between the patient and the physician. Patients should have a choice of their provider of medical teleconsultation Patient's physical examination Some parts of the physical exam might be performed remotely, e.g., inspection and evaluation of the range of motion. The patient should be instructed on how to be prepared for a remote physical exam, using appropriate educational material Fees and reimbursement The teleconsultation is subject to medical fees and reimbursement similar to an in-person visit. Fees should be set before the teleconsultation Ethical considerations Telehealth practice should conform to the same professional ethics that govern in-person care and comply with local jurisdictional laws and regulations of the physician's location [/table] [table] Table 2: Top Physician-and Patient-related Barriers-and Facilitators to Telehealth in Rheumatology in the Arab region [/table]	None	https://link.springer.com/content/pdf/10.1007/s00296-021-05078-w.pdf	None
758a24c2a01d91915ff0093ec337692ac94128f8	pubmed	Society of Cardiovascular Computed Tomography guidance for use of cardiac computed tomography amidst the COVID-19 pandemic Endorsed by the American College of Cardiology	Society of Cardiovascular Computed Tomography guidance for use of cardiac computed tomography amidst the COVID-19 pandemic Endorsed by the American College of Cardiology # Introduction The world is currently suffering through a pandemic outbreak of severe respiratory syndrome coronavirus 2 (SARS-CoV-2) known as Coronavirus Disease 2019 (COVID-19). The United States (US) Centers for Disease Control and Prevention (CDC) currently advises medical facilities to "reschedule non-urgent outpatient visits as necessary".The European Centre for Disease Prevention and Control, the United Kingdom National Health Service and several other international agencies covering Asia, North America and most regions of the world have recommended similar "social distancing" measures.The Society of Cardiovascular Computed Tomography (SCCT) offers guidance that fully support and extend these international recommendations specifically for cardiac CT (CCT) practitioners to decrease risk of COVID-19 transmission in their facilities while allowing for optimal timing considerations for effective utilization of CCT to improve cardiovascular health outcomes. While many institutions will have their own guidelines for clinicians and imagers to follow, these recommendations are meant to help CCT labs which are interested in developing or refining such policies. It is important to emphasize the SCCT's commitment to the health and well-being of CCT technologists, imagers, trainees, and research community, as well as the patients served by CCT by preventing the spread of disease. As this represents initial guidance for a rapidly evolving pandemic, https://doi.org/10.1016/j.jcct.2020.03.002 the SCCT advises that CCT practitioners work closely with their referring physicians to determine the appropriateness and timing of each individual study on a case by case basis, while also considering the local epidemiology of COVID-19 and local institutional guidelines for practice. ## Basic concepts - Social distancing -keeping at least six feet (1.8 m) between individuals in waiting rooms and work spaces as much as feasible. - Encourage sick employees to stay home. Personnel who develop respiratory symptoms (e.g., cough, shortness of breath) or unexplained fever should be instructed not to report to work. - Ensure that your sick leave policies are flexible and consistent with public health guidance and that employees are aware of these policies. Make contingency plans for increased absenteeism - Screen patients and visitors for symptoms of acute respiratory illness (e.g., fever, cough, difficulty breathing) or gastrointestinal symptoms and coronavirus exposure in the last 2 weeks before entering one's healthcare facility.- Ensure technologist and CCT imager hand hygiene best practices. If soap and water are not readily available, use of a hand sanitizer that contains at least 60% alcohol. - Consider standard droplet precautions for patients and healthcare personnel as per institutional infection control protocols. - Increase scheduling intervals or appointment times to allow adequate time to clean equipment as needed. - Leverage telemedicine technologies and isolated workstations to allow for reading and interpretation, that allow for social distancing to limit staff exposure, when possible. - Assign a team member to monitor and incorporate regular updates from the CDC and appropriate regional jurisdictions. ## Patients under investigation (pui) and confirmed covid-19 In patients under investigation (PUI) and with confirmed COVID-19, the benefit of CCT scanning in most clinical scenarios will likely be lower than the risk of COVID-19 exposure and infection to healthcare personnel. These cases should be considered on a case-by-case basis. For these PUI and confirmed COVID-19 patients in which CCT scanning is determined to be necessary, the following issues should be considered: - Ensure proper use of personal protection equipment (PPE). Healthcare personnel including technologists, radiologists and cardiac imagers who come in close contact with confirmed or suspected COVID-19 should wear the appropriate personal protective equipment.Patients should wear a surgical mask during imaging to ensure standard droplet precautions. - Appropriate environmental cleaning and decontamination of rooms by thorough cleaning of the surfaces by a staff member with appropriate PPE as per CDC and local institutional guidelines for airborne viral diseases. 7 ## Cardiac ct indications and timing To advise practitioners of cardiovascular CT on how to implement the CDC recommendation of rescheduling non-urgent visits as necessary and international guidelines on social distancing, the SCCT offers the following guiding points and suggestions for CCT timing based on various indications [fig_ref] Table 2: Timing considerations for common indications for CCT amidst COVID-19 [/fig_ref]. As this is not an exhaustive list, the SCCT advises CCT practitioners to work with referring physicians on a case by case basis. ## Incidental pulmonary findings in patients at risk of covid-19 exposure COVID-19 is a viral pneumonia, with a spectrum of findings ranging from normal lungs to acute respiratory distress syndrome. Typical chest CT findings in known cases are described elsewhere. [bib_ref] Radiology department preparedness for COVID-19: radiology scientific expert panel, Mossa-Basha [/bib_ref] If typical or atypical pulmonary findings are encountered, consultation with a radiologist with thoracic expertise is encouraged, and appropriate documentation and timely communication of these findings is important, especially in cases not known or suspected to have the disease. # Conclusion As this situation is shifting rapidly, the information contained within this document is likely to evolve. The SCCT will maintain an updated version of this statement as more information becomes available on the Society's website at https://scct.org/page/COVID-19. The SCCT advises that members keep informed regarding future updates from the medical and radiological communities on protecting patients, staff, trainees and providers from COVID-19 while deciding on the optimal timing of outpatient and inpatient CCT exams. ## Other resources American College of Cardiology COVID-19 bulletin: https://www. acc.org/latest-in-cardiology/features/accs-coronavirus-disease-2019covid-19-hub American College of Radiology recommendations for the use of chest radiography and computed Tomography (CT) for suspected COVID-19 infection, https://www.acr.org/Advocacy-and-Economics/ ACR-Position-Statements/Recommendations-for-Chest-Radiographyand-CT-for-Suspected-COVID19-Infection British Society of thoracic imaging: COVID-19 resources, https:// www.bsti.org.uk/covid-19-resources/ Centers for disease control and prevention steps for healthcare facilities, https://www.cdc.gov/coronavirus/2019-ncov/healthcarefacilities/steps-to-prepare.html Coronavirus (COVID-19): UK government response, https://www. gov.uk/government/topical-events/coronavirus-covid-19-ukgovernment-response Guiding points to consider when deciding on the role and timing of CCT. - The delivery of CCT services should be performed in a manner which will be safe to technologists and imagers, as well as patients. - Consider deferring CCT exams which can be safely postponed in order to minimize risk of exposure to patients and staff. - CCT may be preferred to transesophageal echocardiography (TEE) in order to rule-out left atrial appendage and intracardiac thrombus prior to cardioversion in order to reduce coughing and aerosolization related to TEE. - The ability of CCT to decisively exclude coronary disease or high risk anatomy may prevent the need for inpatient admissions and resource use. - Consider that elderly patients, those with co-morbidities, and those who may be immunosuppressed are at greater risk of morbidity/mortality from COVID-19, and the benefit and risk of cardiac CT should be evaluated on a case by case basis. - In patients under investigation (PUI) and with confirmed COVID-19, the benefit of CCT in most clinical scenarios will likely be lower than the risk of exposure and infection to healthcare personnel. These cases should be considered on a case-bycase basis. [table] Table 2: Timing considerations for common indications for CCT amidst COVID-19. European Centre for disease prevention and control: COVID-19, https://www.ecdc.europa.eu/en/novel-coronavirus-china Radiology department preparedness for COVID-19: radiology scientific expert panel, https://pubs.rsna.org/doi/10.1148/radiol.2020200988 Society of Thoracic Radiology/American Society of Emergency Radiology COVID-19 position statement, https://thoracicrad.org/ [/table]	None	http://www.journalofcardiovascularct.com/article/S1934592520301258/pdf	None
e1c6f73a2b50c46ff98cc851a1900bae8db0d400	pubmed	Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2022–23 Influenza Season	Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2022–23 Influenza Season [bib_ref] Primary Health Care Sentinel Network; Network for Influenza Surveillance in Hospitals of..., Castilla [/bib_ref] ## Season are quadrivalent, containing hemagglutinin (ha) derived from one influenza a(h1n1)pdm09 virus, one influenza a(h3n2) virus, one influenza b/victoria lineage virus, and one influenza b/yamagata lineage virus. inactivated influenza vaccines (iiv4s), recombinant influenza vaccine (riv4), and live attenuated influenza vaccine (laiv4) are expected to be available. trivalent influenza vaccines are no longer available, but data that involve these vaccines are included for reference. Influenza vaccines might be available as early as July or August, but for most persons who need only 1 dose of influenza vaccine for the season, vaccination should ideally be offered during September or October. However, vaccination should continue after October and throughout the season as long as influenza viruses are circulating and unexpired vaccine is available. For most adults (particularly adults aged ≥65 years) and for pregnant persons in the first or second trimester, vaccination during July and August should be avoided unless there is concern that vaccination later in the season might not be possible. Certain children aged 6 months through 8 years need 2 doses; these children should receive the first dose as soon as possible after vaccine is available, including during July and August. Vaccination during July and August can be considered for children of any age who need only 1 dose for the season and for pregnant persons who are in the third trimester if vaccine is available during those months. Updates described in this report reflect discussions during public meetings of ACIP that were held on . Primary updates to this report include the following three topics: 1) the composition of 2022-23 U.S. seasonal influenza vaccines; 2) updates to the description of influenza vaccines expected to be available for the 2022- [bib_ref] Primary Health Care Sentinel Network; Network for Influenza Surveillance in Hospitals of..., Castilla [/bib_ref] , was changed in October 2021 from ≥2 years to ≥6 months. Third, recommendations for vaccination of adults aged ≥65 years have been modified. ACIP recommends that adults aged ≥65 years preferentially receive any one of the following higher dose or adjuvanted influenza vaccines: quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), quadrivalent recombinant influenza vaccine (RIV4), or quadrivalent adjuvanted inactivated influenza vaccine (aIIV4). If none of these three vaccines is available at an opportunity for vaccine administration, then any other age-appropriate influenza vaccine should be used. This report focuses on recommendations for the use of vaccines for the prevention and control of seasonal influenza during the Introduction Influenza viruses typically circulate annually in the United States, most commonly from the late fall through the early spring. Most persons who become ill after influenza virus infection recover without serious complications or sequelae. However, influenza can be associated with serious illnesses, hospitalizations, and deaths, particularly among older adults, very young children, pregnant persons, and persons of all ages with certain chronic medical conditions [bib_ref] Impact of epidemic type A influenza in a defined adult population, Barker [/bib_ref] [bib_ref] Risk factors for serious outcomes associated with influenza illness in high-versus lowand..., Coleman [/bib_ref] [bib_ref] Vaccine Safety Datalink Adult Working Group. Influenza-and RSV-associated hospitalizations among adults, Mullooly [/bib_ref] [bib_ref] The burden of influenza in young children, Poehling [/bib_ref] [bib_ref] New Vaccine Surveillance Network. The underrecognized burden of influenza in young children, Poehling [/bib_ref] [bib_ref] Pandemic H1N1 Influenza in Pregnancy Working Group. Pandemic 2009 influenza A(H1N1) virus..., Siston [/bib_ref]. Influenza also is an important cause of missed work and school [bib_ref] Influenza and workplace productivity loss in working adults, Van Wormer [/bib_ref] [bib_ref] WAIVE Study Team. The impact of influenza infection on young children, their..., Willis [/bib_ref]. Routine annual influenza vaccination for all persons aged ≥6 months who do not have contraindications has been recommended by CDC and the Advisory Committee on Immunization Practices (ACIP) since 2010. ## Season, including one influenza vaccine labeling change that occurred after the publication of the 2021-22 acip influenza recommendations; and 3) updates to the recommendations concerning vaccination of adults aged ≥65 years. first, the composition of 2022-23 u.s. influenza vaccines includes updates to the influenza a(h3n2) and influenza b/victoria lineage components. u.s.-licensed influenza vaccines will contain ha derived from an influenza a/victoria/2570/2019 (h1n1)pdm09-like virus (for egg-based vaccines) or an influenza a/wisconsin/588/2019 (h1n1)pdm09-like virus (for cell culture-based or recombinant vaccines); an influenza a/darwin/9/2021 (h3n2)-like virus (for egg-based vaccines) or an influenza a/darwin/6/2021 (h3n2)-like virus (for cell culture-based or recombinant vaccines); an influenza b/austria/1359417/2021 (victoria lineage)-like virus; and an influenza b/phuket/3073/2013 (yamagata lineage)-like virus. second, the approved age indication for the cell culture-based inactivated influenza vaccine, flucelvax Vaccination provides important protection from influenza illness and its potential complications. The effectiveness of influenza vaccination varies depending on several factors, such as the age and health of the recipient; the type of vaccine administered; the types, subtypes (for influenza A), and lineages (for influenza B) of circulating influenza viruses; and the degree of similarity between circulating viruses and those included in the vaccine. During each of the six influenza seasons from 2010-11 through 2015-16, influenza vaccination prevented an estimated 1.6-6.7 million illnesses, 790,000-3.1 million outpatient medical visits, 39,000-87,000 hospitalizations, and 3,000-10,000 respiratory and circulatory deaths each season in the United States [bib_ref] Annual estimates of the burden of seasonal influenza in the United States:..., Rolfes [/bib_ref]. During the severe 2017-18 season, notable for an unusually long duration of widespread high influenza activity throughout the United States and higher rates of outpatient visits and hospitalizations compared with recent seasons, vaccination prevented an estimated 7.1 million illnesses, 3.7 million medical visits, 109,000 hospitalizations, and 8,000 deaths [bib_ref] US Influenza Vaccine Effectiveness (Flu VE) Network; Influenza Hospitalization Surveillance Network; Assessment..., Rolfes [/bib_ref] , despite an overall estimated vaccine effectiveness of 38% (62% against influenza A[H1N1]pdm09 viruses, 22% against influenza A[H3N2] viruses, and 50% against influenza B viruses) [bib_ref] US Influenza Vaccine Effectiveness (Flu VE) Network; Influenza Hospitalization Surveillance Network; Assessment..., Rolfes [/bib_ref]. Influenza circulated at historically low levels in the United States and globally during the 2020-21 influenza season. This was coincident with widespread implementation of nonpharmaceutical interventions (e.g., masking, social distancing, and suspension of in-person work and school) intended to prevent transmission of SARS-CoV-2 (the virus that causes . Influenza activity increased during the 2021-22 season, although severity indicators (e.g., influenzaassociated hospitalizations and deaths) were overall lower than in recent previous seasons [bib_ref] GA: US Department of Health and Human Services, CDC, Cdc [/bib_ref]. Timing, intensity, and severity of the 2022-23 influenza season cannot be predicted. Influenza vaccination remains an important tool for the prevention of potentially severe respiratory illness, which might decrease stress on the U.S. health care system during ongoing circulation of SARS-CoV-2. Guidance for vaccine planning during the COVID-19 pandemic is available at https://www.cdc.gov/ vaccines/pandemic-guidance/index.html. This report updates the 2021-22 ACIP recommendations regarding the use of seasonal influenza vaccines [bib_ref] Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory..., Grohskopf [/bib_ref] and provides recommendations and guidance for vaccination providers regarding the use of influenza vaccines in the United States for the 2022-23 season. Various formulations of influenza vaccines are available [fig_ref] TABLE 1: Influenza vaccines -United States, 2022-23 influenza season* Abbreviations [/fig_ref]. Contraindications and precautions for the use of influenza vaccines are summarized [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref]. Abbreviations are used in this report to denote the various types of vaccines (Box). This report focuses on recommendations and guidance for the use of seasonal influenza vaccines for the prevention and control of influenza during the 2022-23 season in the United States. A summary of these recommendations and a Background Document containing additional information on influenza, influenza-associated illness, and influenza vaccines are available at https://www.cdc.gov/vaccines/hcp/acip-recs/ vacc-specific/flu.html. # Methods ACIP provides annual recommendations for the use of influenza vaccines for the prevention and control of seasonal influenza in the United States. The ACIP Influenza Work Group meets by teleconference once to twice per month throughout the year. Work group membership includes several voting members of ACIP, representatives of ACIP liaison organizations, and consultants. Discussions include topics such as influenza surveillance, vaccine effectiveness and safety, vaccination coverage, program feasibility, cost effectiveness, and vaccine supply. Presentations are requested from invited experts, and published and unpublished data are discussed. The Background Document that supplements this report is updated periodically to reflect recent additions to the literature gov/vaccines-blood-biologics/vaccines/vaccines-licensed-use-united-states. Availability and characteristics of specific products and presentations might change or differ from what is described in this table and in the text of this report. † Although a history of severe allergic reaction (e.g., anaphylaxis) to egg is a labeled contraindication to the use of egg-based IIV4s and LAIV4, ACIP recommends that persons with a history of egg allergy may receive any licensed, recommended influenza vaccine that is otherwise appropriate for their age and health status. Those who report having had reactions to egg involving symptoms other than urticaria (e.g., angioedema or swelling, respiratory distress, lightheadedness, or recurrent emesis) or who required epinephrine or another emergency medical intervention should be vaccinated in an inpatient or outpatient medical setting (including but not necessarily limited to hospitals, clinics, health departments, and physician offices) supervised by a health care provider who is able to recognize and manage severe allergic reactions, if a vaccine other than ccIIV4 or RIV4 is used. § The approved dose volume for Afluria Quadrivalent is 0.25 mL for children aged 6 through 35 months and 0.5 mL for persons aged ≥3 years. However, 0. [bib_ref] Intraseason waning of influenza vaccine protection: evidence from the US Influenza Vaccine..., Ferdinands [/bib_ref] - History of severe allergic reaction (e.g., anaphylaxis) to a previous dose of any ccIIV or any component of ccIIV4 § - Moderate or severe acute illness with or without fever - History of Guillain-Barré syndrome within 6 weeks of receipt of influenza vaccine - History of severe allergic reaction to a previous dose of any other influenza vaccine (i.e., any egg-based IIV, RIV, or LAIV) ¶ RIV4 - History of severe allergic reaction (e.g., anaphylaxis) to a previous dose of any RIV or any component of RIV4 § - Moderate or severe acute illness with or without fever - History of Guillain-Barré syndrome within 6 weeks of receipt of influenza vaccine - History of severe allergic reaction to a previous dose of any other influenza vaccine (i.e., any egg-based IIV, ccIIV, or LAIV) ¶ LAIV4 - History of severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine † or to a previous dose of any influenza vaccine (i.e., any egg-based IIV, ccIIV, RIV, or LAIV) § - Concomitant aspirin-or salicylate-containing therapy in children and adolescents § - Children aged 2 through 4 years who have received a diagnosis of asthma or whose parents or caregivers report that a health care provider has told them during the preceding 12 months that their child had wheezing or asthma or whose medical record indicates a wheezing episode has occurred during the preceding 12 months - Children and adults who are immunocompromised due to any cause, including but not limited to immunosuppression caused by medications, congenital or acquired immunodeficiency states, HIV infection, anatomic asplenia, or functional asplenia (e.g., due to sickle cell anemia) - Close contacts and caregivers of severely immunosuppressed persons who require a protected environment Abbreviations: ACIP = Advisory Committee on Immunization Practices; ccIIV = cell culture-based inactivated influenza vaccine (any valency); ccIIV4 = cell culturebased inactivated influenza vaccine, quadrivalent; CSF = cerebrospinal fluid; FDA = Food and Drug Administration; IIV = inactivated influenza vaccine (any valency); IIV4 = inactivated influenza vaccine, quadrivalent; LAIV = live attenuated influenza vaccine (any valency); LAIV4 = live attenuated influenza vaccine, quadrivalent; RIV = recombinant influenza vaccine (any valency); RIV4 = recombinant influenza vaccine, quadrivalent. * When a contraindication is present, a vaccine should not be administered. When a precaution is present, vaccination should generally be deferred but might be indicated if the benefit of protection from the vaccine outweighs the risk for an adverse reaction (see ACIP General Best Practice Guidelines for Immunization, available at https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html). Vaccination providers should check FDA-approved prescribing information for 2022-23 influenza vaccines for the most complete and updated information, including (but not limited to) indications, contraindications, warnings, and precautions. Package inserts for U.S.-licensed vaccines are available at https://www.fda.gov/vaccines-blood-biologics/vaccines/vaccines-licensed-use-united-states. † Although a history of severe allergic reaction (e.g., anaphylaxis) to egg is a labeled contraindication to the use of egg-based IIV4s and LAIV4, ACIP recommends that persons with a history of egg allergy may receive any licensed, recommended influenza vaccine that is otherwise appropriate for their age and health status. Those who report having had reactions to egg involving symptoms other than urticaria (e.g., angioedema or swelling, respiratory distress, lightheadedness, or recurrent emesis) or who required epinephrine or another emergency medical intervention should be vaccinated in an inpatient or outpatient medical setting, including but not necessarily limited to hospitals, clinics, health departments, and physician offices, if a vaccine other than ccIIV4 or RIV4 is used. Vaccine administration should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. § Labeled contraindication noted in package insert. ¶ If administered, vaccination should occur in a medical setting and should be supervised by a health care provider who can recognize and manage severe allergic reactions. Providers can consider consultation with an allergist in such cases, to assist in identification of the component responsible for the allergic reaction. ** Age-appropriate injectable vaccines are recommended for persons with cochlear implant due to the potential for CSF leak, which might exist for a period after implantation. Providers might consider consultation with a specialist concerning risk for persistent CSF leak if an age-appropriate inactivated or recombinant vaccine cannot be used. † † Use of LAIV4 in context of influenza antivirals has not been studied; however, interference with activity of LAIV4 is biologically plausible, and this possibility is noted in the package insert for LAIV4. In the absence of data supporting an adequate minimum interval between influenza antiviral use and LAIV4 administration, the intervals provided are based on the half-life of each antiviral. The interval between influenza antiviral receipt and LAIV4 for which interference might potentially occur might be further prolonged in the presence of medical conditions that delay medication clearance (e.g., renal insufficiency). Influenza antivirals might also interfere with LAIV4 if initiated within 2 weeks after vaccination. Persons who receive antivirals during the period starting with the specified time before receipt of LAIV4 through 2 weeks after receipt of LAIV4 should be revaccinated with an age-appropriate IIV or RIV4. vaccines-blood-biologics/vaccines/vaccines-licensed-use-united-states. † When a contraindication is present, a vaccine should not be administered, consistent with ACIP General Best Practice Guidelines for Immunization (Kroger A, Bahta L, Hunter P. General best practice guidelines for immunization: best practices guidance of the Advisory Committee on Immunization Practices [ACIP]. https://www. cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html). In addition to the contraindications based on history of severe allergic reaction to influenza vaccines that are noted in the table, each individual influenza vaccine is contraindicated for persons who have had a severe allergic reaction (e.g., anaphylaxis) to any component of that vaccine. Vaccine components can be found in package inserts. Although a history of severe allergic reaction (e.g., anaphylaxis) to egg is a labeled contraindication to the use of egg-based IIV4s and LAIV4, ACIP recommends that persons with a history of egg allergy may receive any licensed, recommended influenza vaccine that is otherwise appropriate for their age and health status. Those who report having had reactions to egg involving symptoms other than urticaria (e.g., angioedema or swelling, respiratory distress, lightheadedness, or recurrent emesis) or who required epinephrine or another emergency medical intervention should be vaccinated in an inpatient or outpatient medical setting (including but not necessarily limited to hospitals, clinics, health departments, and physician offices), if a vaccine other than ccIIV4 or RIV4 is used. Vaccine administration should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. § When a precaution is present, vaccination should generally be deferred but might be indicated if the benefit of protection from the vaccine outweighs the risk for an adverse reaction, consistent with ACIP General Best Practice Guidelines for Immunization (Kroger A, Bahta L, Hunter P. General best practice guidelines for immunization: best practices guidance of the Advisory Committee on Immunization Practices [ACIP]. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/ index.html). Providers can consider using the following vaccines in these instances; however, vaccination should occur in an inpatient or outpatient medical setting with supervision by a health care provider who is able to recognize and manage severe allergic reactions: 1) for persons with a history of severe allergic reaction (e.g., anaphylaxis) to any egg-based IIV or LAIV of any valency, the provider can consider administering ccIIV4 or RIV4; 2) for persons with a history of severe allergic reaction (e.g., anaphylaxis) to any ccIIV of any valency, the provider can consider administering RIV4; and 3) for persons with a history of severe allergic reaction (e.g., anaphylaxis) to any RIV of any valency, the provider can consider administering ccIIV4. Providers can also consider consulting with an allergist to help determine which vaccine component is responsible for the allergic reaction. English-language articles on influenza and influenza vaccines. Typically, systematic review and evaluation of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (18) are performed for new recommendations or substantial changes in the current recommendations (e.g., expansion of the recommendation for influenza vaccination to new populations not previously recommended for vaccination or potential preferential recommendations for specific vaccines). Systematic review, GRADE, and the ACIP Evidence to Recommendations Framework were used in the development of the updated recommendations for influenza vaccination of adults aged ≥65 years discussed in this document. Primary updates and changes to the recommendations described in this report include 1) the vaccine virus composition for 2022-23 U.S. seasonal influenza vaccines; 2) updates to the description of influenza vaccines expected to be available for the 2022-23 season, including one influenza vaccine labeling change that occurred after the publication of the 2021-22 ACIP influenza recommendations; and 3) updates to the recommendations concerning vaccination of adults aged ≥65 years. Information relevant to these changes includes the following: ## - recommendations for the composition of northern Hemisphere influenza vaccines are made by the World Health Organization (WHO), which organizes a consultation, usually in February of each year. Surveillance data are reviewed, and candidate vaccine viruses are discussed. Information about the WHO meeting on February 25, 2022, for selection of the 2022-23 Northern Hemisphere vaccine viruses is available at https://www.who.int/ne ws/item/25-02-2022recommendations-announced-for-influenza-vaccinecomposition-for-the-2022-2023-northern-hemisphereinfluenza-season. Subsequently, FDA, which has regulatory authority over vaccines in the United States, convenes a meeting of its Vaccines and Related Biological Products Advisory Committee (VRBPAC). This committee considers the recommendations of WHO, reviews and discusses similar data, and makes a final decision regarding vaccine virus composition of influenza vaccines licensed and marketed in the United States. Materials from the VRBPAC discussion on March 3, 2022, during which the composition of the 2022-23 U.S. influenza vaccines was discussed, are available at https://www. fda.gov/advisory-committees/advisory-committee-calendar/ vaccines-and-related-biological-products-advisory-committeemarch-3-2022-meeting-announcement. ## Box. abbreviation conventions for influenza vaccines discussed in this report - Main influenza vaccine types: ű IIV = inactivated influenza vaccine ű RIV = recombinant influenza vaccine ű LAIV = live attenuated influenza vaccine - Numerals following letter abbreviations indicate valency (the number of influenza virus hemagglutinin [HA] antigens represented in the vaccine): ű 4 for quadrivalent vaccines: one A(H1N1), one A(H3N2), and two B viruses (one from each lineage) ű 3 for trivalent vaccines: one A(H1N1), one A(H3N2), and one B virus (from one lineage) - All influenza vaccines expected to be available in the United States for the 2022-23 season are quadrivalent vaccines. However, abbreviations for trivalent vaccines (e.g., IIV3) might be used in this report when discussing information specific to trivalent vaccines. - Abbreviations for general vaccine categories (e.g., IIV) might be used when discussing information that is not specific to either trivalent or quadrivalent vaccines. - Prefixes are used when necessary to refer to certain specific IIVs: ű a for MF59-adjuvanted inactivated influenza vaccine (e.g., aIIV3 and aIIV4) ű cc for cell culture-based inactivated influenza vaccine (e.g., ccIIV3 and ccIIV4) ű HD for high-dose inactivated influenza vaccine (e.g., HD-IIV3 and HD-IIV4) ű SD for standard-dose inactivated influenza vaccine (e.g. SD-IIV3 and SD-IIV4) ## Primary changes and updates Routine annual influenza vaccination of all persons aged ≥6 months who do not have contraindications continues to be recommended. Primary updates in this report include the following: 1. ## Recommendations for the use of influenza vaccines, 2022-23 groups recommended for vaccination Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. Recommendations regarding timing of vaccination, considerations for specific populations, the use of specific vaccines, and contraindications and precautions are summarized in the sections that follow. ## Timing of vaccination Because timing of the onset, peak, and decline of influenza activity varies, the ideal time to start vaccinating cannot be predicted each season. Decisions about timing necessitate balancing considerations regarding this unpredictability of the influenza season, possible waning of vaccine-induced immunity over the course of a season, and programmatic considerations. Influenza vaccines might be available as early as July or August; however, vaccination during these months is not recommended for most groups because of the possible waning of immunity over the course of the influenza season [bib_ref] Waning vaccine protection against influenza A (H3N2) illness in children and older..., Belongia [/bib_ref] [bib_ref] Influenza vaccine effectiveness: maintained protection throughout the duration of influenza seasons, Radin [/bib_ref] [bib_ref] Intraseason waning of influenza vaccine effectiveness, Ray [/bib_ref] [bib_ref] Influenza vaccine effectiveness among children for the 2017-2018 season, Powell [/bib_ref] [bib_ref] Primary Health Care Sentinel Network; Network for Influenza Surveillance in Hospitals of..., Castilla [/bib_ref] [bib_ref] Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination..., Kissling [/bib_ref] [bib_ref] Intraseason waning of influenza vaccine protection: evidence from the US Influenza Vaccine..., Ferdinands [/bib_ref] [bib_ref] Valencia Hospital Network for the Study of Influenza and other Respiratory Viruses..., Puig-Barberà [/bib_ref] [bib_ref] I-MOVE case-control study team. I-MOVE multicentre case-control study 2010/11 to 2014/15: is..., Kissling [/bib_ref] [bib_ref] Vaccine effectiveness of 2011/12 trivalent seasonal influenza vaccine in preventing laboratoryconfirmed influenza..., Pebody [/bib_ref] [bib_ref] Evaluating the effectiveness of the influenza vaccine during respiratory outbreaks in Singapore's..., Ng [/bib_ref] [bib_ref] Influenza vaccine failure in the tropics: a retrospective cohort study of waning..., Young [/bib_ref] [bib_ref] Influenza vaccine effectiveness and waning effect in hospitalized older adults, Mira-Iglesias [/bib_ref] [bib_ref] Waning vaccine effectiveness against influenza-associated hospitalizations among adults, Ferdinands [/bib_ref]. For most persons who need only 1 dose of influenza vaccine for the season, vaccination should ideally be offered during September or October. However, vaccination should continue after October and throughout the influenza season as long as influenza viruses are circulating and unexpired vaccine is available. Considerations for timing of vaccination include the following: - For most adults (particularly adults aged ≥65 years) and for pregnant persons in the first or second trimester: Vaccination during July and August should be avoided unless there is concern that vaccination later in the season might not be possible. - Children who require 2 doses: Certain children aged 6 months through 8 years require 2 doses of influenza vaccine for the season (see Children Aged 6 Months Through 8 Years: Number of Influenza Vaccine Doses) . These children should receive their first dose as soon as possible (including during July and August, if vaccine is available) to allow the second dose (which must be administered ≥4 weeks later) to be received, ideally, by the end of October. - Children who require only 1 dose: Vaccination during July and August can be considered for children of any age who need only 1 dose of influenza vaccine for the season. While waning of immunity after vaccination over the course of the season has been observed among all age groups [bib_ref] Waning vaccine protection against influenza A (H3N2) illness in children and older..., Belongia [/bib_ref] [bib_ref] Influenza vaccine effectiveness: maintained protection throughout the duration of influenza seasons, Radin [/bib_ref] [bib_ref] Intraseason waning of influenza vaccine effectiveness, Ray [/bib_ref] [bib_ref] Influenza vaccine effectiveness among children for the 2017-2018 season, Powell [/bib_ref] [bib_ref] Primary Health Care Sentinel Network; Network for Influenza Surveillance in Hospitals of..., Castilla [/bib_ref] [bib_ref] Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination..., Kissling [/bib_ref] [bib_ref] Intraseason waning of influenza vaccine protection: evidence from the US Influenza Vaccine..., Ferdinands [/bib_ref] [bib_ref] Valencia Hospital Network for the Study of Influenza and other Respiratory Viruses..., Puig-Barberà [/bib_ref] [bib_ref] I-MOVE case-control study team. I-MOVE multicentre case-control study 2010/11 to 2014/15: is..., Kissling [/bib_ref] [bib_ref] Vaccine effectiveness of 2011/12 trivalent seasonal influenza vaccine in preventing laboratoryconfirmed influenza..., Pebody [/bib_ref] [bib_ref] Evaluating the effectiveness of the influenza vaccine during respiratory outbreaks in Singapore's..., Ng [/bib_ref] [bib_ref] Influenza vaccine failure in the tropics: a retrospective cohort study of waning..., Young [/bib_ref] [bib_ref] Influenza vaccine effectiveness and waning effect in hospitalized older adults, Mira-Iglesias [/bib_ref] [bib_ref] Waning vaccine effectiveness against influenza-associated hospitalizations among adults, Ferdinands [/bib_ref] , there are fewer published studies reporting results specifically among children [bib_ref] Waning vaccine protection against influenza A (H3N2) illness in children and older..., Belongia [/bib_ref] [bib_ref] Influenza vaccine effectiveness: maintained protection throughout the duration of influenza seasons, Radin [/bib_ref] [bib_ref] Intraseason waning of influenza vaccine effectiveness, Ray [/bib_ref] [bib_ref] Influenza vaccine effectiveness among children for the 2017-2018 season, Powell [/bib_ref]. Moreover, children in this group might visit health care providers during the late summer months for medical examinations before the start of school. Vaccination can be considered at this time because it represents a vaccination opportunity. - Pregnant persons in the third trimester: Vaccination during July and August can be considered for pregnant persons who are in the third trimester because vaccination might reduce risk for influenza illness in their infants during the first months after birth, when they are too young to receive influenza vaccine [bib_ref] Maternal Flu Trial (Matflu) Team. Influenza vaccination of pregnant women and protection..., Madhi [/bib_ref] [bib_ref] Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in..., Tapia [/bib_ref] [bib_ref] Year-round influenza immunisation during pregnancy in Nepal: a phase 4, randomised, placebo-controlled..., Steinhoff [/bib_ref] [bib_ref] Effectiveness of maternal influenza immunization in mothers and infants, Zaman [/bib_ref]. For pregnant persons in the first or second trimester during July and August, waiting to vaccinate until September or October is preferable, unless there is concern that later vaccination might not be possible. Community vaccination programs should balance maximizing the likelihood of persistence of vaccine-induced protection through the season with avoiding missed opportunities to vaccinate or vaccinating after onset of influenza circulation occurs. Efforts should be structured to optimize vaccination coverage before influenza activity in the community begins. Vaccination should continue to be offered as long as influenza viruses are circulating and unexpired vaccine is available. To avoid missed opportunities for ## Figure. influenza vaccine dosing algorithm for children aged 6 months through 8 years* -advisory committee on immunization practices, united states, 2022-23 influenza season Options ide = 7.5" ats = 5.0" ns = 4.65" n = 3.57" Did the child receive ≥2 doses of trivalent or quadrivalent in uenza vaccine before July 1, 2022? (Doses need not have been received during same or consecutive seasons.) ## Yes No or unknown Optimally, vaccination should occur before onset of influenza activity in the community. However, because timing of the onset, peak, and decline of influenza activity varies, the ideal time to start vaccinating cannot be predicted each season. Moreover, more than one outbreak might occur in a community in a single year. In the United States, localized outbreaks indicating the start of seasonal influenza activity can occur as early as October. However, in 29 (76%) of 38 influenza seasons from 1982-83 through 2019-20, peak influenza activity (which often is close to the midpoint of influenza activity for the season) has not occurred until January or later, and in 23 (61%) seasons, the peak was in February or later. Activity peaked in February in 17 (45%) of these seasons. An increasing number of observational studies [bib_ref] Waning vaccine protection against influenza A (H3N2) illness in children and older..., Belongia [/bib_ref] [bib_ref] Influenza vaccine effectiveness: maintained protection throughout the duration of influenza seasons, Radin [/bib_ref] [bib_ref] Intraseason waning of influenza vaccine effectiveness, Ray [/bib_ref] [bib_ref] Influenza vaccine effectiveness among children for the 2017-2018 season, Powell [/bib_ref] [bib_ref] Primary Health Care Sentinel Network; Network for Influenza Surveillance in Hospitals of..., Castilla [/bib_ref] [bib_ref] Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination..., Kissling [/bib_ref] [bib_ref] Intraseason waning of influenza vaccine protection: evidence from the US Influenza Vaccine..., Ferdinands [/bib_ref] [bib_ref] Valencia Hospital Network for the Study of Influenza and other Respiratory Viruses..., Puig-Barberà [/bib_ref] [bib_ref] I-MOVE case-control study team. I-MOVE multicentre case-control study 2010/11 to 2014/15: is..., Kissling [/bib_ref] [bib_ref] Vaccine effectiveness of 2011/12 trivalent seasonal influenza vaccine in preventing laboratoryconfirmed influenza..., Pebody [/bib_ref] [bib_ref] Evaluating the effectiveness of the influenza vaccine during respiratory outbreaks in Singapore's..., Ng [/bib_ref] [bib_ref] Influenza vaccine failure in the tropics: a retrospective cohort study of waning..., Young [/bib_ref] [bib_ref] Influenza vaccine effectiveness and waning effect in hospitalized older adults, Mira-Iglesias [/bib_ref] [bib_ref] Waning vaccine effectiveness against influenza-associated hospitalizations among adults, Ferdinands [/bib_ref] have reported decreases in vaccine effectiveness with increasing time postvaccination within a single influenza season. Waning effects have not been observed consistently across age groups, influenza viruses (types, subtypes, and lineages), or seasons. Certain studies suggest waning occurs to a greater degree against influenza A(H3N2) viruses than against influenza A(H1N1) or influenza B viruses [bib_ref] Valencia Hospital Network for the Study of Influenza and other Respiratory Viruses..., Puig-Barberà [/bib_ref] [bib_ref] I-MOVE case-control study team. I-MOVE multicentre case-control study 2010/11 to 2014/15: is..., Kissling [/bib_ref]. This effect also might vary with recipient age; in certain studies, waning was more pronounced among older adults [bib_ref] Waning vaccine protection against influenza A (H3N2) illness in children and older..., Belongia [/bib_ref] [bib_ref] Primary Health Care Sentinel Network; Network for Influenza Surveillance in Hospitals of..., Castilla [/bib_ref] [bib_ref] Valencia Hospital Network for the Study of Influenza and other Respiratory Viruses..., Puig-Barberà [/bib_ref] [bib_ref] Influenza vaccine failure in the tropics: a retrospective cohort study of waning..., Young [/bib_ref] [bib_ref] Waning vaccine effectiveness against influenza-associated hospitalizations among adults, Ferdinands [/bib_ref] and younger children [bib_ref] Waning vaccine protection against influenza A (H3N2) illness in children and older..., Belongia [/bib_ref]. Relatively fewer reports include results specific to children [bib_ref] Waning vaccine protection against influenza A (H3N2) illness in children and older..., Belongia [/bib_ref] [bib_ref] Influenza vaccine effectiveness: maintained protection throughout the duration of influenza seasons, Radin [/bib_ref] [bib_ref] Intraseason waning of influenza vaccine effectiveness, Ray [/bib_ref] [bib_ref] Influenza vaccine effectiveness among children for the 2017-2018 season, Powell [/bib_ref] ; findings suggestive of waning have been reported in certain studies (19-21) but not others [bib_ref] Influenza vaccine effectiveness among children for the 2017-2018 season, Powell [/bib_ref]. Rates of decline in vaccine effectiveness also varied. A multiseason (2011-12 through 2014-15) analysis from the U.S. Influenza Vaccine Effectiveness (U.S. Flu VE) Network found that vaccine effectiveness decreased by approximately 7% per month for influenza A(H3N2) and influenza B and 6%-11% per month for influenza A(H1N1) pdm09 [bib_ref] Intraseason waning of influenza vaccine protection: evidence from the US Influenza Vaccine..., Ferdinands [/bib_ref]. Vaccine effectiveness remained greater than zero for at least 5-6 months after vaccination. In the Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) during the 2015-16 through 2018-19 seasons, vaccine effectiveness against influenza-associated hospitalizations declined by approximately 8%-9% per month for all adults and approximately 10%-11% per month for those aged ≥65 years [bib_ref] Waning vaccine effectiveness against influenza-associated hospitalizations among adults, Ferdinands [/bib_ref]. An analysis of the 2010-11 through 2013-14 seasons noted estimated effectiveness ranging from 54% to 67% during days 0-180 postvaccination; estimated vaccine effectiveness was not significant during the period between days 181 and 365 [bib_ref] Influenza vaccine effectiveness: maintained protection throughout the duration of influenza seasons, Radin [/bib_ref]. A third multiseason analysis (2010-11 through 2014-15) conducted in Europe noted a decline in vaccine effectiveness to 0% at 111 days postvaccination against influenza A(H3N2) viruses. Vaccine effectiveness against influenza B viruses decreased more slowly, and vaccine effectiveness against influenza A(H1N1)pdm09 viruses remained roughly stable at 50%-55% throughout the influenza season [bib_ref] I-MOVE case-control study team. I-MOVE multicentre case-control study 2010/11 to 2014/15: is..., Kissling [/bib_ref]. A meta-analysis of 14 studies examining waning of influenza vaccine effectiveness using the test-negative design found a significant decline in effectiveness within 180 days after vaccination against influenza A (H3N2) and influenza B but not against influenza A(H1N1) [bib_ref] Duration of influenza vaccine effectiveness: a systematic review, meta-analysis, and metaregression of..., Young [/bib_ref]. In addition to the factors observed to be associated with waning immunity across studies, observed decreases in protection might be at least in part attributable to bias, unmeasured confounding, or the late-season emergence of antigenic drift variants of influenza viruses that are less well-matched to the vaccine viruses. Varying data concerning the presence and rate of waning immunity after influenza vaccination, coupled with the unpredictable timing of the influenza season each year, prevent determination of an optimal time to vaccinate. Programmatic issues also are a consideration. Although delaying vaccination might result in greater immunity later in the season, deferral also might result in missed opportunities to vaccinate as well as difficulties in vaccinating a population within a more constrained period. The potential contributions of these factors among persons aged ≥65 years have been assessed using a simulated mathematical model examining various scenarios of vaccination timing, timing of onset of the influenza season, vaccine effectiveness, and rate of waning [bib_ref] Waning of influenza vaccine protection: exploring the trade-offs of changes in vaccination..., Ferdinands [/bib_ref]. In this model, during an influenza season beginning in October and peaking in January, delaying vaccination until October resulted in more hospitalizations if >14% of persons aged ≥65 years who would have been vaccinated in August or September failed to get vaccinated. However, these predictions varied considerably with assumed timing of season onset, rate of waning immunity, and vaccine effectiveness. Vaccination efforts should continue throughout the season because the duration of the influenza season varies, and influenza activity might not occur in certain communities until February, March, or later. Providers should offer influenza vaccine routinely, and organized vaccination campaigns should continue throughout the influenza season, including after influenza activity has begun in the community. Although vaccination by the end of October is recommended, vaccine administered in December or later, even if influenza activity has already begun, might be beneficial in most influenza seasons. Providers should offer influenza vaccination to unvaccinated persons who have already become ill with influenza during the season because the vaccine might protect them against other circulating influenza viruses. ## Guidance for influenza vaccination in specific populations and situations ## Populations at higher risk for medical complications attributable to severe influenza All persons aged ≥6 months who do not have contraindications should be vaccinated annually. However, vaccination to prevent influenza is particularly important for persons who are at increased risk for severe illness and complications from influenza and for influenza-related outpatient, emergency department, or hospital visits. When vaccine supply is limited, vaccination efforts should focus on vaccination of persons at higher risk for medical complications attributable to severe influenza who do not have contraindications. These persons include the following (no hierarchy is implied by order of listing): - All children aged 6 through 59 months. for adults). An IIV4 or RIV4 (as appropriate for the recipient's age) is suitable for persons in all risk groups. LAIV4 is not recommended for certain populations, including certain of these listed groups. Contraindications and precautions for the use of LAIV4 are noted [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref]. ## Persons who live with or care for persons at higher risk for influenza-related complications All persons aged ≥6 months without contraindications should be vaccinated annually. However, emphasis also should be placed on vaccination of persons who live with or care for those who are at increased risk for medical complications attributable to severe influenza. When vaccine supply is limited, vaccination efforts should focus on administering vaccination to persons at higher risk for influenza-related complications as well as persons who live with or care for such persons, including the following: - Health care personnel, including all paid and unpaid persons working in health care settings who have the potential for exposure to patients or to infectious materials. These personnel might include but are not limited to physicians, nurses, nursing assistants, nurse practitioners, physician assistants, therapists, technicians, emergency medical service personnel, dental personnel, pharmacists, laboratory personnel, autopsy personnel, students and trainees, contractual staff persons, and others not directly involved in patient care but who might be exposed to infectious agents (e.g., clerical, dietary, housekeeping, laundry, security, maintenance, administrative, and billing staff persons and volunteers). ACIP guidance for vaccination of health care personnel has been published previously. - Household contacts (including children aged ≥6 months) and caregivers of children aged ≤59 months (<5 years) and adults aged ≥50 years, particularly contacts of children aged <6 months. - Household contacts (including children aged ≥6 months) and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza. Health care personnel and persons who are contacts of persons in these groups (with the exception of contacts of severely immunocompromised persons who require a protected environment) may receive any influenza vaccine that is otherwise indicated. Persons who care for severely immunocompromised persons requiring a protected environment should not receive LAIV4. ACIP and the Healthcare Infection Control Practices Advisory Committee (HICPAC) have previously recommended that health care personnel who receive LAIV should avoid providing care for severely immunocompromised persons requiring a protected environment for 7 days after vaccination and that hospital visitors who have received LAIV should avoid contact with such persons for 7 days after vaccination. However, such persons need not be restricted from caring for or visiting less severely immunocompromised persons. ## Influenza vaccination of persons with covid-19 Vaccination of persons who have tested positive for COVID-19 or who are in quarantine after an exposure should include multiple considerations, such as whether bringing the person into a vaccination setting could expose others to COVID-19, whether the person is acutely ill and the severity of the illness, the presence of risk factors for severe influenza illness, the likelihood of being able to vaccinate at a later date, and the desire to avoid confusing postvaccination symptoms with those of COVID-19. Usually, persons who are in quarantine or isolation should not be brought to a vaccination setting if doing so could expose others to COVID-19. For those who have moderate or severe COVID-19, vaccination should usually be deferred until they have recovered, which is consistent with ACIP General Best Practice Guidelines for Immunization. For persons who have mild or asymptomatic COVID-19, further deferral might be considered to avoid confusing COVID-19 symptoms with postvaccination reactions. Because recommendations for vaccination of this population might continue to evolve, clinicians should check CDC guidance (https://www.cdc.gov/vaccines/pandemic-guidance/index.html) for up-to-date information. ## Children aged 6 through 35 months: influenza vaccine dose volumes Five IIV4s are approved for children aged ≥6 months [fig_ref] TABLE 1: Influenza vaccines -United States, 2022-23 influenza season* Abbreviations [/fig_ref]. Four of these vaccines are egg based (Afluria Quadrivalent, Fluarix Quadrivalent, Flulaval Quadrivalent, and Fluzone Quadrivalent), and one is cell culture based (Flucelvax Quadrivalent). For these vaccines, the approved dose volumes for children aged 6 through 35 months are as follows Per the package insert, each dose may be given at either volume; however, the 0.25-mL prefilled syringes are no longer available. For all of these IIV4s, persons aged ≥36 months (≥3 years) should receive 0.5 mL per dose. Alternatively, healthy children aged ≥24 months (≥2 years) may receive LAIV4, 0.2 mL intranasally (0.1 mL in each nostril). LAIV4 is not recommended for certain populations and is not approved for children aged <2 years (see Contraindications and Precautions for the Use of LAIV4) [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref]. RIV4 is not approved for children aged <18 years. High-dose inactivated influenza vaccine (HD-IIV4) and adjuvanted inactivated influenza vaccine (aIIV4) are not approved for persons aged <65 years. Care should be taken to administer an age-appropriate vaccine at the appropriate volume for each dose. For IIV4s, the recommended volume may be administered from a prefilled syringe containing the appropriate volume (as supplied by the manufacturer), a single-dose vial, or a multidose vial. Single-dose vials should be used for only 1 dose, and multidose vials should be used only for the maximum number of doses specified in the package insert. Any vaccine remaining in a vial after the maximum number of doses has been removed should be discarded, regardless of the volume of the doses obtained or any remaining volume in the vial. ## Children aged 6 months through 8 years: number of influenza vaccine doses Children aged 6 months through 8 years require 2 doses of influenza vaccine administered a minimum of 4 weeks apart during their first season of vaccination for optimal protection [bib_ref] Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza..., Neuzil [/bib_ref] [bib_ref] Effectiveness of the 2003-2004 influenza vaccine among children 6 months to 8..., Ritzwoller [/bib_ref] [bib_ref] New Vaccine Surveillance Network. Vaccine effectiveness against laboratory-confirmed influenza in children 6..., Eisenberg [/bib_ref]. Determination of the number of doses needed is based on 1) the child's age at the time of the first dose of 2022-23 influenza vaccine and 2) the number of doses of influenza vaccine received in previous influenza seasons. - For children aged 6 months through 8 years, the number of doses of influenza vaccine needed for the 2022-23 influenza season is determined as follows : ű Those who have previously received ≥2 total doses of trivalent or quadrivalent influenza vaccine ≥4 weeks apart before July 1, 2022, require only 1 dose for the 2022-23 season. The 2 previous doses of influenza vaccine do not need to have been received in the same season or consecutive seasons. ű Those who have not previously received ≥2 doses of trivalent or quadrivalent influenza vaccine ≥4 weeks apart before July 1, 2022, or whose previous influenza vaccination history is unknown, require 2 doses for the 2022-23 season. The interval between the 2 doses should be ≥4 weeks. Children aged 6 months through 8 years who require 2 doses of influenza vaccine should receive their first dose as soon as possible (including during July and August, if vaccine is available) to allow the second dose (which must be administered ≥4 weeks later) to be received, ideally, by the end of October. Two doses are recommended even if the child turns age 9 years between receipt of dose 1 and dose 2. - Adults and children aged ≥9 years need only 1 dose of influenza vaccine for the 2022-23 season. ## Pregnant persons Pregnant and postpartum persons have been observed to be at higher risk for severe illness and complications from influenza, particularly during the second and third trimesters. Influenza vaccination during pregnancy is associated with reduced risk for respiratory illness and influenza among pregnant and postpartum persons as well as infants during the first several months of life [bib_ref] Maternal Flu Trial (Matflu) Team. Influenza vaccination of pregnant women and protection..., Madhi [/bib_ref] [bib_ref] Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in..., Tapia [/bib_ref] [bib_ref] Year-round influenza immunisation during pregnancy in Nepal: a phase 4, randomised, placebo-controlled..., Steinhoff [/bib_ref] [bib_ref] Effectiveness of maternal influenza immunization in mothers and infants, Zaman [/bib_ref] [bib_ref] Maternal influenza vaccination and effect on influenza virus infection in young infants, Eick [/bib_ref]. ACIP and the American College of Obstetricians and Gynecologists recommend that persons who are pregnant or who might be pregnant or postpartum during the influenza season receive influenza vaccine [bib_ref] ACOG Committee opinion no. 732: influenza vaccination during pregnancy, Acog Committee On Obstetric Practice [/bib_ref]. Any licensed, recommended, and age-appropriate IIV4 or RIV4 may be used. LAIV4 should not be used during pregnancy but can be used postpartum. Influenza vaccine can be administered at any time during pregnancy (i.e., during any trimester), before and during the influenza season. Early vaccination (i.e., during July and August) can be considered for persons who are in the third trimester during these months if vaccine is available because this can provide protection for the infant during the first months of life when they are too young to be vaccinated. Although experience with the use of IIVs during pregnancy is substantial, data specifically reflecting administration of influenza vaccines during the first trimester are limited (see Safety of Influenza Vaccines in the supplementary Background Document). Most studies have not noted an association between influenza vaccination and adverse pregnancy outcomes, including spontaneous abortion (miscarriage) (51-61). One observational Vaccine Safety Datalink (VSD) study conducted during the 2010-11 and 2011-12 seasons noted an association between receipt of IIV containing influenza A(H1N1)pdm09 and risk for miscarriage in the 28 days after receipt of IIV, when an H1N1pdm09-containing vaccine also had been received the previous season [bib_ref] Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09..., Donahue [/bib_ref]. However, in a larger VSD follow-up study, IIV was not associated with an increased risk for miscarriage during the 2012-13, 2013-14, and 2014-15 seasons, regardless of previous season vaccination [bib_ref] Inactivated influenza vaccine and spontaneous abortion in the Vaccine Safety Datalink in..., Donahue [/bib_ref]. Substantially less experience exists with more recently licensed IIVs (e.g., quadrivalent and cell culture-based vaccines) during pregnancy than with previously available products. For RIV (available as RIV3 from 2013-14 through 2017-18 and as RIV4 since 2017-18), data are limited to reports of pregnancies occurring incidentally during clinical trials, Vaccine Adverse Event Reporting System (VAERS) reports, and pregnancy registries. Pregnancy registries and surveillance studies exist for certain products, for which information can be found in package inserts. ## Older adults ACIP recommends that adults aged ≥65 years preferentially receive any one of the following higher dose or adjuvanted influenza vaccines: quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), quadrivalent recombinant influenza vaccine (RIV4), or quadrivalent adjuvanted inactivated influenza vaccine (aIIV4). If none of these three vaccines is available at an opportunity for vaccine administration, then any other ageappropriate influenza vaccine should be administered. Older adults (aged ≥65 years) are at increased risk for severe influenza-associated illness, hospitalization, and death compared with younger persons [bib_ref] GA: US Department of Health and Human Services, CDC, Cdc [/bib_ref] [bib_ref] Mortality associated with influenza and respiratory syncytial virus in the United States, Thompson [/bib_ref]. Influenza vaccines are often less effective in this population. HD-IIV, RIV, and aIIV have been evaluated in comparison with nonadjuvanted SD-IIVs in this age group. Two of these vaccines, HD-IIV and RIV, are higher dose vaccines, which contain an increased dose of HA antigen per virus compared with nonadjuvanted SD-IIVs (60 µg for HD-IIV4 and 45 µg for RIV4, compared with 15 µg for standard-dose inactivated vaccines). The adjuvanted vaccine contains 15 µg of HA per virus, similarly to nonadjuvanted SD-IIVs, but contains the adjuvant MF59. HD-IIV, RIV, and aIIV have shown relative benefit compared with SD-IIVs in certain studies, with the most evidence available for HD-IIV3. Randomized efficacy studies comparing these vaccines with nonadjuvanted SD-IIVs against laboratoryconfirmed influenza outcomes are few in number (66-68) and cover few influenza seasons. Observational studies, predominantly retrospective cohort studies using diagnostic code-defined (rather than laboratory-confirmed) outcomes, are more numerous and include more influenza seasons [bib_ref] Comparative effectiveness of high-dose versus standard-dose influenza vaccines among US Medicare beneficiaries..., Shay [/bib_ref] [bib_ref] Relative effectiveness of cellcultured and egg-based influenza vaccines among elderly persons in..., Izurieta [/bib_ref] [bib_ref] Relative effectiveness of influenza vaccines among the United States elderly, Izurieta [/bib_ref] [bib_ref] Comparative effectiveness of influenza vaccines among U.S. Medicare beneficiaries ages 65 years..., Izurieta [/bib_ref] [bib_ref] Effect of age on relative effectiveness of high-dose versus standard-dose influenza vaccines..., Lu [/bib_ref] [bib_ref] Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged..., Izurieta [/bib_ref] [bib_ref] Comparative effectiveness of high-dose versus standard-dose influenza vaccination in community-dwelling veterans, Richardson [/bib_ref] [bib_ref] Relative vaccine effectiveness of high-dose versus standard-dose influenza vaccines among Veterans Health..., Young-Xu [/bib_ref] [bib_ref] Analysis of relative effectiveness of high-dose versus standard-dose influenza vaccines using an..., Young-Xu [/bib_ref] [bib_ref] High-dose influenza vaccination and mortality among predominantly male, white, senior veterans, United..., Young-Xu [/bib_ref] [bib_ref] Evaluating the relative vaccine effectiveness of adjuvanted trivalent influenza vaccine compared to..., Pelton [/bib_ref]. Certain observational studies have reported relative benefit for HD-IIV, RIV, and aIIV in comparison with nonadjuvanted SD-IIVs, particularly in prevention of influenza-associated hospitalizations. The size of this relative benefit has varied from season to season and is not seen in all studies in all seasons, making it difficult to generalize the findings to all or most seasons. Studies directly comparing HD-IIV, RIV, and aIIV with one another are few and do not support a conclusion that any one of these vaccines is consistently superior to the others across seasons [bib_ref] Relative effectiveness of cellcultured and egg-based influenza vaccines among elderly persons in..., Izurieta [/bib_ref] [bib_ref] Relative effectiveness of influenza vaccines among the United States elderly, Izurieta [/bib_ref] [bib_ref] Comparative effectiveness of influenza vaccines among U.S. Medicare beneficiaries ages 65 years..., Izurieta [/bib_ref] [bib_ref] Evaluating the relative vaccine effectiveness of adjuvanted trivalent influenza vaccine compared to..., Pelton [/bib_ref] [bib_ref] Comparative effectiveness of high dose versus adjuvanted influenza vaccine: a retrospective cohort..., Van Aalst [/bib_ref] [bib_ref] A retrospective cohort study assessing relative effectiveness of adjuvanted versus high-dose trivalent..., Pelton [/bib_ref]. Of note, for the 2020-21 season, quadrivalent formulations of high-dose (HD-IIV4) and adjuvanted (aIIV4) influenza vaccines were introduced. Trivalent formulations of these vaccines are no longer available. Data summarizing comparisons of these newer quadrivalent formulations relative to nonadjuvanted SD-IIV4s against laboratory-confirmed influenza outcomes are not yet available. Literature concerning the efficacy, effectiveness, and safety of HD-IIV, RIV, and aIIV versus nonadjuvanted SD-IIVs and of each of these three vaccines with one another was reviewed, focusing on published studies performed during nonpandemic influenza seasons. A description of the systematic review and GRADE is available at https://www.cdc.gov/vaccines/acip/recs/grade/influenzaolder-adults.html. An abbreviated summary follows. ## Randomized studies comparing hd-iiv, riv, and aiiv with nonadjuvanted sd-iivs: prevention of influenza Illnesses. Randomized studies comparing HD-IIV, RIV, and aIIV with nonadjuvanted SD-IIVs against laboratoryconfirmed influenza illness are few in number and were conducted over few influenza seasons. HD-IIV3 was more effective than SD-IIV3 in prevention of polymerase chain reaction (PCR)-or culture-confirmed influenza-like illness (ILI) in a two-season randomized study conducted among 32,000 persons aged ≥65 years (relative efficacy: 24%; 95% CI: 10%-36%; certainty level: 1, high) [bib_ref] Efficacy of high-dose versus standard-dose influenza vaccine in older adults, Diazgranados [/bib_ref]. Two singleseason randomized trials of RIV versus nonadjuvanted SD-IIV, one a comparison of RIV3 versus nonadjuvanted SD-IIV3 that assessed culture-confirmed ILI (67) and the other a comparison of RIV4 versus nonadjuvanted SD-IIV4 that examined PCRconfirmed ILI (68), did not demonstrate relative benefit of RIV among those aged ≥65 years (pooled relative efficacy: 18%; 95% CI: −17% to 43%; certainty level: 2, moderate). The larger of these two studies noted a relative benefit of RIV4 over nonadjuvanted SD-IIV4 in prevention of PCR-confirmed influenza among the full study population of persons aged ≥50 years (relative efficacy: 30%; 95% CI: 10%-47%) as well as against culture-confirmed ILI among those aged ≥65 years (relative efficacy: 42%; 95% CI: 9%-65%) [bib_ref] PSC12 Study Team. Efficacy of recombinant influenza vaccine in adults 50 years..., Dunkle [/bib_ref]. No data are available from randomized trials of aIIV versus nonadjuvanted SD-IIVs against laboratory-confirmed influenza outcomes during nonpandemic influenza seasons. ## Randomized studies comparing hd-iiv, riv, and aiiv with nonadjuvanted sd-iivs: prevention of influenza-associated hospitalizations and other serious events. No data are available from randomized trials evaluating prevention of laboratory-confirmed influenza-associated hospitalizations as a primary outcome. In a secondary analysis from a twoseason randomized trial of HD-IIV3 versus nonadjuvanted SD-IIV3 assessing serious adverse events (SAEs) (including hospitalizations) associated with laboratory confirmation of influenza performed outside of the study [bib_ref] Prevention of serious events in adults 65 years of age or older:..., Diazgranados [/bib_ref] and a post hoc analysis of pneumonia-and influenza-related hospitalizations from a randomized study of HD-IIV3 versus nonadjuvanted SD-IIV4 [bib_ref] Effect of high-dose trivalent vs standard-dose quadrivalent influenza vaccine on mortality or..., Vardeny [/bib_ref] , there was no difference in risk for these events between the two groups (certainty level: 2, moderate). However, additional data are available from two singleseason, cluster-randomized studies conducted among U.S. nursing homes (in which nursing homes were randomized to vaccine groups rather than individual persons) that examined prevention of pneumonia and influenza diagnostic-coded hospitalizations. One such study noted a benefit of HD-IIV3 relative to nonadjuvanted SD-IIV3 (adjusted relative risk: 0.79; 95% CI: 0.66-0.95; certainty level: 2, moderate) [bib_ref] Comparative effectiveness of high-dose versus standard-dose influenza vaccination on numbers of US..., Gravenstein [/bib_ref]. The second noted a benefit of aIIV3 relative to nonadjuvanted SD-IIV3 (adjusted hazard ratio: 0.79; 95% CI: 0.65-0.96; certainty level: 2, moderate) [bib_ref] Cluster-randomized trial of adjuvanted versus nonadjuvanted trivalent influenza vaccine in 823 US..., Mcconeghy [/bib_ref]. ## Observational studies comparing hd-iiv, riv, and aiiv with nonadjuvanted sd-iivs: prevention of influenza-associated hospitalizations and deaths. Observational studies comparing HD-IIV and aIIV with nonadjuvanted SD-IIVs are more numerous than randomized studies and cover more influenza seasons. Many of these studies assessed diagnostic code-defined (rather than laboratory-confirmed) outcomes. In these studies, an overall modest relative benefit in prevention of diagnostic code-defined influenza-associated hospitalizations has been observed for HD-IIV3 (70-77) and aIIV3 [bib_ref] Relative effectiveness of cellcultured and egg-based influenza vaccines among elderly persons in..., Izurieta [/bib_ref] [bib_ref] Relative effectiveness of influenza vaccines among the United States elderly, Izurieta [/bib_ref] [bib_ref] Comparative effectiveness of influenza vaccines among U.S. Medicare beneficiaries ages 65 years..., Izurieta [/bib_ref] versus nonadjuvanted SD-IIV3s. Relative benefit was not found in every study for all evaluated seasons for either HD-IIV3 or aIIV3. Published observational studies of RIV are fewer than for HD-IIV and aIIV. A retrospective analysis of relative effectiveness of RIV4 versus SD-IIV4 against influenza-coded hospitalizations among Medicare beneficiaries during the 2019-20 season noted a relative effectiveness of 17% (95% CI: 9%-24%; certainty level: 3, low) [bib_ref] Comparative effectiveness of influenza vaccines among U.S. Medicare beneficiaries ages 65 years..., Izurieta [/bib_ref]. Observational studies that address relative benefit in protection against influenza-associated deaths are limited. Two retrospective cohort studies including three influenza seasons noted a relative benefit of HD-IIV3 compared with nonadjuvanted SD-IIV3 (69,78) diagnostic code-defined deaths (pooled rate ratio: 0.69; 95% CI: 0.57-0.84; certainty level: 3, low). Observational Studies Comparing Effectiveness of HD-IIV, RIV, and aIIV with One Another. Data reflecting comparisons of HD-IIV, aIIV, and RIV with one another are more limited than comparisons with nonadjuvanted SD-IIVs. Observational studies have compared HD-IIV3 versus aIIV3 [bib_ref] Relative effectiveness of cellcultured and egg-based influenza vaccines among elderly persons in..., Izurieta [/bib_ref] [bib_ref] Relative effectiveness of influenza vaccines among the United States elderly, Izurieta [/bib_ref] [bib_ref] Comparative effectiveness of influenza vaccines among U.S. Medicare beneficiaries ages 65 years..., Izurieta [/bib_ref] [bib_ref] Evaluating the relative vaccine effectiveness of adjuvanted trivalent influenza vaccine compared to..., Pelton [/bib_ref] [bib_ref] Comparative effectiveness of high dose versus adjuvanted influenza vaccine: a retrospective cohort..., Van Aalst [/bib_ref] [bib_ref] A retrospective cohort study assessing relative effectiveness of adjuvanted versus high-dose trivalent..., Pelton [/bib_ref] , HD-IIV3 versus RIV4 [bib_ref] Comparative effectiveness of influenza vaccines among U.S. Medicare beneficiaries ages 65 years..., Izurieta [/bib_ref] , and aIIV3 versus RIV4 [bib_ref] Comparative effectiveness of influenza vaccines among U.S. Medicare beneficiaries ages 65 years..., Izurieta [/bib_ref]. A retrospective cohort analysis noted relative effectiveness of RIV4 compared with HD-IIV3 (relative effectiveness: 11%; 95% CI: 3%-18%; certainty level: 3, low) and with aIIV3 (relative effectiveness: 11%; 95% CI: 3%-17%; certainty level: 3, low); these data covered only a single influenza season. Data do not point to a consistent relative benefit of one of these three influenza vaccines over another across multiple seasons. Safety. In comparative safety studies, certain injection site and systemic reactions were observed more frequently in older persons vaccinated with HD-IIV3 and aIIV3 compared with nonadjuvanted SD-IIV3 [bib_ref] Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and..., Falsey [/bib_ref] [bib_ref] Comparison of the safety and immunogenicity of an MF59®-adjuvanted with a non-adjuvanted..., Frey [/bib_ref]. In a randomized trial of RIV4 versus nonadjuvanted SD-IIV4 among persons aged ≥50 years, frequencies of solicited injection site events were similar or lower among RIV4 recipients; frequency of fever was similar between the two vaccines. Frequencies of SAEs were similar between the two groups, and none was judged to be related to a study vaccine [bib_ref] PSC12 Study Team. Efficacy of recombinant influenza vaccine in adults 50 years..., Dunkle [/bib_ref]. One postlicensure randomized clinical trial in the United States evaluated the comparative safety of aIIV3 compared with HD-IIV3 in 757 adults aged ≥65 years [bib_ref] Safety, reactogenicity, and health-related quality of life after trivalent adjuvanted vs trivalent..., Schmader [/bib_ref]. For the primary outcome, the proportion of participants who reported moderate to severe injection site pain that limited or prevented activity after aIIV3 (12 participants [3.2%]) was noninferior compared with the proportion reporting this outcome after vaccination with HD-IIV3 (22 participants [5.8%]). No participant sought medical care for a solicited reaction symptom, and none had a SAE determined by study investigators to be related to vaccine within 43 days after vaccination. ## Immunocompromised persons ACIP recommends that persons with compromised immunity (including but not limited to persons with congenital and acquired immunodeficiency states, persons who are immunocompromised due to medications, and persons with anatomic and functional asplenia) should receive an age-appropriate IIV4 or RIV4. ACIP recommends that LAIV4 not be used for these groups because of the uncertain but biologically plausible risk for disease attributable to the live vaccine virus. Use of LAIV4 in persons with these and other conditions is discussed in more detail (see Dosage, Administration, Contraindications, and Precautions) [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref]. Immunocompromised states comprise a heterogeneous range of conditions with varying risks for severe infections. In many instances, limited data are available regarding the effectiveness of influenza vaccines in the setting of specific immunocompromised states [bib_ref] Seasonal influenza vaccine in immunocompromised persons, Bosaeed [/bib_ref]. Timing of vaccination might be a consideration (e.g., vaccinating during a period either before or after an immunocompromising intervention). The Infectious Diseases Society of America has published detailed guidance for the selection and timing of vaccines for persons with specific immunocompromising conditions [bib_ref] Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination..., Rubin [/bib_ref]. Immune response to influenza vaccines might be blunted in persons with certain conditions, such as congenital immune deficiencies, and in persons receiving cancer chemotherapy or immunosuppressive medications. ## Persons with a history of guillain-barré syndrome after influenza vaccination A history of Guillain-Barré syndrome (GBS) within 6 weeks of a previous dose of any type of influenza vaccine is considered a precaution for influenza vaccination [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref]. Persons who are not at higher risk for severe influenza complications (see Populations at Higher Risk for Medical Complications Attributable to Severe Influenza) and who are known to have experienced GBS within 6 weeks of a previous influenza vaccination typically should not be vaccinated. As an alternative to vaccination, providers might consider using influenza antiviral chemoprophylaxis for these persons. However, the benefits of influenza vaccination might outweigh the possible risks for certain persons who have a history of GBS within 6 weeks after receipt of influenza vaccine and who also are at higher risk for severe complications from influenza. ## Persons with a history of egg allergy Most available influenza vaccines, with the exceptions of RIV4 (Flublok Quadrivalent, licensed for those aged ≥18 years) and ccIIV4 (Flucelvax Quadrivalent, licensed for those aged ≥6 months), are prepared by propagation of virus in embryonated eggs and might contain trace amounts of egg proteins, such as ovalbumin. For persons who report a history of egg allergy, ACIP recommends the following: - Persons with a history of egg allergy who have experienced only urticaria (hives) after exposure to egg should receive influenza vaccine. Any licensed, recommended influenza vaccine (i.e., any IIV4, RIV4, or LAIV4) that is otherwise appropriate for the recipient's age and health status can be used. - Persons who report having had reactions to egg involving symptoms other than urticaria (e.g., angioedema or swelling, respiratory distress, lightheadedness, or recurrent vomiting) or who required epinephrine or another emergency medical intervention can similarly receive any licensed, recommended influenza vaccine (i.e., any IIV4, RIV4, or LAIV4) that is otherwise appropriate for their age and health status. If a vaccine other than ccIIV4 or RIV4 is used, the selected vaccine should be administered in an inpatient or outpatient medical setting, including but not necessarily limited to hospitals, clinics, health departments, and physician offices. Vaccine administration should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. All vaccination providers should be familiar with their office emergency plan and be certified in cardiopulmonary resuscitation. No postvaccination observation period is recommended specifically for egg-allergic persons. However, ACIP recommends that vaccination providers consider observing patients (seated or supine) for 15 minutes after administration of any vaccine to decrease the risk for injury should syncope occur. ## Persons with previous allergic reactions to influenza vaccines As is the case for all vaccines, influenza vaccines contain various components that might cause allergic and anaphylactic reactions. Most influenza vaccine package inserts list among contraindications to their use a history of previous severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or to a previous dose of any influenza vaccine. For ccIIV4 and RIV4, a history of a severe allergic reaction to any vaccine component is listed as a contraindication; no labeled contraindication is specified for a history of allergic reaction to any other influenza vaccine. However, severe allergic reactions, although rare, can occur after influenza vaccination, even among persons with no previous reactions or known allergies. Although vaccine components can be found in package inserts, identifying the causative component without further evaluation (i.e., through evaluation and testing for specific allergies) can be difficult. Severe allergic reactions after vaccination with an RIV have been reported to VAERS, some of which have occurred among persons reporting previous allergic reactions to egg or to influenza vaccines and which might represent a predisposition to development of allergic manifestations in affected persons [bib_ref] Allergic reactions after egg-free recombinant influenza vaccine: reports to the US Vaccine..., Woo [/bib_ref] [bib_ref] Postmarketing safety surveillance of trivalent recombinant influenza vaccine: reports to the Vaccine..., Woo [/bib_ref] [bib_ref] Postmarketing safety surveillance of quadrivalent recombinant influenza vaccine: Reports to the Vaccine..., Woo [/bib_ref]. Because these rare but severe allergic reactions can occur, ACIP recommends the following for persons with a history of severe allergic reaction to a previous dose of an influenza vaccine: - For egg-based IIV4s and LAIV4: ű A history of severe allergic reaction (e.g., anaphylaxis) to any influenza vaccine (i.e., any egg-based IIV, ccIIV, RIV, or LAIV of any valency) is a contraindication to future receipt of all egg-based IIV4s and LAIV4. Each individual egg-based IIV4 and LAIV4 is also contraindicated for persons who have had a severe allergic reaction (e.g., anaphylaxis) to any component of that vaccine (excluding egg) (see Persons with a History of Egg Allergy). - For ccIIV4: ű A history of a severe allergic reaction (e.g., anaphylaxis) to any egg-based IIV, RIV, or LAIV of any valency is a precaution for the use of ccIIV4. If ccIIV4 is administered in such instances, vaccination should occur in an inpatient or outpatient medical setting and should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. Providers also can consider consultation with an allergist to help determine the vaccine component responsible for the allergic reaction. ű A history of a severe allergic reaction (e.g., anaphylaxis) to any ccIIV of any valency or to any component of ccIIV4 is a contraindication to future receipt of ccIIV4. - For RIV4: ű A history of a severe allergic reaction (e.g., anaphylaxis) to any egg-based IIV, ccIIV, or LAIV of any valency is a precaution for the use of RIV4. If RIV4 is administered in such instances, vaccination should occur in an inpatient or outpatient medical setting and should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. Providers can also consider consultation with an allergist to help determine the vaccine component responsible for the allergic reaction. ű A history of a severe allergic reaction (e.g., anaphylaxis) to any RIV of any valency or to any component of RIV4 is a contraindication to future receipt of RIV4. ## Vaccination issues for travelers In temperate climate regions of the Northern and Southern Hemispheres, influenza activity is seasonal, occurring during approximately October-May in the Northern Hemisphere and April-September in the Southern Hemisphere. In the tropics, influenza might occur throughout the year. Travelers can be exposed to influenza when traveling to an area where influenza is circulating or when traveling as part of large tourist groups (e.g., on cruise ships) that include persons from areas of the world where influenza viruses are circulating [bib_ref] Alaska/Yukon Territory Respiratory Outbreak Investigation Team. Large summertime influenza A outbreak among..., Uyeki [/bib_ref] [bib_ref] Influenza virus infection in travelers to tropical and subtropical countries, Mutsch [/bib_ref] [bib_ref] Incidence and risk factors for acute respiratory illnesses and influenza virus infections..., Ratnam [/bib_ref] [bib_ref] Influenza outbreaks among passengers and crew on two cruise ships: a recent..., Millman [/bib_ref]. Travelers who want to reduce their risk for influenza should consider influenza vaccination, preferably at least 2 weeks before departure. In particular, persons who live in the United States and are at higher risk for influenza complications and who were not vaccinated with influenza vaccine during the previous Northern Hemisphere fall or winter should consider receiving influenza vaccination before departure if they plan to travel to the tropics, to the Southern Hemisphere during the Southern Hemisphere influenza season (April-September), or with organized tourist groups or on cruise ships to any location. Persons at higher risk who received the previous season's influenza vaccine before travel should consult with their health care provider to discuss the risk for influenza and other travel-related diseases before embarking on travel during the summer. All persons (regardless of risk status) who are vaccinated in preparation for travel before the upcoming influenza season's vaccine is available should receive the current vaccine the following fall or winter. Influenza vaccine formulated for the Southern Hemisphere might differ in viral composition from the Northern Hemisphere vaccine. For persons traveling to the Southern Hemisphere during the Southern Hemisphere influenza season, receipt of a current U.S.-licensed Southern Hemisphere influenza vaccine formulation before departure might be reasonable but might not be feasible because of limited access to or unavailability of Southern Hemisphere formulations in the United States. Most Southern Hemisphere influenza vaccine formulations are not licensed in the United States, and they are typically not commercially available. More information on influenza vaccines and travel is available at https://wwwnc.cdc. gov/travel/diseases/influenza-seasonal-zoonotic-and-pandemic. ## Use of influenza antiviral medications Administration of IIV4 or RIV4 to persons receiving influenza antiviral medications for treatment or chemoprophylaxis of influenza is acceptable. Data concerning vaccination with LAIV4 in the setting of influenza antiviral use are not available. However, influenza antiviral medications might interfere with the action of LAIV4 because this vaccine contains live influenza viruses. The package insert for LAIV4 notes that antiviral agents might reduce the effectiveness of the vaccine if given within the interval from 48 hours before to 14 days after vaccination. However, the newer influenza antivirals peramivir and baloxavir have longer half-lives than oseltamivir and zanamivir, approximately 20 hours for peramivir (100) and 79 hours for baloxavir, and could interfere with the replication of LAIV4 if administered >48 hours before vaccination. Potential interactions between influenza antivirals and LAIV4 have not been studied, and the ideal intervals between administration of these medications and LAIV4 are not known. Assuming a period of at least 5 half-lives for substantial decrease in drug levels (102), a reasonable assumption is that that peramivir might interfere with the mechanism of LAIV4 if administered from 5 days before through 2 weeks after vaccination and baloxavir might interfere if administered from 17 days before through 2 weeks after vaccination. The interval between influenza antiviral receipt and LAIV4 during which interference might occur could be further prolonged in the presence of medical conditions that delay medication clearance (e.g., renal insufficiency). Persons who receive these medications during these periods before or after receipt of LAIV4 should be revaccinated with another appropriate influenza vaccine (e.g., IIV4 or RIV4). ## Administration of influenza vaccines with other vaccines IIV4s and RIV4 may be administered simultaneously or sequentially with other inactivated vaccines or live vaccines. Injectable vaccines that are given concomitantly should be administered at separate anatomic sites. LAIV4 can be administered simultaneously with other live or inactivated vaccines. However, if two live vaccines are not given simultaneously, at least 4 weeks should pass after administration of one live vaccine (such as LAIV4) before another live vaccine is administered. Current guidance concerning administration of current U.S.approved or -authorized COVID-19 vaccines indicates that these vaccines may be given with influenza vaccines (https:// www.cdc.gov/vaccines/covid-19/clinical-considerations/ interim-considerations-us.html). Providers should be aware of the potential for increased reactogenicity with coadministration and should consult updated CDC guidance as more information becomes available. If administered simultaneously, COVID-19 vaccines and influenza vaccines that might be more likely to cause an injection site reaction (e.g., aIIV4 or HD-IIV4) should be administered in different limbs, if possible. In an interim analysis of a study of concomitant administration of HD-IIV4 and a booster dose of an mRNA COVID-19 vaccine (administered in separate upper arm sites) compared with administration of either vaccine alone among 296 persons aged ≥65 years, overall reactogenicity up to 7 days postvaccination was similar between the coadministration group and the group that received the mRNA COVID-19 vaccine alone; reactogenicity rates in the group receiving HD-IIV4 alone were lower. No SAEs were observed. Immune response was similar between the mRNA COVID-19 and coadministration groups [bib_ref] Safety and immunogenicity of a high-dose quadrivalent influenza vaccine administered concomitantly with..., Izikson [/bib_ref]. Relatively limited data are available on the concomitant administration of influenza vaccines with other vaccines. Studies of live attenuated zoster vaccine and IIV3 (104) or IIV4 (105) among persons aged ≥50 years noted similar antibody responses whether the two vaccines were administered concomitantly or 4 weeks apart. In certain studies, reduced responses have been noted to 13-valent pneumococcal conjugate vaccine (PCV13) [bib_ref] controlled trial of a 13-valent pneumococcal conjugate vaccine administered concomitantly with an..., Frenck [/bib_ref] [bib_ref] A randomized, double-blind trial to evaluate immunogenicity and safety of 13-valent pneumococcal..., Schwarz [/bib_ref] , tetanus antigens (108), and pertussis antigens (108) when coadministered with IIV3 to adults; in most instances, the clinical significance of this is uncertain. Simultaneous administration of IIV4 and 23-valent pneumococcal polysaccharide vaccine (PPSV23) to persons aged ≥65 years was associated with lower seroprotection rates to one influenza B antigen at 4-6 weeks postvaccination compared with sequential administration 2 weeks apart. Seroprotection was not significantly different between the two groups for any of the four influenza antigens at 6 months postvaccination [bib_ref] Immunogenicity of simultaneous versus sequential administration of a 23-valent pneumococcal polysaccharide vaccine..., Nakashima [/bib_ref]. Reassuring safety profiles have been noted for simultaneous administration of IIVs with live attenuated zoster vaccine [bib_ref] Safety and immunogenicity profile of the concomitant administration of ZOSTAVAX and inactivated..., Kerzner [/bib_ref] [bib_ref] Immunogenicity and safety of zoster vaccine live administered with quadrivalent influenza virus..., Levin [/bib_ref] ; PCV13 [bib_ref] controlled trial of a 13-valent pneumococcal conjugate vaccine administered concomitantly with an..., Frenck [/bib_ref] [bib_ref] A randomized, double-blind trial to evaluate immunogenicity and safety of 13-valent pneumococcal..., Schwarz [/bib_ref] ; PPSV23 [bib_ref] Immunogenicity of simultaneous versus sequential administration of a 23-valent pneumococcal polysaccharide vaccine..., Nakashima [/bib_ref] [bib_ref] Immunogenicity and safety of concomitant MF59-adjuvanted influenza vaccine and 23-valent pneumococcal polysaccharide..., Song [/bib_ref] ; tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine among adults (108); and Tdap in pregnancy [bib_ref] Safety of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis and influenza..., Sukumaran [/bib_ref]. Although increased prevalence of injection site or systemic adverse reactions has been noted with concurrent administration in certain studies, these symptoms have usually been reported to be mild or moderate. Among children aged 6 through 23 months, coadministration of IIV3 and PCV13 was associated with increased risk for fever on the day of vaccination and the day after (i.e., days 0-1 postvaccination) in an observational study conducted during the 2011-12 season [bib_ref] Risk of fever after pediatric trivalent inactivated influenza vaccine and 13-valent pneumococcal..., Stockwell [/bib_ref]. A randomized clinical trial during the 2017-18 influenza season suggested that delaying IIV4 administration by 2 weeks in children receiving diphtheria and tetanus toxoids and acellular pertussis (DTaP) and PCV13 did not reduce fever prevalence after vaccination [bib_ref] Fever after influenza, diphtheriatetanus-acellular pertussis, and pneumococcal vaccinations, Walter [/bib_ref]. Increased risk for febrile seizures in this age group has been noted within days 0-1 after coadministration of IIV with PCV7, PCV13, or DTaP vaccines during the 2006-07 through 2010-11 seasons [bib_ref] Vaccine Safety Datalink. Febrile seizure risk after vaccination in children 6 to..., Duffy [/bib_ref] and with PCV13 during the 2014-15 season [bib_ref] Post licensure surveillance of influenza vaccines in the Vaccine Safety Datalink in..., Li [/bib_ref]. Although concerning to parents, most febrile seizures are brief and have a good prognosis [bib_ref] Febrile seizures, Patterson [/bib_ref]. After considering the risks and benefits, no changes in the recommendations for administration of these vaccines were made. Surveillance of febrile seizures is ongoing through VAERS, and the VSD annual influenza safety surveillance includes monitoring for seizures after vaccinations. Studies of concomitant administration of LAIV with other vaccines are limited. Concurrent administration of LAIV3 with measles, mumps, and rubella (MMR) and varicella vaccine to children was not associated with diminished immunogenicity of antigens in any of the vaccines in one study [bib_ref] LAIV Study Group. Safety and immunogenicity of concurrent administration of live attenuated..., Nolan [/bib_ref] ; diminished response to rubella was observed in another study examining coadministration of LAIV3 and MMR [bib_ref] Influenza vaccine concurrently administered with a combination measles, mumps, and rubella vaccine..., Lum [/bib_ref]. No safety concerns were noted in these studies. In recent years, several vaccines containing nonaluminum adjuvants have been licensed for use in the United States for the prevention of various infectious diseases. These include AS01B (in Shingrix, recombinant zoster subunit vaccine) (119), MF59 (in Fluad Quadrivalent [aIIV4]) (120), and cytosine phosphoguanine oligodeoxynucleotide (in Heplisav-B, a recombinant hepatitis B surface antigen vaccine). Data are limited regarding coadministration of these vaccines with other adjuvanted or nonadjuvanted vaccines, including COVID-19 vaccines. Coadministration of Shingrix with nonadjuvanted IIV4 has been studied, and no evidence of decreased immunogenicity or safety concerns was noted [bib_ref] Immunogenicity and safety of an adjuvanted herpes zoster subunit vaccine coadministered with..., Schwarz [/bib_ref]. The immunogenicity and safety of simultaneous or sequential administration of two nonaluminum adjuvant-containing vaccines have not been evaluated, and the ideal interval between such vaccines when given sequentially is not known. In the study of , most reactogenicity symptoms resolved within 4 days. Because of the limited data on the safety of simultaneous administration of two or more vaccines containing nonaluminum adjuvants and the availability of nonadjuvanted influenza vaccine options, selection of a nonadjuvanted influenza vaccine may be considered in situations in which influenza vaccine and another vaccine containing a nonaluminum adjuvant are to be administered concomitantly. However, influenza vaccination should not be delayed if a specific vaccine is not available. As recommended for all vaccines, vaccines with nonaluminum adjuvants should be administered at separate anatomic sites from other vaccines that are given concomitantly. ## Influenza vaccine composition and available vaccines influenza vaccine composition for the 2022-23 season All influenza vaccines licensed in the United States will contain components derived from influenza viruses antigenically similar to those recommended by FDA (https://www.fda.gov/ advisory-committees/advisory-committee-calendar/vaccinesand-related-biological-products-advisory-committee-march-3-2022-meeting-announcement). All influenza vaccines expected to be available in the United States for the 2022-23 season will be quadrivalent vaccines. ## Vaccines available for the 2022-23 season Availability of specific types and brands of licensed seasonal influenza vaccines in the United States is determined by the manufacturers of the vaccines. Information presented concerning vaccines expected to be available and their approved indications and usage reflects current knowledge and is subject to change. Various influenza vaccines will be available for the 2022-23 season [fig_ref] TABLE 1: Influenza vaccines -United States, 2022-23 influenza season* Abbreviations [/fig_ref]. For many vaccine recipients, more than one type or brand of vaccine might be appropriate within approved indications and ACIP recommendations. A licensed influenza vaccine that is appropriate for the recipient's age and health status should be used. Specific age indications for licensed influenza vaccines are summarized [fig_ref] TABLE 1: Influenza vaccines -United States, 2022-23 influenza season* Abbreviations [/fig_ref]. Current prescribing information should be consulted for authoritative, up-to-date information. Contraindications and precautions for the different types of influenza vaccines are summarized [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref] , as are dose volumes . Not all influenza vaccines are likely to be uniformly available in any specific practice setting or geographic locality. Vaccination should not be delayed to obtain a specific product when an appropriate one is available. Within these guidelines and approved indications, ACIP makes no preferential recommendation for the use of any one influenza vaccine over another when more than one licensed, recommended, and age-appropriate vaccine is available, with the exception of selection of influenza vaccines for persons aged ≥65 years (see Older Adults). Since the publication of the previous season's recommendations, FDA has approved a labeling change for Flucelvax Quadrivalent (see Recent Influenza Vaccine Labeling Changes). Additional new licensures and changes to FDAapproved labeling might occur after publication of this report. As these changes occur and new vaccines become available, they will be reflected in the online version of . For children aged 36 months (3 years) through 17 years and adults aged ≥18 years, the dose volume for IIV4s is 0.5 mL per dose, with the exception of Fluzone High-Dose Quadrivalent (HD-IIV4, licensed for persons aged ≥65 years), for which the correct volume is 0.7 mL per dose. If a smaller vaccine dose (e.g., 0.25 mL) is inadvertently administered to a person aged ≥36 months, the remaining volume needed to make a full dose should be administered during the same vaccination visit or, if measuring the needed remaining volume is a challenge, administering a repeat dose at the full volume is acceptable. If the error is discovered later (after the recipient has left the vaccination setting), a full dose should be administered as soon as the recipient can return. Vaccination with a formulation approved for adult use should be counted as a single dose if inadvertently administered to a child. IIV4s are administered intramuscularly (IM). For adults and older children, the deltoid muscle is the preferred site. Infants and younger children should be vaccinated in the anterolateral thigh. Additional specific guidance regarding site selection and needle length for IM injection is provided in the ACIP General Best Practice Guidelines for Immunization. One IIV4, Afluria Quadrivalent, is licensed for IM injection via the PharmaJet Stratis jet injector for persons aged 18 through 64 years. Persons in this age group may receive Afluria Quadrivalent via either needle and syringe or this specific jet injection device. Children aged 6 months through 17 years and adults aged ≥65 years should receive this vaccine by needle and syringe only. No other IIV4s are licensed for administration by jet injector. Contraindications and Precautions for the Use of IIV4s. Manufacturer package inserts and updated CDC and ACIP guidance should be consulted for information on contraindications and precautions for individual influenza vaccines. Each IIV, whether egg-based or cell culture-based, has a labeled contraindication for persons with a history of a severe allergic reaction to any component of that vaccine [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref]. Although egg is a component of all IIV4s other than ccIIV4, ACIP makes specific recommendations for the use of influenza vaccine for persons with egg allergy (see Persons with a History of Egg Allergy). All egg-based IIV4s are contraindicated in persons who have had a severe allergic reaction (e.g., anaphylaxis) to a previous dose of any influenza vaccine (any egg-based IIV, ccIIV, RIV, or LAIV of any valency). Use of ccIIV4 is contraindicated in persons who have had a severe allergic reaction (e.g., anaphylaxis) to any ccIIV of any valency. A history of severe allergic reaction (e.g., anaphylaxis) to any other influenza vaccine (i.e., any egg-based IIV, RIV, or LAIV of any valency) is a precaution for the use of ccIIV4 (see Persons with Previous Allergic Reactions to Influenza Vaccines) [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref]. If ccIIV4 is administered in such an instance, vaccination should occur in an inpatient or outpatient medical setting and should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. Providers can also consider consultation with an allergist to help identify the vaccine component responsible for the reaction. Information about vaccine components can be found in the package inserts for each vaccine. Prophylactic use of antiviral agents is an option that can be considered for preventing influenza among persons who cannot receive vaccine, particularly for those who are at higher risk for medical complications attributable to severe influenza. Moderate or severe acute illness with or without fever is a general precaution for vaccination. A history of GBS within 6 weeks after receipt of a previous dose of influenza vaccine is considered a precaution for the use of all influenza vaccines [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref]. ## Quadrivalent recombinant influenza vaccine (riv4) Available Vaccine. One recombinant influenza vaccine, Flublok Quadrivalent (RIV4), is expected to be available during the 2022-23 influenza season. RIV4 is approved for persons aged ≥18 years. This vaccine contains recombinant HA produced in an insect cell line using genetic sequences from cell-derived influenza viruses and is manufactured without the use of influenza viruses or eggs. Dosage and Administration: RIV4 is administered by IM injection via needle and syringe. A 0.5-mL dose contains 45 µg of HA derived from each vaccine virus (180 µg total). ## Contraindications and precautions for the use of riv4. RIV4 is contraindicated in persons who have had a severe allergic reaction (e.g., anaphylaxis) to a previous dose of any RIV of any valency or any component of RIV4. A history of a severe allergic reaction (e.g., anaphylaxis) to any other influenza vaccine (i.e., any egg-based IIV, ccIIV, or LAIV of any valency) is a precaution for the use of RIV4. If RIV4 is administered in such an instance, vaccination should occur in an inpatient or outpatient medical setting and should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. Providers can also consider consulting with an allergist to help identify the vaccine component responsible for the reaction. Moderate or severe acute illness with or without fever is a general precaution for vaccination. A history of GBS within 6 weeks after receipt of a previous dose of influenza vaccine is considered a precaution for the use of all influenza vaccines [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref]. RIV4 is not licensed for children aged <18 years. ## Quadrivalent live attenuated influenza vaccine (laiv4) Available Vaccine. One live attenuated influenza vaccine, FluMist Quadrivalent (LAIV4), is expected to be available during the 2022-23 influenza season. LAIV4 is approved for persons aged 2 through 49 years. LAIV4 contains live attenuated influenza viruses that are propagated in eggs. These viruses are cold adapted (so that they replicate efficiently at 25°C) and temperature sensitive (so that their replication is restricted at higher temperatures, 39°C for influenza A viruses and 37°C for influenza B viruses). These viruses replicate in the nasopharynx, which is necessary to promote an immune response. No preference is expressed for LAIV4 versus other influenza vaccines used within specified indications. Dosage and Administration. LAIV4 is administered intranasally using the supplied prefilled, single-use sprayer containing 0.2 mL of vaccine. Approximately 0.1 mL (i.e., half of the total sprayer contents) is sprayed into the first nostril while the recipient is in the upright position. An attached dose-divider clip is removed from the sprayer to permit administration of the second half of the dose into the other nostril. If the recipient sneezes immediately after administration, the dose should not be repeated. However, if nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness, or another appropriate vaccine should be administered instead. Each total dose of 0.2 mL contains 10 6.5-7.5 fluorescent focus units of each vaccine virus. Contraindications and Precautions for the Use of LAIV4. Conditions considered by ACIP to be contraindications and precautions for the use of LAIV4 are summarized [fig_ref] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23... [/fig_ref]. These include two labeled contraindications that appear in the package insert (99) and other conditions for which there is uncertain but biologically plausible potential risk associated with live viruses or limited data for use of LAIV. Contraindications to use of LAIV4 include the following: - Severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or to a previous dose of any influenza vaccine (i.e., any egg-based IIV, ccIIV, RIV, or LAIV of any valency; a labeled contraindication noted in the package insert). However, ACIP makes an exception for allergy to egg (see Persons with a History of Egg Allergy). - Children and adolescents receiving concomitant aspirin-or salicylate-containing medications, because of the potential risk for Reye syndrome (a labeled contraindication noted in the package insert). - Children aged 2 through 4 years who have received a diagnosis of asthma or whose parents or caregivers report that a health care provider has told them during the preceding 12 months that their child had wheezing or asthma or whose medical record indicates a wheezing episode has occurred during the preceding 12 months. - Children and adults who are immunocompromised due to any cause, including but not limited to immunosuppression caused by medications, congenital or acquired immunodeficiency states, HIV infection, anatomic asplenia, or functional asplenia (such as that due to sickle cell anemia). - Close contacts and caregivers of severely immunosuppressed persons who require a protected environment. - Pregnancy. - Persons with active communication between the cerebrospinal fluid (CSF) and the oropharynx, nasopharynx, nose, or ear or any other cranial CSF leak. - Persons with cochlear implants, because of the potential for CSF leak that might exist for a period after implantation (providers might consider consultation with a specialist concerning the risk for persistent CSF leak if an age-appropriate inactivated or recombinant vaccine cannot be used). - Receipt of influenza antiviral medication within the previous 48 hours for oseltamivir and zanamivir, previous 5 days for peramivir, and previous 17 days for baloxavir. The interval between influenza antiviral receipt and LAIV4 during which interference might potentially occur might be further prolonged in the presence of medical conditions that delay medication clearance (e.g., renal insufficiency). Precautions for use of LAIV4 include the following: - Moderate or severe acute illness with or without fever. - History of GBS within 6 weeks after receipt of any influenza vaccine. - Asthma in persons aged ≥5 years. - Other underlying medical condition (other than those listed under contraindications) that might predispose to complications after wild-type influenza virus infection (e.g., chronic pulmonary, cardiovascular [except isolated hypertension], renal, hepatic, neurologic, hematologic, or metabolic disorders [including diabetes mellitus]). ## Recent influenza vaccine labeling changes flucelvax quadrivalent Since the publication of the 2021-22 ACIP influenza vaccine recommendations, a labeling change for Flucelvax Quadrivalent (ccIIV4) has occurred. Flucelvax Quadrivalent was initially approved in 2016 for persons aged ≥4 years. Approval for persons aged ≥18 years was based on a randomized immunogenicity and safety trial that compared Flucelvax Quadrivalent with the previously approved trivalent formulation of Flucelvax (ccIIV3), which had previously been licensed for persons aged ≥18 years on the basis of data from a randomized clinical efficacy trial. Approval for children aged 4 through 17 years also was based on immunogenicity and safety data compared with ccIIV3, with a postmarketing requirement to conduct a clinical efficacy study. In March 2021, FDA approved Flucelvax Quadrivalent for persons aged ≥2 years on the basis of a randomized clinical efficacy trial conducted among 4,514 children aged ≥2 to <18 years over three influenza seasons (Southern Hemisphere 2017 and Northern Hemisphere 2017-18 and 2018-19). Subsequently, in October 2021, FDA approved Flucelvax Quadrivalent for persons aged ≥6 months. Approval was based on a randomized immunogenicity and safety study conducted among 2,402 children aged 6 through 47 months (of whom 894 were aged 6 through 23 months). Children were randomized in a 2:1 ratio to receive either Flucelvax Quadrivalent (0.5 mL/dose containing 15 µg HA per virus for all ages) or a licensed comparator egg-based IIV4 (0.25 mL/dose containing 7.5 µg HA per virus for those aged 6 through 35 months and 0.5 mL/dose containing 15 µg HA per virus for those aged 36 through 47 months). Flucelvax Quadrivalent met prespecified immunogenicity criteria for all four viruses. No new safety signals were noted, and prevalence of solicited injection site and systemic reactions was similar between the two groups. ## Storage and handling of influenza vaccines In all instances, approved manufacturer packaging information should be consulted for authoritative guidance concerning storage and handling of specific influenza vaccines. Typically, influenza vaccines should be protected from light and stored at temperatures that are recommended in the package insert. Recommended storage temperatures are typically 36°F-46°F (2°C-8°C) and should be maintained at all times with adequate refrigeration and temperature monitoring. Vaccine that has frozen should be discarded. Specific recommendations for appropriate refrigerators and temperature monitoring equipment can be found in the Vaccine Storage and Handling Toolkit, available at https://www. cdc.gov/vaccines/hcp/admin/storage/toolkit/index.html. Vaccines should not be used beyond the expiration date on the label. In addition to the expiration date, multidose vials also might have a beyond-use date (BUD), which specifies the number of days the vaccine can be kept once first accessed. After being accessed for the first dose, multidose vials should not be used after the BUD. If no BUD is provided, then the listed expiration date is to be used. Multidose vials should be returned to recommended storage conditions between uses. Package information might also specify a maximum number of doses contained in multidose vials (regardless of remaining volume). No more than the specified number of doses should be removed, and any remainder should be discarded. Single-dose vials should not be accessed for more than 1 dose. Providers should contact the manufacturer for information on permissible temperature excursions and other departures from recommended storage and handling conditions that are not discussed in the package labeling. ## Additional sources of information regarding influenza and influenza vaccines influenza surveillance, prevention, and control Updated information regarding influenza surveillance, detection, prevention, and control is available at https:// www.cdc.gov/flu. U.S. surveillance data are updated weekly throughout the year on FluView (https://www.cdc.gov/flu/ weekly) and can be viewed in FluView Interactive (https:// www.cdc.gov/flu/weekly/fluviewinteractive.htm). In addition, periodic updates regarding influenza are published in MMWR (https://www.cdc.gov/mmwr/index.html). Additional information regarding influenza and influenza vaccines can be obtained from CDCINFO by calling 1-800-232-4636. State and local health departments should be consulted about availability of influenza vaccines, access to vaccination programs, information related to state or local influenza activity, reporting of influenza outbreaks and influenza-related pediatric deaths, and advice concerning outbreak control. ## Vaccine adverse event reporting system The National Childhood Vaccine Injury Act of 1986 requires health care providers to report any adverse event listed by the vaccine manufacturer as a contraindication to future doses of the vaccine or any adverse event listed in the VAERS Reportable Events Following Vaccination (https://vaers.hhs. gov/docs/VAERS_Table_of_Reportable_Events_Following_ Vaccination.pdf ) that occurs within the specified period after vaccination. In addition to mandated reporting, health care providers are encouraged to report any clinically significant adverse event after vaccination to VAERS. Information on how to report a vaccine adverse event is available at https:// vaers.hhs.gov/index.html. ## National vaccine injury compensation program The National Vaccine Injury Compensation Program (VICP), established by the National Childhood Vaccine Injury Act of 1986, as amended, is a mechanism through which compensation can be provided to persons who might have been injured as a result of receiving a vaccine covered by VICP. The Vaccine Injury https://www.hrsa.gov/sites/default/files/hrsa/vicp/vaccine-injurytable-01-03-2022.pdf) lists the vaccines covered by VICP and the associated injuries and conditions that might receive a legal presumption of causation. If the injury or condition is not in the table or does not meet the requirements in the table, persons must prove that the vaccine caused the injury or condition. Claims must be filed with specified time frames. Persons of all ages who receive a VICP-covered vaccine might be eligible to file a claim. Additional information is available at https://www.hrsa.gov/ vaccine-compensation or by calling 1-800-338-2382. ## Additional resources [fig] TABLE 4: Dose volumes for inactivated influenza vaccines approved for children aged 6 through 35 months* -United States, 2022(15 µg) § Abbreviation: HA = hemagglutinin. * For persons aged ≥36 months (≥3 years), the dose volume is 0.5 mL per dose for all inactivated influenza vaccines with the exception of Fluzone High-Dose Quadrivalent (HD-IIV4), which is licensed for persons aged ≥65 years and for which the dose volume is 0.7 mL per dose. † The approved dose volume for Afluria Quadrivalent is 0.25 mL for children aged 6 through 35 months and 0.5 mL for persons aged ≥3 years. However, 0.25-mL prefilled syringes are not expected to be available for the 2022-23 season. For children aged 6 through 35 months, a 0.25-mL dose must be obtained from a multidose vial. § Per the package insert, Fluzone Quadrivalent is currently approved for children aged 6 through 35 months at either 0.25 mL or 0.5 mL per dose; however, 0.25-mL prefilled syringes are no longer available. If a prefilled syringe of Fluzone Quadrivalent is used for a child in this age group, the dose volume will be 0.5 mL per dose. The 0.5-mL single-dose vials should be accessed for only 1 dose and multidose vials for only 10 doses, regardless of the volume of the doses obtained or any remaining volume in the vial. Any vaccine remaining in a vial after the maximum number of doses has been removed should be discarded. [/fig] [table] TABLE 1: Influenza vaccines -United States, 2022-23 influenza season* Abbreviations: ACIP = Advisory Committee on Immunization Practices; FDA = Food and Drug Administration; HA = hemagglutinin; IIV4 = inactivated influenza vaccine, quadrivalent; IM = intramuscular; LAIV4 = live attenuated influenza vaccine, quadrivalent; MDV = multidose vial; NAS = intranasal; PFS = prefilled syringe; RIV4 = recombinant influenza vaccine, quadrivalent; SDV = single-dose vial. * Vaccination providers should consult FDA-approved prescribing information for 2022-23 influenza vaccines for the most complete and updated information, including but not limited to indications, contraindications, warnings, and precautions. Package inserts for U.S.-licensed vaccines are available at https://www.fda. [/table] [table] TABLE 2: Contraindications and precautions for the use of influenza vaccines -United States, 2022-23 influenza season* [/table]	None	https://www.cdc.gov/mmwr/volumes/71/rr/pdfs/rr7101a1-H.pdf	Summary This report updates the 2021–22 recommendations of the Advisory Committee on Immunization Practices (ACIP) concerning the use of seasonal influenza vaccines in the United States (MMWR Recomm Rep 2021;70[No. RR-5]:1–24). Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. For each recipient, a licensed and age-appropriate vaccine should be used. With the exception of vaccination for adults aged ≥65 years, ACIP makes no preferential recommendation for a specific vaccine when more than one licensed, recommended, and age-appropriate vaccine is available. All seasonal influenza vaccines expected to be available in the United States for the 2022–23 season are quadrivalent, containing hemagglutinin (HA) derived from one influenza A(H1N1)pdm09 virus, one influenza A(H3N2) virus, one influenza B/Victoria lineage virus, and one influenza B/Yamagata lineage virus. Inactivated influenza vaccines (IIV4s), recombinant influenza vaccine (RIV4), and live attenuated influenza vaccine (LAIV4) are expected to be available. Trivalent influenza vaccines are no longer available, but data that involve these vaccines are included for reference. Influenza vaccines might be available as early as July or August, but for most persons who need only 1 dose of influenza vaccine for the season, vaccination should ideally be offered during September or October. However, vaccination should continue after October and throughout the season as long as influenza viruses are circulating and unexpired vaccine is available. For most adults (particularly adults aged ≥65 years) and for pregnant persons in the first or second trimester, vaccination during July and August should be avoided unless there is concern that vaccination later in the season might not be possible. Certain children aged 6 months through 8 years need 2 doses; these children should receive the first dose as soon as possible after vaccine is available, including during July and August. Vaccination during July and August can be considered for children of any age who need only 1 dose for the season and for pregnant persons who are in the third trimester if vaccine is available during those months Updates described in this report reflect discussions during public meetings of ACIP that were held on October 20, 2021; January 12, 2022; February 23, 2022; and June 22, 2022. Primary updates to this report include the following three topics: 1) the composition of 2022–23 U.S. seasonal influenza vaccines; 2) updates to the description of influenza vaccines expected to be available for the 2022–23 season, including one influenza vaccine labeling change that occurred after the publication of the 2021–22 ACIP influenza recommendations; and 3) updates to the recommendations concerning vaccination of adults aged ≥65 years. First, the composition of 2022–23 U.S. influenza vaccines includes updates to the influenza A(H3N2) and influenza B/Victoria lineage components. U.S.-licensed influenza vaccines will contain HA derived from an influenza A/Victoria/2570/2019 (H1N1)pdm09-like virus (for egg-based vaccines) or an influenza A/Wisconsin/588/2019 (H1N1)pdm09-like virus (for cell culture–based or recombinant vaccines); an influenza A/Darwin/9/2021 (H3N2)-like virus (for egg-based vaccines) or an influenza A/Darwin/6/2021 (H3N2)-like virus (for cell culture–based or recombinant vaccines); an influenza B/Austria/1359417/2021 (Victoria lineage)-like virus; and an influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus. Second, the approved age indication for the cell culture–based inactivated influenza vaccine, Flucelvax Quadrivalent (ccIIV4), was changed in October 2021 from ≥2 years to ≥6 months. Third, recommendations for vaccination of adults aged ≥65 years have been modified. ACIP recommends that adults aged ≥65 years preferentially receive any one of the following higher dose or adjuvanted influenza vaccines: quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), quadrivalent recombinant influenza vaccine (RIV4), or quadrivalent adjuvanted inactivated influenza vaccine (aIIV4). If none of these three vaccines is available at an opportunity for vaccine administration, then any other age-appropriate influenza vaccine should be used This report focuses on recommendations for the use of vaccines for the prevention and control of seasonal influenza during the 2022–23 influenza season in the United States. A brief summary of the recommendations and a link to the most recent Background Document containing additional information are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html . These recommendations apply to U.S.-licensed influenza vaccines used according to Food and Drug Administration–licensed indications. Updates and other information are available from CDC’s influenza website ( https://www.cdc.gov/flu ). Vaccination and health care providers should check this site periodically for additional information.
409e6614020a8faa55323aa2cba32ed201424fc7	pubmed	Anti-cancer therapy and clinical trial considerations for gynecologic oncology patients during the COVID-19 pandemic crisis☆	Anti-cancer therapy and clinical trial considerations for gynecologic oncology patients during the COVID-19 pandemic crisis☆ # Introduction The COVID-19 pandemic has rapidly and drastically changed the care of gynecologic cancer patients. Regardless of geographic location, COVID-19 will impact all practitioners; however, the degree will vary based on COVID-19 burden and available local resources. Given this variability, decisions regarding cancer care delivery should be individualized, and institutional and government mandates prioritized based on locoregional factors. Special considerations are needed with regard to decisions of systemic cancer-directed therapy and clinical trial enrollment during this unprecedented time. Chemotherapy and other anticancer treatments may result in significant immune compromise in patients, rendering them more susceptible to viral and other infectious illnesses. The recent Wuhan experience of 1524 patients reported in JAMA Oncology noted that the infection rate in cancer patients was double that of general population (OR, 2.31; 95% CI, 1.89-3.02) [bib_ref] SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in..., Yu [/bib_ref]. In addition, over 41% of COVID-19 infections were contracted in the hospital. Cancer patients admitted were at higher risk of severe events (composite endpoint: percentage of patients admitted to ICU, ventilated, or death) compared with patients without cancer (seven [39%] of 18 patients vs 124 [8%] of 1572 patients; Fisher's exact p = 0.0003). Lastly, patients who underwent chemotherapy or surgery within the previous month had a numerically higher risk of severe events [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref]. Though these were small series reported in China with differences in cancer care and no gynecologic cancer patients diagnosed with COVID-19 during the study period, the findings are informative in helping us understand the potential risks to our patients with cancer. Given this information, we must carefully weigh the risk that COVID-19 presents to patients receiving anti-neoplastic therapy and participating on clinical trials. Traveling to treatment centers and interacting with the healthcare team increases patients' risk of COVID-19 exposure and transmission. Cancer treatment causes its own toxicities requiring acute care, and possibly hospitalization, and can increase severe COVID-19 infection risk via immunocompromise. Nonetheless, chemotherapy has a therapeutic benefit, and careful deliberation is required in the decision-making surrounding anti-cancer therapy and clinical trials management during this challenging time . ## Frontline considerations in covid-19 burdened regions -Neoadjuvant chemotherapy for ovarian cancer compared with primary surgical debulking can reduce morbidity and reduce risk of hospitalization over primary surgical debulking especially in high COVID-19 burden areas [bib_ref] Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS):..., Kehoe [/bib_ref] [bib_ref] Neoadjuvant chemotherapy in advanced ovarian cancer: what kind of evidence is needed..., Vergote [/bib_ref]. -Delaying interval debulking surgery beyond 3-4 cycles of neoadjuvant chemotherapy can reduce morbidity and hospitalization for patients with ovarian cancer. -Choose regimens that necessitate the fewest infusion visits (i.e., q 3 week paclitaxel/carboplatin) [bib_ref] Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel..., Ozols [/bib_ref]. Consider avoiding/limiting the prescription of dose-dense, intraperitoneal, and HIPEC regimens. -Consider oral hormonal mono-therapy in patients with low-grade serous ovarian cancers. -For early endometrial cancer, treatment with progesterone therapy or a progesterone containing IUD may decrease bleeding and provide temporizing benefit if primary surgery is delayed for lower grade cancers [bib_ref] Updates on conservative management of endometrial cancer, Corzo [/bib_ref]. -For advanced/recurrent endometrial cancer consider the use of megestrol acetate, or megestrol acetate alternating with tamoxifen for endometrial cancer with endometrioid histology, or if estrogen/progesterone receptor status positive [bib_ref] Gynecologic Oncology Group s, Phase II trial of alternating courses of megestrol..., Fiorica [/bib_ref] [bib_ref] Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma:..., Thigpen [/bib_ref]. Oral everolimus/letrozole may have a better response rate compared to hormonal therapy alone but the impact of the increased toxicity and possible immunosuppression should be considered. -Avoid radiation if possible unless for curative intent (i.e., locally advanced cervical cancer) -For patients with recurrent cervical cancer who have received prior cisplatin, consider paclitaxel/carboplatin over paclitaxel/cisplatin based regimen due to shorter total time in infusion center and less toxicity [bib_ref] Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical..., Kitagawa [/bib_ref]. -For Stage IV primary high grade endometrial and cervical cancers, consider delaying/deferring non-curative treatment, especially if patients are older or possess significant co-morbidities unless to control symptoms that may necessitate/lead to hospitalization. Goals of care discussion are of paramount importance in this situation. General considerations for cancer directed therapy. Prior to start of therapy -Consider goals of therapy: Frontline curative intent should be prioritized, maintenance therapy should be evaluated in terms of incremental survival benefit, and palliative treatment should be utilized to mitigate uncontrolled cancer symptoms that may lead to inpatient hospitalization -Transfer patients to infusion centers not at main hospital campuses where patients with COVID-19 are being evaluated and treated. -Consider local administration of chemotherapy if a patient lives far from the current infusion site or it requires traveling to a COVID-19 "hotspot". -Test for COVID-19 prior to cancer directed therapy if testing capabilities allow -Try to limit frequency of infusions; avoid weekly infusions -Consider single agent therapy or holding cancer-directed therapy for patients N65 years old, patients at any age with significant co-morbidity (DM, chronic lung disease and cardiovascular disease) or ECOG status ≥2 [bib_ref] Preliminary estimates of the prevalence of selected underlying health conditions among patients..., -R [/bib_ref]. Patients with these co-morbid conditions appear to be at higher risk for severe COVID-19 disease than those without. Fatality was highest in persons ≥85 years old, ranging from 10% to 27%, followed by 3% to 11% among persons aged 65-84 years, 1% to 3% among persons aged 55-64 years, b1% among persons aged 20-54 years, and no fatalities among persons aged ≤19 years [bib_ref] Severe outcomes among patients with coronavirus disease 2019 (COVID-19) -United States, -R [/bib_ref]. More recent reports note very few fatalities in ≤19 years age group. -Consider oral therapies over infusion-based treatments when appropriate; be mindful that some oral regimens may have more toxicities than infusion-based therapies. -With select exceptions (i.e. high risk GTD), avoid inpatient administration of chemotherapy, when possible. -Screen all patients for symptoms of COVID-19 and ensure temperature b99.5 prior to treatment and consider testing if possible, prior to chemotherapy During therapy -Utilize telemedicine to reduce the frequency of in person evaluation and allow for patients to proceed directly to infusion center for treatment. -Obtain local collection of labs whenever possible. -Consider liberal use of granulocyte colony stimulating factor. Prioritize home administration or use of pegfilgrastim on-body injector in lieu of return for pegfilgrastim on day 2. -Consider outpatient management of neutropenic fever when clinically stable with moxifloxacin 400 mg po daily or ciprofloxacin po 500-750 mg BID and Augmentin 875 mg BID po. Maintain close follow-up with daily phone contact for at least 3 days to ensure no clinical deterioration [bib_ref] Oral antibiotics for fever in low-risk neutropenic patients with cancer: a double-blind,..., Kern [/bib_ref]. Post-therapy -Delay imaging during or after completion of treatment to a post-COVID surge timeframe unless critical to patients' immediate care. -Ensure that goals of care discussions with patients (including DNR/DNI status) are prioritized prior to or shortly after admission, even if via telephone or telemedicine. -Increase interval for routine port flushes to 8-12 weeks. The general considerations outlined in Tables 1 and 2 should be utilized when deliberating front-line anti-cancer therapy. For specific treatment options see [fig_ref] Table 3: Front-line cancer-specific chemotherapy considerations for women with early-stage gynecologic malignancies during the... [/fig_ref] in selecting primary treatment for early stage and late stage gynecologic malignancies, respectively. In advanced ovarian cancer the decision between primary debulking surgery (PDS) and neoadjuvant chemotherapy (NACT) must be made with respect to COVID-19 burden and available resources. Careful decision-making regarding surgery should be utilized in older patients, those with significant medical co-morbidities, poor nutritional status, and those who may require prolonged ICU/hospital stay or require nursing home/facility placement post-surgery. While NACT can avoid many of these challenges, it does require a biopsy for pathologic confirmation, and chemotherapy will still result in an immunocompromised state. Randomized phase 3 trials, including EORTC and CHORUS, demonstrated that NACT is not inferior to primary surgical cytoreduction with respect to overall and progression-free survival, with lower morbidity [bib_ref] Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS):..., Kehoe [/bib_ref] [bib_ref] Neoadjuvant chemotherapy in advanced ovarian cancer: what kind of evidence is needed..., Vergote [/bib_ref]. NACT in patients with advanced stage disease is a viable alternative to PDS when resources for surgical intervention are restricted during the pandemic crisis. For high-grade serous ovarian cancer, a 3 week taxane/platinum regimen is optimal and dose-dense and intraperitoneal regimens should probably be avoided [bib_ref] Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel..., Ozols [/bib_ref]. With NACT, consider delaying interval debulking surgery beyond 3-4 cycles to reduce surgical morbidity and hospitalization in high COVID burden areas. Hormonal therapy has demonstrated efficacy in low grade serous ovarian cancer; consider transitioning from chemotherapy to hormonal monotherapy. Progesterone therapy with megestrol acetate or levonorgestrel intrauterine device for early stage, grade 1/2 endometrioid endometrial cancer can be utilized in lieu of surgery due to limited capability secondary to resource limitations [bib_ref] Updates on conservative management of endometrial cancer, Corzo [/bib_ref]. In advanced stage endometrioid and/or hormone receptor positive tumors, oral megestrol acetate, or megestrol acetate alternating with tamoxifen can be utilized [bib_ref] Gynecologic Oncology Group s, Phase II trial of alternating courses of megestrol..., Fiorica [/bib_ref] [bib_ref] Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma:..., Thigpen [/bib_ref]. Increased efficacy of oral everolimus and letrozole must be balanced with greater toxicity and immunosuppression. Radiation therapy should be utilized for curative intent. Chemoradiation offers improved survival in locally advanced cervical cancer and should be prioritized [bib_ref] Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in..., Lanciano [/bib_ref] [bib_ref] Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for..., Morris [/bib_ref] [bib_ref] Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer, Rose [/bib_ref]. For metastatic cervical cancer, use of q 3-week paclitaxel and carboplatin can reduce total time in infusion center and toxicity [bib_ref] Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical..., Kitagawa [/bib_ref]. Consider the overall survival benefit with bevacizumab versus risk of fistula and hospitalization in cervical cancer [bib_ref] Improved survival with bevacizumab in advanced cervical cancer, Tewari [/bib_ref]. ## Maintenance therapy considerations -If utilizing maintenance therapy, consider the risk/benefit ratio with respect to exposure and infection during infusion versus the risk of immunosuppression with PARP inhibitor (PARPi) therapy -While bevacizumab can delay recurrence in the primary and recurrent settings this treatment does necessitate frequent visits to the cancer center -Oral PARPi should be considered in patients with high benefit to risk ratio (i.e. BRCA1/2 mutations and HRD) -Patients should wait up to 8-12 weeks for recovery of blood counts from front line chemotherapy prior to starting maintenance PARPi; if not recovered, consider not starting PARPi maintenance -Consider deferring/delaying IV maintenance therapy -The risk benefit ratio should be considered based on resources available and the risk for infection at the time of infusion -For patients currently on IV maintenance therapy review individualized COVID-19 risk factors and benefit of continued maintenance -For those in prolonged remission, consider holding maintenance therapy during COVID-19 crisis. Issues to deliberate when starting/continuing anti-cancer therapy in gynecologic oncology patients during COVID-19. ## Issue consideration What is the goal of treatment for your patient? - Are you impacting OS? Cure? - Are you expecting meaningful prolongation of PFS? What is the health status of your individual patient? - Can you assess their overall morbidity and mortality due to cancer? Use of Geriatric Screening G8 for older patients (9) What is the likelihood of toxicity from anti-cancer treatment? - Utilization of CARG toxicity tool to predict grade 3-5 toxicity - http://www.mycarg. org/Chemo_Toxicity_Calculator Are there alternatives of similar efficacy which minimize toxicity from anti-cancer therapy and/or risk from exposure to the health care system? - Oral agents (oral ≠ non-toxic) - Fewer in-person visits - Treatment holidays Consideration of oral or intrauterine options, when available: levonorgestrel IUD [bib_ref] Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer, Ledermann [/bib_ref] or megestrol acetate (23) for Gr 1/2 endometrioid histology [bib_ref] Treatment of low-risk endometrial cancer and complex atypical hyperplasia with the levonorgestrel-releasing..., Pal [/bib_ref] [bib_ref] High-dose megestrol acetate in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology..., Lentz [/bib_ref] Consider for score 0-1: MTX weekly 50 mg/m2 IM [bib_ref] Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational..., Osborne [/bib_ref] Can also consider dactinomycin for all low risk GTD to reduce number of visits but must weigh against toxicity and need for central access [bib_ref] Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational..., Osborne [/bib_ref] Two main classes of maintenance therapies FDA approved for ovarian cancer include IV anti-angiogenic agent (bevacizumab) and oral PARPi (olaparib, niraparib, rucaparib), [bib_ref] OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or..., Aghajanian [/bib_ref] [bib_ref] Incorporation of bevacizumab in the primary treatment of ovarian cancer, Burger [/bib_ref] [bib_ref] Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer..., Coleman [/bib_ref] [bib_ref] Investigators PE-OG, Niraparib in patients with newly diagnosed advanced ovarian cancer, Gonzalez-Martin [/bib_ref] [bib_ref] Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer, Ledermann [/bib_ref] [bib_ref] Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer, Moore [/bib_ref] [bib_ref] investigators SOE-O, Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed..., Pujade-Lauraine [/bib_ref] [bib_ref] Olaparib plus bevacizumab as first-line maintenance in ovarian cancer, Ray-Coquard [/bib_ref]. While both agents prolong progression-free survival, one must consider incremental benefit and the risk of traveling for infusion as well as the risk of immunosuppression and COVID-19 infection when selecting use. Oral agents are preferred and PARPi can be utilized especially in biomarker positive (i.e. BRCA 1/2 mutation and HRD) patients. When utilizing PARPi maintenance adequate time should be allowed for bone marrow recovery and consideration should be given to delaying initiation of PARPi . Selection of PARPi should take into consideration the need for laboratory analysis, and ease of modifications for toxicity and dosing via telehealth modalities. Thoughtful incorporation of bevacizumab with chemotherapy in high-risk disease (stage IV, symptomatic pleural effusion/ascites) may decrease symptoms more quickly and keep patients from needing hospitalization or other interventions; the risk of added toxicity must be considered. In the maintenance setting, consider bevacizumab use based on assessment of COVID-19 exposure risk vs. benefit. ## Considerations for surveillance and recurrent disease -Routine surveillance of asymptomatic patients should be postponed as appropriate, or conducted via telemedicine. -Consider delaying start of new therapy for patients with asymptomatic recurrence (and/or CA125 only recurrence for ovarian cancer patients). -For patients with symptomatic, recurrent disease, choice of therapy should be predicated on minimizing exposure to other contacts, risk from therapy, and life expectancy/prognosis. -Consider lower dosing intensity and less myelosuppressive regimens to reduce lymphopenia and neutropenia. While the exact role of lymphopenia and neutropenia in COVID-19 infections remains unclear, lymphopenia has been described to be associated with poor outcome or more severe disease for patients with COVID-19 infections [bib_ref] Clinical and immunologic features in severe and moderate coronavirus disease, Chen [/bib_ref] [bib_ref] Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study, Tan [/bib_ref]. -In certain patients, oral therapies may be a preferred alternative to minimize visits and exposure to the medical setting. In patients with grade 1/2 endometrioid endometrial cancers, oral hormonal therapy regimens such as megestrol acetate or alternating megestrol acetate/tamoxifen can be considered [bib_ref] Gynecologic Oncology Group s, Phase II trial of alternating courses of megestrol..., Fiorica [/bib_ref] [bib_ref] Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma:..., Thigpen [/bib_ref]. PARPi can be used as treatment for BRCA associated or platinum-sensitive HRD ovarian cancers [bib_ref] Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation, Kaufman [/bib_ref] [bib_ref] Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label,..., Moore [/bib_ref]. Oral chemotherapies (etoposide or cyclophosphamide) are other options for patients with ovarian cancer [bib_ref] Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in..., Garcia [/bib_ref] [bib_ref] Sequential prolonged oral topotecan and prolonged oral etoposide as second-line therapy in..., Rose [/bib_ref]. -One should be cognizant of the risks and benefits of further therapy, considering the risk for potential COVID-19 complications. Best supportive care may provide better outcomes for patients in whom the likelihood of benefit from further therapy is low (e.g., platinumrefractory ovarian cancer). Principles surrounding surveillance and treatment of recurrent gynecologic malignancies mirror considerations for front-line therapy and center around minimizing the risk of COVID-19 exposure and the risk of toxicity from therapy in these patients . While prospective data regarding early treatment of asymptomatic recurrence are limited, a randomized trial of 527 patients treated for recurrent ovarian cancer based on CA125 level alone compared to clinical or symptomatic relapse demonstrated no difference in overall survival between these two groups. Additionally, case series have reported that between 41 and 83% of endometrial cancer patients and between 46 and 95% of cervical cancer patients will have symptoms at the time of recurrence, even in the setting of surveillance, suggesting that remote telemedicine visits can identify many patients with potential recurrence [bib_ref] An update on posttreatment surveillance and diagnosis of recurrence in women with..., Salani [/bib_ref]. For patients in whom chemotherapy is being considered, emerging data have reported both higher rate of COVID-19 infection in cancer patients as well as increased risk of severe events, especially in patients who have received recent cancer-directed therapy [bib_ref] SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in..., Yu [/bib_ref] [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref]. As such, when making decisions about proceeding with therapy for recurrent disease and choice of therapy regimen, careful consideration must be made regarding the benefits of therapy in terms of symptomatic relief, survival, and prevention of hospitalization, compared to the risks of [bib_ref] Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel..., Ozols [/bib_ref] ; consider thoughtful incorporation of bevacizumab (i.e., stage IV, significant ascites) [bib_ref] Incorporation of bevacizumab in the primary treatment of ovarian cancer, Burger [/bib_ref] Chemotherapy followed by aromatase inhibitor therapy vs. aromatase inhibitor monotherapy [bib_ref] Hormonal maintenance therapy for women with low-grade serous cancer of the ovary..., Gershenson [/bib_ref] Platinum/taxane Chemotherapy every 3 weeksChemoradiation for curative cases [bib_ref] Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in..., Lanciano [/bib_ref] [bib_ref] Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for..., Morris [/bib_ref] [bib_ref] Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer, Rose [/bib_ref] Neoadjuvant chemoradiation [bib_ref] Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the..., Moore [/bib_ref] Inpatient EMA-CO for choriocarcinoma [bib_ref] EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272..., Bower [/bib_ref] EMA-EP for placental site trophoblastic tumor (PSTT) [bib_ref] Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with..., Newlands [/bib_ref] Single agent doxorubicin q 3 wks [bib_ref] Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced..., Seddon [/bib_ref] Preferred oral maintenance PARPi vs. bevacizumab use based on assessment of COVID 19 exposure risk vs. benefit or observation only Low threshold to transition to oral hormonal maintenance Avoid radiation unless indicated for curative intent Paclitaxel/carboplatin [bib_ref] Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical..., Kitagawa [/bib_ref] or taxane/platinum with bevacizumab every 3 weeks (weigh survival benefit versus risk of fistula) [bib_ref] Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical..., Kitagawa [/bib_ref] [bib_ref] Improved survival with bevacizumab in advanced cervical cancer, Tewari [/bib_ref] Aromatase inhibitors in ER + uLMS [bib_ref] Phase 2 trial of aromatase inhibition with letrozole in patients with uterine..., George [/bib_ref] Oral pazopanib [bib_ref] Outcome of uterine sarcoma patients treated with pazopanib: a retrospective analysis based..., Benson [/bib_ref] Consideration of oral options: megestrol acetate, or megestrol acetate alternating tamoxifen, oral everolimus/ letrozole, weigh increased toxicity over above hormone regimens [bib_ref] Gynecologic Oncology Group s, Phase II trial of alternating courses of megestrol..., Fiorica [/bib_ref] [bib_ref] Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma:..., Thigpen [/bib_ref] Stage IV and high risk for COVID-19 morbidity consider delaying/deferring non-curative intent treatment; goals of care discussion Stage IV (high grade) and high risk for COVID-19 morbidity -consider delaying/deferring non-curative intent treatment; goals of care discussion increased exposure to the medical setting for therapy, possible complications of therapy, and potential for increased risk of COVID-19 infection or severity. Immunotherapy is increasingly used to treat gynecologic cancers [bib_ref] Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results..., Chung [/bib_ref] [bib_ref] Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer, Makker [/bib_ref]. Currently no evidence demonstrates that immunotherapy, in cancer patients, increases COVID-19 susceptibility. Strong overlap between immune-related (IR) pneumonitis and COVID-19 infection exists, including cough, dyspnea, fever and CT findings of ground-glass opacities and interstitial changes. ## Considerations for immunotherapy Patients on immunotherapy with unexplained fever and pulmonary symptoms or new CT findings (symptomatic or undergoing bronchoscopy and/or corticosteroid intervention) should have COVID-19 testing. While corticosteroids are a mainstay of treatment of IR-related pneumonitis, steroids can prolong immunosuppression; increase risk of infections; delay viral clearance; and increase viral pneumonitis mortality [bib_ref] On the use of corticosteroids for 2019-nCoV pneumonia, Shang [/bib_ref]. Currently, the WHO and CDC recommend that corticosteroids not be used in treatment of COVID-19 viral pneumonia or ARDS unless indicated for another reason (asthma, COPD, septic shock). Carefully evaluate anticipated benefit before starting immunotherapy. Pre-existing lymphopenia is associated with lower immunotherapy response and predicts more severe COVID-19 infections [bib_ref] Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study, Tan [/bib_ref] [bib_ref] Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients..., Diehl [/bib_ref]. Immunotherapy administration at higher dose and longer treatment intervals can decrease clinic visit frequency [bib_ref] A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R)..., Lala [/bib_ref]. ## Considerations for older and medically vulnerable patients -Consider the goals of care for the patient with respect to relief of symptoms or improvement in overall survival. -Evaluation of the patient's health status with respect to COVID-19 morbidity will help determine treatment -Determine how the toxicity from treatment will put the patient at risk -Decrease the frequency of visits to reduce the risk with less frequent schedules or oral alternatives Older patients (≥65) and/or those with medical comorbidities are at significantly increased risk of morbidity and mortality if the contract COVID-19. In addition to general considerations to mitigate COVID-19 infections , consider assessment of frailty and prediction of toxicity risk in this most vulnerable population. The Geriatric 8 panel (G8) is a concise version of the geriatric assessment tool (18 items) and assesses frailty. The lower the score (b 14), the more frail the patient may be and the higher the risk for chemotherapy related toxicities. The 8-item scale may be completed by phone using the patient's reported weight [bib_ref] Detection of frailty in elderly cancer patients: improvement of the G8 screening..., Petit-Moneger [/bib_ref]. The Cancer Aging Research Group (CARG) toxicity calculator (http://www.mycarg.org/Chemo_Toxicity_Calculator) is a simple, complimentary, online tool that provides a percentage of chemotherapy related toxicity (grade 3-5) based on patient information and selected regimens. These assessments, combined with candid goals of therapy discussions, can help counsel older patients and assist with treatment decisions. ## Considerations for uterine leiomyosarcoma -There is no proven benefit from adjuvant therapy in early stage uterine leiomyosarcoma -Single agent doxorubicin requires less frequent visits and may represent the best choice to limit visits during treatment -Oral tyrosine-kinase inhibitor, pazopanib is an approved treatment option for sarcoma [bib_ref] Outcome of uterine sarcoma patients treated with pazopanib: a retrospective analysis based..., Benson [/bib_ref]. The doxorubicin, ifosfamide, and the combination of gemcitabine and docetaxel represent the mainstays of front-line treatment for those patients with advanced or recurrent uterine leiomyosarcoma (uLMS). There is no proven benefit to adjuvant therapy in stage I or stage II uLMS [bib_ref] Difficult choices in stage I uterine leiomyosarcoma -it's okay to "stand there, Hensley [/bib_ref]. For advanced or recurrent uLMS the gemcitabine/docetaxel doublet has demonstrated activity in prior trials, but requires administration on days 1 and 8 of a 21 day cycle and is associated with significant hematologic toxicity, including neutropenia, necessitating use of granulocyte colony stimulating factors [bib_ref] Fixeddose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma:..., Hensley [/bib_ref] [bib_ref] Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine..., Hensley [/bib_ref] [bib_ref] Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase..., Hensley [/bib_ref]. Single agent doxorubicin is probably the optimal first-line treatment option during the COVID-19 crisis. In a phase III trial comparing doxorubicin q 21 days to the combination of gemcitabine and docetaxel every three weeks in patients with unresectable or metastatic soft tissue sarcoma, response rates, progression-free survival and overall survival were similar in both arms [bib_ref] Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced..., Seddon [/bib_ref]. Dose delays and dose reductions were frequent in both groups, with the main reason being febrile neutropenia. Singleagent doxorubicin in the front-line setting should be considered, after balancing these risks with gemcitabine/docetaxel and the patient's risk of cardiac dysfunction with doxorubicin during the COVID-19 crisis. Pazopanib is an oral tyrosine-kinase which represents an option with activity in uLMS [bib_ref] Outcome of uterine sarcoma patients treated with pazopanib: a retrospective analysis based..., Benson [/bib_ref]. Aromatase inhibitors have limited toxicity and can result in stable disease in patients with ER positive uLMS [bib_ref] Phase 2 trial of aromatase inhibition with letrozole in patients with uterine..., George [/bib_ref]. With all of these non-curative therapies, the toxicity and risk of viral infection during treatment must be weighed against the potential benefit of these therapies. ## Considerations for malignant germ cell tumors -Stage I grade 1 immature teratomas can be followed without treatment [59] -Stage I dysgerminomas can be followed without treatment but tumor markers including LDH, hCG, and AFP should be checked to exclude a mixed tumor [59] -Active surveillance could be considered in patients with complete staging who have a stage IA, grade 2/3 immature teratoma [60] -The risks and benefits of bleomycin should be considered due to the concern for pulmonary toxicity and the risk of respiratory failure with COVID-19 [bib_ref] Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized..., De Wit [/bib_ref] Malignant germ cell tumors are chemo-sensitive and curable tumors that occur in young healthy patients and should be high priority if resources are limited. Conservative therapy can be considered but complete surgical staging including omentectomy and lymph node assessment is critical if adjuvant therapy is omitted. Active surveillance in grade 2/3 immature teratomas is currently being investigated in pediatric studies. However, there is some indication that pediatric tumors may have a less aggressive biology [bib_ref] Prognostic factors in children with extragonadal malignant germ cell tumors: a pediatric..., Marina [/bib_ref]. Stage IA yolk sac tumors and embryonal carcinoma could possibly be followed without treatment in extremely resource limited settings. In all cases of active surveillance, tumor markers should be followed to make sure they decline appropriately. Bleomycin can cause pulmonary toxicity in about 10% of patients and there is concern that this could increase the risk with co-existing COVID-19 infection [bib_ref] Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized..., De Wit [/bib_ref]. Bleomycin can be safely omitted in dysgerminomas with no detriment in survival [bib_ref] Adjuvant therapy of completely resected dysgerminoma with carboplatin and etoposide: a trial..., Williams [/bib_ref]. Based on the experience with non-seminomatous testicular cancers, the relapse rate increases by about 8% when bleomycin is not included in the chemotherapy regimen [bib_ref] Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized..., De Wit [/bib_ref]. Therefore, the risks and benefits as well as the resources and rate of viral infection should be carefully considered when considering this chemotherapy regimen. ## Considerations for gestational trophoblastic disease (gtd) -Hysterectomy can be considered if fertility is not desired to reduce the need for chemotherapy if resources allow [64] -A second D&C will result in remission in 38% of patients [bib_ref] Second curettage for low-risk nonmetastatic gestational trophoblastic neoplasia, Osborne [/bib_ref] -Standard 5-day or 8-day methotrexate regimens are preferred in low risk GTD (WHO ≤ 6) [66,67] -A 5-day oral regimen has been described in low risk GTD with similar efficacy to IM regimens [bib_ref] Treatment of nonmetastatic gestational trophoblastic disease with oral methotrexate, Barter [/bib_ref] -Weekly methotrexate at 50 mg/m2 can be considered for very low risk disease (WHO 0-1) -Dactinomycin at 1.25 mg/m2 has been shown to be more efficacious than weekly methotrexate in patients with a WHO score ≤ 6 [69] -EMA-CO should be given to patients with a WHO score ≥ 6 even though this regimen requires hospitalization [bib_ref] Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with..., Newlands [/bib_ref] GTD is a chemo-sensitive and curable disease that occurs in premenopausal patients. A second D&C would be recommended to avoid chemotherapy in 38% of patients [bib_ref] Second curettage for low-risk nonmetastatic gestational trophoblastic neoplasia, Osborne [/bib_ref]. Either the 8-day or 5-day regimens are acceptable for women with a WHO score of ≤6 but both regimens require frequent visits for the injections which may increase exposure to viral infection [bib_ref] The role of low-dose methotrexate and folinic acid in gestational trophoblastic tumours..., Bagshawe [/bib_ref] [bib_ref] Single-agent methotrexate chemotherapy for the treatment of nonmetastatic gestational trophoblastic tumors, Lurain [/bib_ref]. A small series of an oral 5-day regimen has been described with outcomes that are similar to those reported with methotrexate injections and could be considered to reduce the risk of exposure or when infusion resources are limited [bib_ref] Treatment of nonmetastatic gestational trophoblastic disease with oral methotrexate, Barter [/bib_ref]. Dactinomycin at 1.25 mg/m2 has the advantage of every 2 week dosing and has been shown to be superior to weekly methotrexate [bib_ref] Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational..., Osborne [/bib_ref]. However, the success rate for this regimen was only 44% in women with a WHO score of 5-6 and generally should be given through a central line to reduce the risk of extravasation injury. All regimens should be continued until 3 treatments past a normal hCG defined as (b5 mIU/ml) [bib_ref] 15 years of progress in gestational trophoblastic disease: scoring, standardization, and salvage, Brown [/bib_ref]. The inpatient EMA-CO regimen is recommended for patients with high risk disease (WHO N 6). ## Clinical trial considerations -Prioritize Tier 1 studies where there is high potential benefit (i.e., trial that offers drug where alternative treatments are limited) in resourcestratified environments. -Identify and inform sponsors when there will be deviations for visits/ labs/physical exam/radiology tests that are not essential such as pharmacokinetics tests -Be aware of your institutional regulatory guidelines regarding how COVID-19-related deviations should be tracked and reported. -Prioritize shipping oral drugs to patients to minimize in-person visits. -Consider COVID-19 burden and ability to enroll new patients on trial (safety, staffing resources including clinical trial nurses, data mangers, and regulatory staff) Conducting clinical trials during the COVID-19 crisis is challenging and will vary based on geographic location and institutional resources. Clinical trial guidelines are available from the FDA, National Cancer Institute, NRG Oncology, and local institutions. Develop COVID-19 guidelines for investigator-initiated trials internally and distribute to participating sites. Clinical trials should be prioritized based on the study type and benefit potential [fig_ref] Table 5: Prioritization criteria for clinical trials during the COVID-19 pandemic [/fig_ref]. Tier 2 and non-essential Tier 3 (tissue and non-therapeutic studies) are not enrolling at many centers. Before enrolling new patients consider COVID-19 burden and trial conduct capability including staffing, imaging, procedures, and research labs acquisition. Minimize non-critical visits and patient interactions between physicians and research coordinators using telemedicine to conduct visits and assessment of toxicity, symptoms, and concomitant medications. Arrange for delivery of investigative oral drugs directly to patients if possible and obtain labs and imaging locally. Inform and follow sponsor and IRB guidelines regarding deviations and patients diagnosed with COVID-19 while on study. # Author contributions ## Declaration of competing interest Dr. Huh has nothing to disclose. Dr. Armstrong reports grants from Astra Zeneca, Clovis, Pfizer, Tesary, Syndax, Esai/Morphotek, from null, outside the submitted work. Dr. Naumann reports personal fees from Astra-Zeneca, grants and personal fees from BioSutro, grants from Bristol-Myers-Squib, personal fees from Clovis, grants and personal fees from Merck, personal fees from Eisai, grants and personal fees from Tesaro/GSK, grants and personal fees from GOG Foundation, grants from OncoMed, outside the submitted work. Dr. Kesterson reports personal fees from GSK/Tesaro, personal fees from Clovis Oncology, outside the submitted work. Dr. Fader reports personal fees and other from Mersana, personal fees from Merck, outside the submitted work. Dr. Liu reports advisory board participation for AstraZeneca, Clovis Oncology, Tesaro/GSK, Genentech, Merck, and Mersana Therapeutics, outside the submitted work; and Institutional PI on industrysponsored trials from Acetylon Pharmaceuticals, Aravive Biologics, Arch Oncology, AstraZeneca, Atara Biotherapeutics, Boston Biomedical, Bristol-Myers Squibb, Agenus, Clovis Oncology, CytomX Therapeutics, Genentech/Roche, Regeneron Pharmaceuticals, Surface Oncology, Tesaro/GSK, and Vigeo Therapeutics. Dr. Westin reports grants and personal fees from AstraZeneca, grants and personal fees from Clovis Oncology, grants and personal fees from GSK/Tesaro, grants and personal fees from Roche/ Genentech, grants and personal fees from Novartis, personal fees from Merck, personal fees from Pfizer, personal fees from Eisai, grants from Cotinga Pharmaceuticals, grants from Bayer, grants from ArQule, personal fees from CIrculogene, outside the submitted work. Dr. Pothuri reports grants, personal fees and non-financial support outside the submitted work; Institutional PI for industry sponsored trials from Tesaro/GSK, AstraZeneca, Merck, Genetech/Roche, and Clovis Oncology. Compensated advisory boards include Tesaro/GSK, AstraZeneca, and Eisai. Dr. Moore reports personal fees and other from Astra Zeneca, grants, personal fees and other from Genentech/Roche, grants, personal fees and other from Immunogen, grants, personal fees and other from Clovis, grants, personal fees and other from Tesaro, personal fees and other from Pfizer, personal fees from Janssen, personal fees from Aravive, personal fees from VBL Therapeutics, personal fees and other from Onco Med, personal fees from Samumed, grants and other from Lilly, personal fees from Eisai, personal fees from Vavotar, personal fees from Abbvie, personal fees from Tarveda, outside the submitted work. Dr. Alvarez Secord reports grants from AbbVie, Amgen, Astra Zeneca, Clovis, Astellas Pharma Inc., Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Endocyte, Exelixis, Incyte, Merck, PharmaMar, Immutep Ltd., Roche/Genentech, Seattle Genetics, Inc., Tesaro/GSK, VBL Therapeutics, National Cancer Trial Network; honoraria from Aravive, Astra Zeneca, Clovis, Cordgenics, Eisai, Janssen/Johnson & Johnson, Merck, Mersana, OncoQuest, Roche/Genentech, Tesaro/ GSK Advisory Boards; participation on Clinical Trial Steering Committees (uncompensated) for Roche/Genentech, and VBL Therapeutics; and member of GOG-Foundation Board of Directors, outside the submitted work. Dr. Chan reports personal fees from Acerta, personal fees from Aravive, personal fees from Biodesix, personal fees from Clovis, personal fees from Janssen/J and J, personal fees from Oxigene/Mateon, grants and personal fees from Roche/Genentech, grants and personal fees from Glaxosmithkline/Tesaro, grants and personal fees from Astra Zeneca, personal fees from Eisai, outside the submitted work. [table] Table 3: Front-line cancer-specific chemotherapy considerations for women with early-stage gynecologic malignancies during the COVID-19 pandemic. Study of Active Surveillance for Low Risk and a Randomized Trial of Carboplatin vs. Cisplatin for Standard Risk Pediatric and Adult Patients with Germ Cell Tumors) [60] [/table] [table] Table 4: Front-line cancer-specific chemotherapy considerations for women with advanced-stage gynecologic malignancies during the COVID-19 pandemic. [/table] [table] - Immunotherapy: COVID-19 infection and early immunotherapyrelated pneumonitis have similar presentations. In the case of suspected pneumonitis, test for COVID-19 prior to start of steroids and collaborate with pulmonary consultants.-Access to PFTs and bronchoscopy may be limited and decisions may need to be determined based on clinical findings and severity of symptoms. -Consider utilizing less frequent dosing intervals for immune checkpoint inhibitors [/table] [table] Table 5: Prioritization criteria for clinical trials during the COVID-19 pandemic. Clinical research protocols (1) involving treatments for acute, life threatening health conditions (i.e., some cancer trials) or(2) where stopping the intervention could be harmful (i.e., some investigational drugs, or vaccines or preventative drug).b Clinical research protocols (1) evaluating treatments for chronic conditions or(2)involving assessment of the safety or efficacy of an intervention in which, if stopped, the potential societal benefit of the science would be significantly and adversely impacted, for example where a research assessment (blood collection or imaging study) is only valuable if at a very specific time.R. Wendel Naumann: Conceptualization, Methodology, Writingoriginal draft, Writing -review & editing. [/table]	None	http://www.gynecologiconcology-online.net/article/S009082582030994X/pdf	None
3397c80a7e237870160cba7d7f7f628373eb9c2c	pubmed	Antibiotic Prophylaxis in Obstetric Procedures	Antibiotic Prophylaxis in Obstetric Procedures Objective: To review the evidence and provide recommendations on antibiotic prophylaxis for obstetrical procedures.Outcomes: Outcomes evaluated include need and effectiveness of antibiotics to prevent infections in obstetrical procedures.Evidence:Published literature was retrieved through searches of Medline and The Cochrane Library on the topic of antibiotic prophylaxis in obstetrical procedures. Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and articles published from January 1978 to June 2009 were incorporated in the guideline. Current guidelines published by the American College of Obstetrics and Gynecology were also incorporated. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. # Introduction I nfectious complications following obstetric surgical procedures are a significant source of morbidity and potential mortality. They include urinary tract infection, endometritis, wound infection, perineal infection, and sepsis, which lead to prolonged hospital stays and increased health care costs. Much work has been done to study the effect of prophylactic antibiotics in reducing infectious morbidity. A plethora of antibiotic types, dosing schedules, and routes of administration have been investigated. There is evidence to support the use of prophylactic antibiotics for a number of procedures in obstetrics. Unfortunately, few comparative trials have been conducted, leaving the clinician with uncertainty as to which regimen is superior. The presence of antibiotic resistant organisms is a reality in Canadian health care facilities. [bib_ref] A comparison of infection control program resources, activities, and antibiotic resistant organism..., Zoutman [/bib_ref] These organisms include methicillin resistant Staphylococcus aureus, vancomycin resistant Enterococcus, and extended-spectrum beta-lactamase-producing organisms. Both morbidity and mortality are increased in infections caused by these organisms, as they may be more virulent and are more difficult to treat because therapeutic options are limited. Antibiotic resistance development results mainly from the inappropriate use of antibiotics. Incomplete courses of antibiotic therapies and the unnecessary use of broader spectrum regimens play a role. [bib_ref] How antibiotics can make us sick: the less obvious adverse effects of..., Dancer [/bib_ref] Adherence to both treatment and prophylaxis guidelines likely assists in reducing infection and antibiotic resistance. Physician adherence to antibiotic prophylaxis guidelines is variable and usually at odds with published guidelines. [bib_ref] Global Network for Perinatal and Reproductive Health. An international survey of practice..., Huskins [/bib_ref] [bib_ref] Use of antimicrobial prophylaxis for major surgery: baseline results from the National..., Bratzler [/bib_ref] In addition to antibiotic prophylaxis, it is essential to review all factors that affect infectious risk reduction in obstetrical care.Adherence to appropriate skin preparation procedure, including hair clipping as opposed to shaving, and effective antisepsis of both patient and staff are required. [bib_ref] Preoperative hair removal to reduce surgical site infection, Tanner [/bib_ref] Sterile surgical fields must be ensured, and ongoing quality assessment of sterilization technique, air ventilation, and postoperative wound care is needed. Consistent infection control surveillance and reporting of infectious complications track ability to minimize these morbidities and possibly to identify clusters of infection and the emergence of antibiotic resistant organisms. This will dictate changes to operative routines to respond to evolving microbial diversity that seems inevitable. ## Antibiotic prophylaxis in obstetric procedures SEPTEMBER JOGC SEPTEMBRE 2010 l 879 ## Principles of antibiotic prophylaxis The purpose of antibiotic prophylaxis in surgical procedures is not to sterilize tissues but to reduce the colonization pressure of microorganisms introduced at the time of operation to a level that the patient's immune system is able to overcome. [bib_ref] Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory..., Mangram [/bib_ref] Prophylaxis does not prevent infection caused by postoperative contamination. Prophylactic antibiotic use differs from treatment with antibiotics 5 in that the former is intended to prevent infection, whereas the latter is intended to resolve an established infection, typically requiring a longer course of therapy. Prophylaxis is intended for elective procedures when the incision will be closed in the operating room. Before an agent can be considered for use as a prophylactic antibiotic, there must be evidence that it reduces postoperative infection. It must also be safe and inexpensive, and it must be effective against organisms likely to be encountered in the surgical procedure. The agent must be administered in a way that ensures that serum and tissue levels are adequate before an incision is made and that therapeutic levels of the agent can be maintained in serum and tissue during surgery and for a few hours (at most) after the incision is closed. [bib_ref] Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory..., Mangram [/bib_ref] Wound infections-surgical site infections-in the form of cellulitis, abscess, or dehiscence can occur following laparotomy. Pelvic infections, such as an abscess or infected hematoma, are a risk with any surgical procedure that enters the abdominal cavity. Cuff cellulitis is a specific risk for hysterectomy. Endometritis can result from Caesarean section or surgical abortion. Urinary tract infections can occur as a result of any procedure that involves catheterization of the bladder. A 1999 guideline published by the US Centers for Disease Control and Prevention lists the specific and stringent criteria that must be met for diagnosis of a surgical site infection. [bib_ref] Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory..., Mangram [/bib_ref] Accurate surveillance for SSI monitoring requires followup for 30 days postoperatively, and the trend towards early discharge from hospital makes surveillance a challenge. It is estimated that up to 84% of surgical site infections occur following discharge from hospital. [bib_ref] Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory..., Mangram [/bib_ref] If prophylactic antibiotics are to be given, they should be administered shortly prior to or at bacterial inoculation. [bib_ref] The timing of prophylactic administration of antibiotics and the risk of surgical-wound..., Classen [/bib_ref] The majority of studies suggest that a single dose is effective, but for lengthy procedures (> 3 hours) the dose should be repeated at intervals 1or 2 times the half-life of the drug. It has also been suggested that with large blood loss (> 1500 mL), a second dose should be given. 10 ## Use of antibiotic prophylaxis in obstetrics Procedures reviewed in this section include Caesarean section, operative vaginal delivery, manual removal of placenta, repair of third or fourth degree perineal laceration, cervical cerclage, and postpartum dilatation and curettage. Recent changes to endocarditis prophylaxis guidelines are also be reviewed. ## Caesarean section The single most important risk factor for postpartum maternal infection is Caesarean section. [bib_ref] Clinical risk factors for puerperal infection, Gibbs [/bib_ref] Women having Caesarean section have a 5-to 20-fold greater risk of infection than women having vaginal delivery. Rates of wound infection and serious infectious complications can be as high as 25%. [bib_ref] Incidence of hospital-acquired infections associated with caesarean section, Henderson [/bib_ref] There is no consistent application of definitions for SSI, and the practice of post-discharge surveillance varies widely. [bib_ref] Forum: surveillance of surgical site infections, Lee [/bib_ref] There has been debate about the benefit of prophylactic antibiotics for a woman who has an elective Caesarean section with intact membranes and without labour. A meta-analysis of 4 studies found that antibiotic prophylaxis resulted in a decrease in postoperative fever (RR 0.25; 95% CI 0.14 to 0.44) and endometritis (RR 0.05; 95% CI 0.01 to 0.38). [bib_ref] Prophylactic use of antibiotics for nonlaboring patients undergoing cesarean delivery with intact..., Chelmow [/bib_ref] Taken together, these data support the recommendation to use prophylactic antibiotics for all women undergoing Caesarean section. Controversy also exists about whether prophylactic antibiotics in Caesarean section should be given prior to skin incision or at the time of the umbilical cord clamping. Traditionally, prophylaxis has been delayed in an effort to avoid masking a neonatal infection and to prevent an unnecessary septic work-up. However, recent evidence may change this practice. A randomized trial compared maternal infectious and neonatal outcomes in women randomized to receive cefazolin 15 to 60 minutes before incision versus at cord clamp. Three hundred fifty-seven women were enrolled. Overall maternal infectious morbidity was reduced in the pre-treatment group (RR 0.4; 95% CI 0.18 to 0.87); in particular, endometritis was reduced (RR 0.2; 95% CI 0.15 to 0.94). No increase in neonatal sepsis, investigation, or length of stay was observed. [bib_ref] Administration of cefazolin prior to skin incision is superior to cefazolin at..., Sullivan [/bib_ref] A recent meta-analysis supports the use of prophylactic antibiotics prior to Caesarean incision to prevent total infectious morbidity (RR 50; 95% CI 0.33 to 0.78, P = 0.002). Neonatal outcomes were not affected. [bib_ref] Timing of perioperative antibiotics for cesarean delivery: a metaanalysis, Costantine [/bib_ref] The most widely studied antibiotics for surgical prophylaxis are cephalosporins. Cefazolin is a first-generation cephalosporin and is a Pregnancy Category B drug. When given intravenously, its half-life is 1.8 hours. It provides good coverage for gram positive organisms and has modest gram negative coverage. In a 1999 guideline, the US Centers for Disease Control and Prevention recommended its use at Caesarean section. [bib_ref] Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory..., Mangram [/bib_ref] It is recommended that 1 to 2 grams should be administered intravenously not more than 30 minutes before the skin is cut. An additional dose can be considered if blood loss exceeds 1500 mL or at 4 hours if the procedure lasts more than 4 hours (i.e., up to 2 half-lives of the drug). [bib_ref] Antibiotic prophylaxis against postoperative wound infections, Gordon [/bib_ref] Trials have shown that broader spectrum antibiotics for Caesarean section do reduce infectious morbidity. Superiority trials with cefazolin have not been conducted. Given the potential for antibiotic resistance in both mother and neonate, recommendations for the use of broader spectrum antibiotics require further study. 20 ## Operative vaginal delivery A 2004 Cochrane review investigated the use of prophylactic antibiotics for operative vaginal delivery, with either forceps or vacuum assisted deliveries, to determine if prophylaxis reduces the incidence of postpartum infections. [bib_ref] Antibiotic prophylaxis for operative vaginal delivery, Liabsuetrakul [/bib_ref] The review identified only one trial of 393 women, and only 2 of 9 outcomes deemed appropriate by the reviewers were assessed in this study: endometritis and length of hospital stay. These did not differ between those who received prophylaxis and those who received no treatment. The review concluded there were insufficient data on which to base recommendations for practice and that further research is needed. No additional studies addressing this issue have been published to date. ## Manual removal of placenta There is limited information regarding the use of prophylactic antibiotics to reduce the development of postpartum endometritis following manual removal of the placenta. A Cochrane review, updated in April 2009, did not identify any randomized controlled trials. [bib_ref] Prophylactic antibiotics for manual removal of retained placenta in vaginal delivery, Chongsomchai [/bib_ref] The World Health Organization suggests that prophylaxis should be offered but recognizes that there is no direct evidence of the value of antibiotic prophylaxis after manual removal of the placenta and bases the recommendation on studies involving Caesarean section and abortion and on observational studies of other intrauterine manipulations.The effect of operator glove change before manual removal of the placenta at Caesarean section was studied in a group of 228 women, with operators changing gloves in one half of the cases. No difference in post-Caesarean endometritis was noted between the 2 groups. [bib_ref] Effect of changing gloves before placental extraction on incidence of postcesarean endometritis, Turrentine [/bib_ref] However, the incidence of endometritis was decreased when the placenta delivered spontaneously rather than being manually removed at Caesarean section in a study of 333 women, all of whom received prophylactic antibiotics (15% vs. 26%, RR 0.6; P = 0.01). 25 ## Third or fourth degree perineal laceration A 2005 Cochrane review 26 on this subject found there were no randomized trials comparing prophylactic antibiotics with placebo or no treatment in fourth degree perineal tears during vaginal birth. A well-designed randomized trial was recommended. This was undertaken by Duggal et al. [bib_ref] Antibiotic prophylaxis for prevention of postpartum perineal wound complications: a randomized controlled..., Duggal [/bib_ref] and published in 2008. This prospective trial followed 107 women post third or fourth degree laceration repair for 2 weeks; the women had been randomly assigned to receive a single intravenous dose of cefotetan, cefoxitin, or placebo. Four of 49 (8%) who received antibiotics and 14 of 58 (24%) who received placebo developed perineal wound complication (P = 0.037). This suggests a benefit to using prophylactic antibiotics to reduce morbidity following significant perineal laceration. 27 ## Elective and emergency cerclage, with or without exposed membranes There is insufficient evidence to support the use of prophylactic antibiotics with the placement of cervical cerclage in any clinical setting. One study [bib_ref] Continuous low-dose antibiotics and cerclage for recurrent second-trimester pregnancy loss, Shiffman [/bib_ref] investigated the use of continuous low-dose antibiotics in women with a history of second trimester pregnancy loss with the placement of cerclage at 14 to 24 weeks' gestation on the basis of transvaginal sonographic findings of cervical funnelling. Each of the 10 patients had a live birth, and pregnancy was prolonged by a mean of 13.4 ± 4.2 weeks beyond the previous pregnancy. There was no control group. [bib_ref] Continuous low-dose antibiotics and cerclage for recurrent second-trimester pregnancy loss, Shiffman [/bib_ref] In a second retrospective study of 116 mid-trimester cerclage placements, antibiotic use was not associated with a decreased risk of delivery before 28 weeks' gestation. [bib_ref] Factors associated with success of emergent second-trimester cerclage, Terkildsen [/bib_ref] Randomized clinical trials are needed to confirm the role of antibiotics in these high-risk pregnancies. ## Postpartum dilatation and curettage No studies were identified that investigated the use of prophylactic antibiotics for postpartum dilatation and curettage. ## Dosage of antibiotic prophylaxis in obesity Increased BMI is associated with higher rates of both obstetric and infectious complications. [bib_ref] The impact of maternal BMI status on pregnancy outcomes with immediate short-term..., Heslehurst [/bib_ref] Controlled trials assessing the required dosage for antibiotic prophylaxis based on patient BMI have not been assessed in our specialty. Expert opinion recommends twice the normal dose of prophylaxis for morbidly obese patients, who have a BMI > 35. [bib_ref] Antibiotic prophylaxis against postoperative wound infections, Gordon [/bib_ref] Future research in this area is needed. ## Recommendations for penicillin / cephalosporin allergy Penicillin allergy is self-reported by up to 10 % of patients, yet only 10 % of those are actually allergic when skin testing is performed. [bib_ref] The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns..., Lee [/bib_ref] [bib_ref] Results of the National Institute of Allergy and Infectious Diseases collaborative clinical..., Sogn [/bib_ref] [bib_ref] Penicillin skin testing in patients with a history of beta-lactam allergy, Del Real [/bib_ref] True anaphylactic response to penicillin is rare, occurring in 1 to 4 of 10 000 administrations.An allergic reaction to cephalosporins in those with a penicillin allergy occurs at rates of 0.17% to 8.4%. [bib_ref] Penicillin allergy and the cephalosporins, Dash [/bib_ref] [bib_ref] Safety of cephalosporin administration to patients with histories of penicillin allergy, Daulat [/bib_ref] [bib_ref] Adverse drug reactions to a cephalosporins in hospitalized patients with a history..., Fonacier [/bib_ref] An alternative to cephalosporins should be given only to individuals with a history of penicillin anaphylaxis (shortness of breath or evidence of airway edema rather than just rash or other allergic reaction) or cephalosporin allergy. Alternative prophylactic antibiotics include clindamycin 600 mg IV or erythromycin 500 mg IV. ## Prevention of infective endocarditis An American Heart Association guidelinepublished in 2007 found no evidence that genitourinary procedures cause IE or that administration of antibiotics prevents IE following such procedures. The American Heart Association therefore does not recommend prophylactic antibiotics for patients undergoing genitourinary procedures; this is a change from their 1997 guideline. They identified 4 conditions that are at highest risk of adverse outcome . For patients with the conditions listed in who have an established gastrointestinal or genitourinary tract infection or for those who receive antibiotic therapy for another reason (e.g., to prevent wound infection), they suggest it may be reasonable that the choice of antibiotic also be active against enterococci (i.e., ampicillin, piperacillin, or vancomycin). They also suggest that it may be reasonable for patients at high risk of IE who have a known enterococcal urinary tract infection or colonization to receive antibiotic treatment prior to any urinary tract manipulation. A review on this recommendation change has been recently published. 39 [table] Table 1: Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care [/table] [table] Table 2 Table 3: Cardiac conditions associated with the highest risk of adverse outcome from endocarditis Prosthetic cardiac valve or prosthetic material used for cardiac valve repair Previous infective endocarditis Congenital heart disease (CHD) Unrepaired cyanotic CHD (including palliative shunts and conduits) Completely repaired CHD with prosthetic material < 6 months after procedure Repaired CHD with residual defects at/near site of prosthetic material Cardiac transplant recipient with cardiac valvulopathy Adapted from Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al. 38 Prophylactic antibiotic recommendations for obstetrical procedures [/table]	None	None	None
71d0539ff332dc615437f226e74a98df952faafb	pubmed	Clinical practice guidelines for post-mastectomy breast reconstruction: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021	Clinical practice guidelines for post-mastectomy breast reconstruction: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021 ## Level of evidence and recommendation strength Level of evidence standard [bib_ref] Clinical practice guidelines for sentinel lymph node biopsy in patients with early-stage..., Ye [/bib_ref] Recommendation strength standard [bib_ref] Clinical practice guidelines for sentinel lymph node biopsy in patients with early-stage..., Ye [/bib_ref] Recommendation strength review committee There were 76 voting committee members for this guideline: 62 breast surgeons (81.6%), four oncologists (5.3%), four radiologists (5.3%), two pathologists (2.6%), two radiation therapists (2.6%), and two epidemiologists (2.6%). ## Target audience Clinicians specializing in breast diseases in China. ## Recommendations Recommendation 1: Indications.II A 3.2 Delayed breast reconstructionII A 3.3 Delayed-immediate breast reconstruction [bib_ref] Delayed-immediate breast reconstruction, Kronowitz [/bib_ref] [bib_ref] Delayed versus delayed-immediate autologous breast reconstruction: a blinded evaluation of aesthetic outcomes, Albino [/bib_ref] II A [bib_ref] Breast reconstruction after breastcancer surgery, Beier [/bib_ref] [bib_ref] Breast reconstruction with anatomical implants: a review of indications and techniques based..., Gardani [/bib_ref] [bib_ref] Immediate transverse rectus abdominis musculocutaneous (TRAM) flap breast reconstruction in underweight Asian..., Kim [/bib_ref] II A 4.2 Deep inferior epigastric perforator (DIEP) flap breast reconstruction [bib_ref] Breast reconstruction after breastcancer surgery, Beier [/bib_ref] [bib_ref] Breast reconstruction with anatomical implants: a review of indications and techniques based..., Gardani [/bib_ref] [bib_ref] Risk of recurrence and death in patients with breast cancer after delayed..., Adam [/bib_ref] II A ## Indications ## Level of evidence ## Latissimus dorsi flap (LDF) breast reconstruction [bib_ref] Breast reconstruction after breastcancer surgery, Beier [/bib_ref] [bib_ref] Breast reconstruction with anatomical implants: a review of indications and techniques based..., Gardani [/bib_ref] II A Recommendation 5: Prosthetic breast reconstruction. ## Prosthetic breast reconstruction Level of evidence Recommendation strength 5.1 Immediate implant-based breast reconstruction (one-stage method) [bib_ref] Breast reconstruction with anatomical implants: a review of indications and techniques based..., Gardani [/bib_ref] II A 5.2 Combined tissue expander and prosthetic breast reconstruction (two-stage method) [bib_ref] Breast reconstruction with anatomical implants: a review of indications and techniques based..., Gardani [/bib_ref] II A [bib_ref] Quality of life and patient satisfaction after one-stage implant-based breast reconstruction with..., Negenborn [/bib_ref] [bib_ref] Mesh versus acellular dermal matrix in immediate implant-based breast reconstruction -a prospective..., Gschwantler-Kaulich [/bib_ref] [bib_ref] Surgical studies of reconstructive breast surgery -an overview of the topics at..., Paepke [/bib_ref] II A 7.2 Titanium-coated polypropylene mesh (TCPM) [bib_ref] Mesh versus acellular dermal matrix in immediate implant-based breast reconstruction -a prospective..., Gschwantler-Kaulich [/bib_ref] [bib_ref] Surgical studies of reconstructive breast surgery -an overview of the topics at..., Paepke [/bib_ref] II A # Discussion Among malignancies in Chinese women, breast cancer has the highest incidence. [bib_ref] Cancer statistics in China, Chen [/bib_ref] With improvements in breast cancer screening and early diagnosis in China, the quality of life of approximately 30% of patients with early-stage breast cancer can be improved through breast-conserving surgery. However, more than 60% of breast cancer patients still require mastectomy. [bib_ref] Current status and factors influencing surgical options for breast cancer in China:..., Yang [/bib_ref] [bib_ref] Comparison of breastconserving therapy vs mastectomy in women under age 40: national..., Lazow [/bib_ref] The National Comprehensive Cancer Network (NCCN) guidelines suggest that all breast cancer patients who undergo mastectomy should be able to choose to undergo breast reconstruction surgery.Additionally, the NCCN guidelines indicate that inflammatory breast cancer is an absolute contraindication for breast reconstruction [bib_ref] Challenging a traditional paradigm: 12-year experience with autologous free flap breast reconstruction..., Chang [/bib_ref] and that smoking and obesity are relative contraindications. [bib_ref] Obesity and breast reconstruction: complications and patientreported outcomes in a multicenter, prospective..., Srinivasa [/bib_ref] [bib_ref] Smoking as an independent risk factor for postoperative complications in plastic surgical..., Toyoda [/bib_ref] [bib_ref] The association between smoking and plastic surgery outcomes in 40,465 patients: an..., Goltsman [/bib_ref] Regardless of whether prosthetic or autologous breast reconstruction is performed, smoking and obesity increase the risk of various breast reconstruction-related complications. [bib_ref] Obesity and breast reconstruction: complications and patientreported outcomes in a multicenter, prospective..., Srinivasa [/bib_ref] [bib_ref] Smoking as an independent risk factor for postoperative complications in plastic surgical..., Toyoda [/bib_ref] [bib_ref] The association between smoking and plastic surgery outcomes in 40,465 patients: an..., Goltsman [/bib_ref] Locally advanced breast cancer, radiotherapy history, stage IV breast cancer with distant metastasis, and connective tissue disease are not contraindications for breast reconstruction. The expert group believes that breast reconstruction for these patients is not supported by a high level of medical evidence. Breast reconstruction can be categorized as immediate, delayed, and delayed-immediate according to the timing. Immediate breast reconstruction refers to breast reconstruction performed with mastectomy.Delayed breast reconstruction is generally performed one year after mastectomy or more than six months after radiotherapy.In delayedimmediate breast reconstruction, a tissue expander is implanted during mastectomy to preserve the skin and aesthetic structure of the breast region to the fullest extent. [bib_ref] Delayed-immediate breast reconstruction, Kronowitz [/bib_ref] Autologous breast reconstruction is an important breast reconstruction method. [bib_ref] Breast reconstruction after breastcancer surgery, Beier [/bib_ref] [bib_ref] Breast reconstruction with anatomical implants: a review of indications and techniques based..., Gardani [/bib_ref] Commonly used autologous flaps for breast reconstruction include the transverse rectus abdominis myocutaneous flap, [bib_ref] Breast Transverse Rectus Abdominus Muscle Procedure, Goodenough [/bib_ref] deep inferior epigastric perforator flap, [bib_ref] Risk of recurrence and death in patients with breast cancer after delayed..., Adam [/bib_ref] and latissimus dorsi flap (LDF). Among all breast reconstruction methods, prosthetic breast reconstruction is the most common surgical procedure after breast cancer surgery. [bib_ref] Breast reconstruction after breastcancer surgery, Beier [/bib_ref] [bib_ref] Breast reconstruction with anatomical implants: a review of indications and techniques based..., Gardani [/bib_ref] Prosthetic breast reconstruction includes one-stage and two-stage reconstruction (with a tissue expander combined with prosthetic breast reconstruction). [bib_ref] Breast reconstruction after breastcancer surgery, Beier [/bib_ref] The expert group agrees that two-stage reconstruction requires two surgeries and may obtain better breast aesthetics through adjustments made during the second surgery. Combined LDF and prosthetic breast reconstruction is another surgical procedure for breast reconstruction. The use of LDF alone for breast reconstruction may not achieve an ideal aesthetic effect due to insufficient donor-site volume, and a prosthesis will need to be implanted under the LDF to replenish the volume of the reconstructed breast. The expert group believes that combined LDF and prosthetic breast reconstruction can not only compensate for the deficiency of insufficient donor-site tissue in LDF breast reconstruction but also avoid the problem of insufficient surface coverage of the prosthesis. The strength and thickness of prosthesis coverage during prosthetic breast reconstruction are key factors that determine the appearance of the breast after reconstruction. Patches used for breast reconstruction can be divided into two categories: patches made of bioderived materials, Chinese Medical Journal 2021;134 [bib_ref] Surgical studies of reconstructive breast surgery -an overview of the topics at..., Paepke [/bib_ref] www.cmj.org such as acellular dermal matrix, [bib_ref] Quality of life and patient satisfaction after one-stage implant-based breast reconstruction with..., Negenborn [/bib_ref] [bib_ref] Mesh versus acellular dermal matrix in immediate implant-based breast reconstruction -a prospective..., Gschwantler-Kaulich [/bib_ref] [bib_ref] Surgical studies of reconstructive breast surgery -an overview of the topics at..., Paepke [/bib_ref] and patches made of synthetic materials, such as titanium-coated polypropylene mesh. [bib_ref] Mesh versus acellular dermal matrix in immediate implant-based breast reconstruction -a prospective..., Gschwantler-Kaulich [/bib_ref] [bib_ref] Surgical studies of reconstructive breast surgery -an overview of the topics at..., Paepke [/bib_ref] With advances in breast cancer diagnosis and treatment concepts as well as socioeconomic and cultural development in China, the aesthetic requirements of breast cancer patients are gradually increasing, as is the percentage of patients undergoing breast reconstruction. [bib_ref] Current status and factors influencing surgical options for breast cancer in China:..., Yang [/bib_ref] Conflicts of interest None.	None	None	To promote the standardization of post-mastectomy breast reconstruction in China, the Chinese Society of Breast Surgery (CSBrS) determined the key issues in postmastectomy breast reconstruction in clinical practice through a literature review and expert discussions, and then developed the CSBrS Clinical Practice Guidelines for Post-mastectomy Breast Reconstruction (2021 version) by systematically assessing relevant published evidence according to the Grading of Recommendations Assessment, Development, and Evaluation recommendations and based on the accessibility of clinical practice in China. This guideline provides a reference for Chinese breast surgeons.
4a960c7740861196a085ed726d505217750af5ee	pubmed	The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the treatment of adolescent sexual offenders with paraphilic disorders	The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the treatment of adolescent sexual offenders with paraphilic disorders The primary aim of these guidelines was to evaluate the role of pharmacological agents in the treatment of adolescents with paraphilic disorders who are also sexual offenders or at-risk of sexual offending. Psychotherapeutic and psychosocial treatments were also reviewed. Adolescents with paraphilic disorders specifically present a different therapeutic challenge as compared to adults. In part, the challenge relates to adolescents being in various stages of puberty and development, which may limit the use of certain pharmacological agents due to their potential side effects. In addition, most of the published treatment programmes have used cognitive behavioural interventions, family therapies and psychoeducational interventions. Psychological treatment is predicated in adolescents on the notion that sexually deviant behaviour can be controlled by the offender, and that more adaptive behaviours can be learned. The main purposes of these guidelines are to improve the quality of care and to aid physicians in their clinical decisions. These guidelines brought together different expert views and involved an extensive literature research. Each treatment recommendation was evaluated and discussed with respect to the strength of evidence for efficacy, safety, tolerability and feasibility. An algorithm is proposed for the treatment of paraphilic disorders in adolescent sexual offenders or those who are at risk.ARTICLE HISTORY # Introduction Preliminary note: Most (if not all) of the literature on this subject concerns adolescents who committed sexual offences according to the laws of their country. They are deviant according to legal/societal norms of their country. The use of the term ''deviant'' does not imply a moral statement from the authors of this text. ''Juvenile sexual offenders'' or ''juvenile sex offenders'' were defined as youths between the ages of 12 and 18 who have either been officially charged with a sexual crime (e.g., child molestation, rape, exhibitionism, voyeurism), have performed an act that could be officially charged, or committed sexually abusive/aggressive behaviour or any sexual act with a person of any age against the victim's will or in an aggressive, exploitative or threatening manner; the term ''child molester'' refers to those who choose only or primarily child victims younger than the offender [bib_ref] Epidemiology and treatment of juvenile sexual offending, Gerardin [/bib_ref] [bib_ref] Standards of care for juvenile sexual offenders of the international association for..., Miner [/bib_ref]. Most of the sexual offenders are males [bib_ref] Sexual offending runs in families: a 37-year nationwide survey, Langströ M [/bib_ref] and this paper will focus on them. Deviant sexual behaviour often starts with the development of deviant sexual fantasies associated with masturbation. Studies of the natural history of the paraphilic disorders show that deviant sexual behaviour often begins in later adolescence or early adulthood.showed that 42% of males with a paraphilic disorder exhibited deviant sexual arousal by age 15 and 57% by age 19; in the case of paedophilia against same-sex children (homosexual paedophilia) this appeared to show also an earlier onset with 53% reporting deviant arousal by age 15 and 74% by age 18. In some offenders, the severity of the deviant sexual behaviour increases with age, from exhibitionism, voyeurism or fetishism, to rape or child sexual abuse [bib_ref] Sexually inappropriate behaviour: development in the sex offender, Longo [/bib_ref]. This raises questions about how to identify deviant sexual interest occurring in adolescence, prior to sexual acting out, and to implement a prevention strategy. In theory, if successful evidence-based treatment intervention, either psychological or pharmacological, occurred during adolescence with identified adolescent sexual offenders and adolescents suffering from paraphilic disorders, this could have an important impact on adult deviant sexual behaviour and, in the case of paedophilia, on the incidence of the sexual abuse of children [bib_ref] Pharmacological treatment of the juvenile sex offender, Bradford [/bib_ref]. However, the treatment of adolescents with pharmacological agents requires special considerations compared to adults. ## Paraphilic disorders: definitions The terms ''sex offenders'' or ''sexual offenders'' and ''paraphilic disorders'' will be used in the following text. In order to clarify the respective use of these words, it is important to remember that, not all sexual offenders suffer from a paraphilic disorder, but only part of them, and that, not all patients with a paraphilic disorder are sexual offenders (in some cases, they only suffer from deviant sexual fantasies or urges, or their deviant sexual behaviour does not involve a non-consenting person or a child). Paraphilic disorders (from the Greek ''para'' meaning around or beside and ''philos'' meaning love) are sexual stimuli or acts that are deviations from socially accepted sexual behaviour, but are necessary, and in some cases sufficient, for some persons, to experience sexual arousal and orgasm [bib_ref] Current concepts in the pharmacotherapy of paraphilias, Garcia [/bib_ref]. Paraphilic disorders are distributed from a spectrum of nearly normal behaviour to being hurtful or destructive of oneself or others. In the Diagnostic and Statistical Manual Disorder, Fourth Edition, Text Revision (DSM-IV-TR, American Psychiatric Association 2000) or the International Classification of Mental Diseases (ICD-10th, World Health Organisation 1992), paraphilias were classified in the ''Sexual and Gender Identity Disorders'' chapter and were characterised by ''recurrent, intense, sexually arousing fantasies, sexual urges or behaviours, generally involving (1) non-human objects, (2) the suffering or humiliation of oneself or one's partner, or (3) children or other non-consenting persons that occur over a period of 6 months'' (criterion A), which ''cause clinically significant distress or impairment in social, occupational, or other important areas of functioning'' (criterion B). In the case of paedophilia, the sexual activity involves prepubescent children, generally aged 13 years or younger. In general, paedophiles must be at least 16 years old and must be at least 5 years older than the victim. For juvenile or younger paedophiles, no age is specified and clinical judgment must be used (i.e., sexual maturity of the child and age difference between the victim and the perpetrator). Along with a residual category called ''paraphilia not otherwise specified'', DSM IV-TR described eight specific disorders of this type: exhibitionism, fetishism, frotteurism, paedophilia, sexual masochism, sexual sadism, voyeurism and transvestic fetishism. In the DSM-5 (American Psychiatric Association 2013), these criteria should be addressed in the presence of three main aspects: first, the sexual arousal by deviant sexual stimuli, second, the negative consequences for the individual or the society and, finally, the fact that the person acts on his or her urges or that the urges or fantasies cause significant distress, interpersonal difficulty or impairment in functioning. The most important change in DSM-5 is the distinction between paraphilias and paraphilic disorders: ''a paraphilia by itself would not automatically justify or require psychiatric intervention. A paraphilic disorder is a paraphilia that causes distress or impairment to the individual or harm to others''. In this concept, having paraphilia would be a necessary but not a sufficient condition to determine a paraphilic disorder. Paraphilic disorders are not illegal; however, acting in response to paraphilic urges may be illegal (sex offence) and, in some cases, it could result in severe legal sanctions as is frequently observed in the case of paedophilia. Patients with paraphilic disorders usually come to medical or legal attention by committing an act against a child or a non-consenting adult because most of them, especially adolescents, do not find their sexual fantasies distressing or ego-dystonic enough to voluntarily seek treatment or they may feel ashamed and do not dare to ask for medical advice prior to sexual acting out. For some individuals, paraphilic fantasies or stimuli are obligatory for erotic arousal and are always included in their sexual activity (exclusive paraphilic disorders). In other cases, the paraphilic preferences occur only episodically, whereas at other times, the person is able to function sexually without deviant stimuli or fantasies. In a sample of 1,600 child and adolescent sexual offenders (mean age 14 years (range 5-19)),reported that denial was frequently observed. As observed in adults, comorbidities are frequently reported (mostly substance abuse, affective disorders, cognitive difficulties with poor academic performances and learning problems, and antisocial behaviour) [bib_ref] Recent research related to juvenile sex offending: findings and directions for further..., Malin [/bib_ref]. [bib_ref] The psychiatric diagnoses of twenty-two adolescents who have sexually molested other children, Galli [/bib_ref] reported in a sample of 22 paraphilic adolescents: 94% conduct disorders, 71% attention deficit and hyperactivity disorder (ADHD), 23% major depressive disorder, 27% bipolar disorder, 72% substance abuse. In their sample, 95% of the subjects met DSM III-R criteria for two or more paraphilias. Impulse-control disorders, posttraumatic stress disorders or conduct disorders were also described in association with paraphilic disorders [bib_ref] The psychosocial characteristics of juvenile sexual offenders referred to an adolescent forensic..., Dolan [/bib_ref] [bib_ref] Psychiatric comorbidity and compulsive/impulsive traits in compulsive sexual behavior, Raymond [/bib_ref]. Personality disorders were frequently observed in paraphilic subjects (33-52%) (borderline or antisocial personality disorders in most cases) [bib_ref] Psychopathology and personality disorders in adolescent sex offenders, Shaw [/bib_ref]. The most common characteristic observed in juvenile sexual offenders was a history of victimisation. Past histories of sexual (50%) or physical abuse (66 vs. 20% in non-sexual offenders) were reported in these subjects [bib_ref] Sexual learning and experiences among adolescent sexual offenders, Longo [/bib_ref] [bib_ref] Explanations of pedophilia: a four factor model, Finkelhor [/bib_ref] [bib_ref] Psychiatric diagnoses in adolescent sex offenders, Kavousi [/bib_ref] [bib_ref] Sexual abuse history among adult sex offenders and non-sex offenders: a meta-analysis, Jespersen [/bib_ref]. [bib_ref] Does childhood sexual abuse victimization translate into juvenile sexual offending? New evidence, Delisi [/bib_ref] also found a 6-fold increase of likelihood of sexual offending, based on data from 2,520 incarcerated male juvenile offenders, in youths with childhood sexual abuse histories. [bib_ref] Measuring the effectiveness of treatment for the aggressive adolescent sexual offender, Becker [/bib_ref] have suggested a probable basis for the development of a deviant sexual arousal pattern in these children. They make the assumption that deviant sexual arousal and behaviour are learned in individuals through modelling and conditioning experiences. Family relationships were also frequently described as dysfunctional with parents having substance abuse problems, criminal and impulsive behaviours or psychiatric disturbances [bib_ref] Adolescent sibling-incest offenders: differences in family and individual functioning when compared to..., Worling [/bib_ref]. In addition, early exposure to sex or pornography and to sexual violence might play a role in further sex offending [bib_ref] What is so special about male adolescent sexual offending? A review and..., Seto [/bib_ref]. Moreover, frequency of pornography use adds significantly to the prediction of sexual recidivism, which was assessed up to 15 years after release in sexual offenders [bib_ref] Pornography use and sexual aggression: the impact of frequency and type of..., Kingston [/bib_ref]. [bib_ref] Comparing sexuality, aggressiveness, and antisocial behavior of alleged juvenile sexual and violent..., Driemeyer [/bib_ref] stated that adolescent sex offenders (n¼32) were less experienced sexually, had less confidence in their interpersonal skills, and reported more sexual deviance than alleged violent offenders (n¼32). Compared with peer sexual abusers, child sexual abusers have a less delinquent predisposition, less substance-abuse proneness and less antisocial functioning [bib_ref] Do adolescent child abusers, peer abusers, and non-sex offenders have different personality..., Glowacz [/bib_ref]. In the same way, female adolescent sexual offenders who have committed a sexual offence against a younger child (25 cases) have considerably fewer problems in the domains of school, family and friends as compared to those who have committed sexual offences with a peer victim (15 cases) or a misdemeanour sexual offence (31 cases) (Van der Put 2013). Female offenders have also a more severe history of victimisation [bib_ref] Juvenile female sexual offenders: clinical characteristics and treatment issues, Mathews [/bib_ref]. Adolescents who sexually abused a sibling, versus a non-sibling, were more likely to have histories of sexual abuse and been exposed to domestic violence and pornography (n¼100 cases vs. n¼66) [bib_ref] Sexual offending in adolescence: a comparison of sibling offenders and nonsibling offenders..., Latzman [/bib_ref]. In summary, adolescent sexual offenders form a heterogeneous group including individuals with antisocial personality disorders, adolescents with problematic family background and adolescents with atypical sexual interests, where different risk factors are predictive of recidivism. In the same way, among juvenile offenders, [bib_ref] Assessment and treatment of adolescent sexual offenders: implications of recent research on..., Pullman [/bib_ref] have identified a subgroup of sexual offenders with unique risk and aetiological factors including childhood sexual abuse and atypical sexual interests. Adolescents who commit child sexual homicides (less than 1% of the total murders committed by juveniles in the USA) often experienced violent sexual fantasies before their crimes. Patients with mental retardation have a similar or even slightly increased proportion of sexual problems as compared to subjects of average intelligence, but the types of problems are different. They more often show inappropriate, non-assaultive sexual behaviour, such as public masturbation and exhibitionism, and they are less discriminating in their choice of victim [bib_ref] Sex offenders, Hayes [/bib_ref]. Finally, juvenile sex offending has also been found to occur in pre-adolescent and younger children.reported sexual aggression in children with a mean age of onset between 6 and 9 years. Their victims are mostly siblings or friends. Most of these offenders have been physically or sexually abused, have frequent learning difficulties, impaired relationships, and dysfunctional families (with inter-parental violence). Yet, longitudinal studies are lacking and it is not known which children will persist in their sexual behaviour problems in adolescence and adulthood [bib_ref] Epidemiology and treatment of juvenile sexual offending, Gerardin [/bib_ref].studied patterns of co-offending by female sexual offenders (FSOs), using 21 years of the US National Incident-Based Reporting System data to analyse incidents of sexual offending committed by four female groupings: solo FSOs (n¼29,238), co-ed pairs consisting of one male and one , all-female groups (n¼2669), and multiple perpetrator groups that consisted of a combination of three or more FSOs and male sexual offenders (n¼4268). Using a multinomial logistic regression model, the data showed significant differences in offender, victim, and crime context incident characteristics. The data also indicated that incidents with solo FSOs and allfemale groups have similar characteristics, co-ed pairs and multiple perpetrator incidents have similar characteristics, and these two categorizations are fairly distinct from one another. ## Epidemiology of sexual offending and risk factors for recidivism Of all arrests for sexual crimes in the USA in 2011, juvenile arrests represented 14% of forcible rapes. A 14% rate of bestiality was reported among juvenile sexual offenders . In parallel, the number of juvenile sexual offender programmes has been rising, especially in the USA. Recidivism is a major concern in sexual offenders. Most people recognise that incarceration alone will not solve sexual violence. Sexual recidivism rates have been found to be lower than for adults ranging from 7% [bib_ref] Study characteristics and recidivism base rates in juvenile sex offender recidivism, Caldwell [/bib_ref] to 30% [bib_ref] Long-term follow-up of criminal recidivism in young sex offenders: temporal patterns and..., Langströ [/bib_ref]. According to [bib_ref] What we do not know about juvenile sexual re-offence risk?, Caldwell [/bib_ref] , it rarely exceeds 15% as compared to non-sexual recidivism, which ranges from 37 to 89% depending on the lengths of follow-up and the characteristics of the sample. In a meta-analysis, [bib_ref] The effectiveness of sexual offender treatment for juveniles as measured by recidivism:..., Reitzel [/bib_ref] have reported, in juvenile sexual offenders, an average recidivism rate (based on an average 59-month follow-up period across studies) of 12.5% for sexual crimes as compared to about 25% for non-sexual crimes (2986 subjects). In comparison, in adults (61 follow-up studies) [bib_ref] Predicting relapse: a metaanalysis of sexual offender recidivism studies, Hanson [/bib_ref] reported a sexual offence recidivism rate of 13.4% (23,393 cases). In adults, sexual offence recidivism was best predicted by the type of sexual deviancy, and to a lesser extent, by general criminological factors (age, total prior offences) and failure to complete treatment. [bib_ref] Sexual offender treatment efficacy revisited, Alexander [/bib_ref] conducted a review on 79 sexual offender treatment outcome studies published between 1943 and 1996 including 10,988 subjects (7% were juvenile sexual offenders); analyses based on location of treatment resulted in close recidivism rates whatever the location (6.3-8.5%) (outpatient setting, prison, hospital or unspecified) (based on re-arrests). The rates of recidivism were respectively 5.8% for rapists and 2.1% for child molesters. It seems that treating the offenders, at least in adults, is critical in preventing sexual violence and reducing victimisation [bib_ref] Epidemiology and treatment of juvenile sexual offending, Gerardin [/bib_ref] [bib_ref] Treatment effectiveness for male adolescent sexual offenders: a meta-analysis and review, Walker [/bib_ref] [bib_ref] Sexually abusive youth: a review of recidivism studies and methodological issues for..., Fortune [/bib_ref] [bib_ref] The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the..., Thibaut [/bib_ref] [bib_ref] Preventing sexual abusers of children from reoffending: systematic review of medical and..., Långströ M [/bib_ref]. In the same way, [bib_ref] The effectiveness of sexual offender treatment for juveniles as measured by recidivism:..., Reitzel [/bib_ref] in a metaanalysis, have reported that, in juvenile sexual offenders, the sexual recidivism rate was 7.4% for those who received treatment (any kind) (n¼1655), as compared with 19% in the control groups (n¼1331). The average follow-up period was 59 months. It has also been shown that longer follow-up periods resulted in higher recidivism rates for adolescents who offend sexually (for review, see [bib_ref] 20-Year prospective follow-up study of specialized treatment for adolescents who offended sexually, Worling [/bib_ref]. Apart from failure to complete the treatment programme, research and meta-analyses suggest that sexual deviance and antisocial behaviour are both related to sexual recidivism in adolescents [bib_ref] Adolescent sexual offender recidivism: success of specialized treatment and implications for risk..., Worling [/bib_ref] [bib_ref] The characteristics of persistent sexual offenders: a meta-analysis of recidivism studies, Hanson [/bib_ref]. Poor social skills were directly related to recidivism, whereas cognitive distortions and deviant sexual fantasies mediated the role of learning problems and deviant sexual experiences [bib_ref] Predictors of recidivism in Australian juvenile sex offenders: implications for treatment, Kenny [/bib_ref]. [bib_ref] Factors related to recidivism among juvenile sexual offenders, Rasmussen [/bib_ref] examined the criminal history records of 170 youths who were convicted as juvenile sexual offenders. Factors associated with recidivism included a prior history of criminal behaviour, multiple victims, and failure to complete sexual offender treatment. A meta-analysis of 59 independent studies comparing male adolescent sexual offenders (n¼3855) with non-sexual offenders (n¼13,393) on variables reflecting general delinquency risk factors (antisocial tendencies), childhood abuse, exposure to violence, family and interpersonal problems, sexuality, psychopathology, and cognitive abilities was conducted by [bib_ref] What is so special about male adolescent sexual offending? A review and..., Seto [/bib_ref]. The results showed that adolescent sexual offending cannot be considered as a simple manifestation of general antisocial tendencies. Adolescent sexual offenders had much less extensive criminal histories, fewer antisocial peers, and fewer substance use problems compared with nonsexual offenders. Special explanations suggesting a role for sexual abuse history, early exposure to sex or pornography, exposure to sexual violence, other abuse or neglect, social isolation, atypical sexual interests, anxiety, and low self-esteem received support. Explanations focusing on attitudes and beliefs about women or sexual offending, family communication problems or poor parent-child attachment, exposure to nonsexual violence, social incompetence, conventional sexual experience, and low intelligence were not supported. Ranked by effect size, the largest group difference was obtained for atypical sexual interests, followed by sexual abuse history, and, in turn, criminal history, antisocial associations, and substance abuse. In the same way, Christiansen and Vincent (2013) using a dataset from the national juvenile court data archive, reported that the strongest individual predictors of sexual recidivism in adjudicated juvenile sex offenders were: prior sexual and non-sexual offending, hands-off offending, offending against a child, younger school grade/age at time of initial offence, minority status (Asian or Hispanic ethnicity) and not attending school. Subsequently, [bib_ref] Testing the ''sexually abused-abuser hypothesis'' in adolescents: a population-based study, Aebi [/bib_ref] tested the link between past sexual abuse, either with or without contact, and sexually offending behaviour in a nationally representative sample of male and female adolescents attending 9th grade public schools in Switzerland while controlling for other types of abuse, mental health problems, substance use, and non-sexual violent behaviours. Selfreported data were collected from 6628 students (3434 males, 3194 females, mean age ¼ 15.50 years, SD ¼ 0.66 years). Exposure to contact and non-contact types of sexual abuse was assessed using the Child Sexual Abuse Questionnaire and sexually offending behaviour by the presence of any behaviour indicating sexual coercion. Two hundred and forty-five males (7.1%) and 40 females (1.2%) reported having sexually coerced another person. A strong relationship between past sexual abuse, with and without physical contact, and sexual-offending behaviour in male and female adolescents was shown and reducing exposure to non-contact sexual abuse (like Internet-based sexual exploitation) was also suggested to prevent sexual violence in youths. ## Risk assessment Risk assessment is a key element in the prevention of recidivism among juvenile sexual offenders. It is generally held that when assessing risk of sexual reoffending, actuarial assessments are superior to unstructured clinical judgment [bib_ref] The estimate of risk of adolescent sexual offense recidivism (ERASOR): preliminary psychometric..., Worling [/bib_ref] [bib_ref] The accuracy of recidivism risk assessments for sexual offenders: a meta-analysis of..., Hanson [/bib_ref]. Some risk assessment tools have been developed for adolescent sexual offenders. [bib_ref] Review of risk assessment instruments for juvenile sex offenders: what is next?, Hempel [/bib_ref] have reviewed the current literature (19 studies) on the predictive accuracy of six risk assessment instruments: the Juvenile Sex Offender Assessment Protocol II (J-SOAP-II) (static risk scale) [bib_ref] Another piece of the puzzle: psychometric properties of the J-SOAP-II, Fanniff [/bib_ref] , the Juvenile Sexual Offence Recidivism Risk Assessment Tool II (J-SORRAT-II;, the Estimate of Risk of Adolescent Sexual Offence Recidivism (ERASOR; [bib_ref] The estimate of risk of adolescent sexual offense recidivism (ERASOR): preliminary psychometric..., Worling [/bib_ref] , the Juvenile Risk Assessment Scale (JRAS; [bib_ref] Juvenile risk assessment scale (JRAS): a predictive validity study, Hiscox [/bib_ref] , the Structured Assessment of Violent Risk in Youth (SAVRY;, and, finally, the Hare Psychopathy Checklist: Youth Version (PCL: YV;. Specialised tools such as the ERASOR or the J-SOAP-II appeared better in terms of accuracy for prediction of sexual recidivism. This was further confirmed by [bib_ref] A prospective investigation of factors that predict desistance from recidivism for adolescents..., Worling [/bib_ref] , in a cohort of 81 adolescent male sexual offenders. In North America, three structured risk assessment instruments are now in common use for adolescent males: ERASOR, J-SOAP-II, and more recently J-SORRAT-II. In the US, use of one or more of these instruments (mostly ERASOR and J-SOAP-II) has increased significantly from about two-fifths of the programmes in 2002 to over three-quarters of the programmes in 2009 as compared to two-thirds of the programmes in Canada in [bib_ref] Drug treatment of paraphilic and nonparaphilic sexual disorders, Guay [/bib_ref] [bib_ref] Current practices and emerging trends in sexual abuser management. The Safer Society, Mcgrath [/bib_ref]. In the studies by [bib_ref] Assessment of accused juvenile sex offenders in Germany: a comparison of five..., Klein [/bib_ref] [bib_ref] Protective factors and recidivism in accused juveniles who sexually offended, Klein [/bib_ref] , using the SAVRY and the Structured Assessment of Protective Factors for violence risk (SAPROF), risk factors and protective factors were significantly and negatively correlated. Protective factors failed to achieve a significant incremental predictive accuracy beyond that captured by the SAVRY risk factors alone. Nevertheless, these assessment tools should only be used as one component of a comprehensive assessment protocol (Adolescents who have engaged in sexually abusive behaviour: effective policies and practices adopted by the Association for the Treatment of Sexual Abusers, Executive Board of Directors on October 30, 2012) (http://www.atsa.com/pdfs/Policy/ AdolescentsEngagedSexuallyAbusiveBehavior.pdf). ## Outcome measures Studies examining the efficacy of treatment programmes implemented in populations of adolescent sexual offenders have used different outcome measures. In most cases, they have used self-report questionnaires. Some studies have defined recidivism as the re-arrest and/or re-conviction of a juvenile after the completion of treatment. However, acts of sexual aggression are often underreported and re-arrest or reconviction rates may not accurately reflect rates of recidivism, especially when the duration of follow-up is too short. The penile plethysmograph measures penile tumescence, typically with a strain gage, when the subject attends to slides, audio-or videotapes depicting various appropriate and deviant sexual stimuli. The magnitude of the individual's erection response to a category of stimuli is considered an indication of his sexual interest in that behaviour or in persons of that age and gender. According to [bib_ref] Current practices and emerging trends in sexual abuser management. The Safer Society, Mcgrath [/bib_ref] , this method is used in less than 10% of adolescents in North America. Sexual arousal testing using a phallometric technique has come into some criticism as being too intrusive in adolescence; however, this argument needs to be considered against the possible consequences of not overseeing a possibly dangerous paraphilic interest [bib_ref] Pharmacological treatment of the juvenile sex offender, Bradford [/bib_ref]. [bib_ref] Discriminative and predictive validity of the penile plethysmograph in adolescent sex offenders, Clift [/bib_ref] have reported that post-treatment inability to suppress deviant sexual arousal to male and female children was significantly related to sexual offence recidivism over the 6-year follow-up period of the study (n¼132 male adolescents). However, the ethical question of further exposing minors to sexually explicit materials (deviant or not deviant) complicates this issue. Mental health professionals, however, should be aware that, in some countries, possession of audio-visual sexual material (especially including children) even for diagnostic or therapy purposes may be against the law (American Psychiatric Association 2013) and that presenting such material to adolescents may, in legal terms, count as ''sexual abuse of minors''. Viewing time measures compute the length of time an individual views slides of males and females of different ages as well as information from a standardised questionnaire. Individuals in the slides are clothed. Among community and residential programmes for male adolescents developed in North America, about one-third used viewing time measures [bib_ref] Current practices and emerging trends in sexual abuser management. The Safer Society, Mcgrath [/bib_ref]. Visual Reaction Time has been shown to discriminate between individuals of different sexual interests. Visual reaction time measures are sensitive to age preferences [bib_ref] Visual reaction time and plethysmography as measures of sexual interests in child..., Abel [/bib_ref] [bib_ref] Use of visual reaction time to assess male adolescents who molest children, Abel [/bib_ref] [bib_ref] A comparison of objective measures of sexual arousal and interest: visual reaction..., Letourneau [/bib_ref] [bib_ref] Viewing time measures and sexual interest: another piece of the puzzle, Gress [/bib_ref] [bib_ref] Indirect measures of sexual interest in child sex offenders: a multimethod approach, Banse [/bib_ref]. Visual reaction time evaluation of sexual interest is less intrusive and may offer an objective measure of deviant sexual interests in adolescence but also possibly a large-scale screening tool [bib_ref] On sexual violence, Bradford [/bib_ref]. However,have questioned the use of rapid serial visual presentation of child or animal images in adolescent sexual offenders: adolescent cognitive abilities may not be able to allow them to concentrate on the task and deviant sexual interest may be present to different degrees in adolescents. In fact, its use as an outcome measure with adolescents is a subject of controversy among professionals as no normative data exist for adolescents. ## Treatment goals Initially, interventions for juvenile sexual offenders were largely based on adult sexual offender interventions, with little consideration of developmental aspects that are specific to adolescence. Recently interventions that address youth-specific factors associated with sexual behaviour problems and include an important family focus have been reported (for review of the past history of these interventions: [bib_ref] Juveniles who sexually offend: recommending a treatment program and level of care, Dwyer [/bib_ref]. In addition, traditional treatment approaches failed to prioritise issues involving cultural competence. [bib_ref] Culturally competent practice with African American juvenile sex offenders, Venable [/bib_ref] have pointed out the importance of developing this aspect. Reducing sexual acting-out risk and improving psychosocial functioning are the ultimate aims of any treatment programme for sexual offenders. In addition to psychological and behavioural therapies, always used as first-line treatment approaches, several pharmacological treatment options are available in the most severe cases. The treatment choice will essentially depend on the following parameters: patient's previous medical and psychiatric history, patient's observance, intensity of deviant sexual fantasies and sexual preoccupations, comorbid hypersexuality (see [bib_ref] Sexual addictions, Garcia [/bib_ref] , risk of sexual violence, and completion of growth and puberty. Psychological treatment is predicated in adolescents on the notion that sexually deviant behaviour can be reduced and controlled by the offender and that more adaptive behaviours can be learned. Treatment goals with cognitive behavioural therapies in adolescent sexual offenders include: helping offenders to reduce deviant sexual arousal, challenging cognitive distortions and rationalizations that support or trigger offending behaviour, accepting responsibility for sexual behaviour, improving victim empathy and social skills, improving family relationships and reducing personal trauma if any. The number and type of treatment programmes have largely increased but studies, which evaluate their efficacy, using a controlled design, remain scarce. Although the full discussion of the hormonal changes at puberty and the various stages of pubertal development is beyond the scope of this particular paper, it is clear that the development of secondary sex characteristics occurs during puberty and that many of these changes are completed by age 15 in males. These changes are dependent on hormonal levels. Puberty would be regarded as being delayed in onset if it has not occurred on average by age 15. There is also a growth spurt that occurs within an onset of anywhere between 10.5 and 16 years of age, with considerable variability [bib_ref] Pharmacological treatment of the juvenile sex offender, Bradford [/bib_ref]. This means that these factors have to be taken into account with any pharmacological intervention in adolescence. Most specifically if that pharmacological intervention affects hormone levels such as the use of antiandrogens in adolescence then this clearly has to be very carefully and very specifically evaluated before such intervention occurs. There is good evidence that selective serotonin reuptake inhibitors (SSRIs), affecting the neurotransmitter serotonin (5 hydroxytryptamine), can be an effective treatment of sexually deviant behaviour without an effect on hormonal levels ). This class of pharmacological agents has already been used in treating a number of adolescent conditions including obsessive-compulsive disorders as well as depressive disorders [bib_ref] The neurobiology, neuropharmacology, and pharmacological treatment of the paraphilias and compulsive sexual..., Bradford [/bib_ref] [bib_ref] Obsessive-compulsive and spectrum disorder: overview and quality-of-life issues, Hollander [/bib_ref]. Nonetheless, the US Food and Drug Administration (FDA) released safety warnings stating that use of antidepressants may increase the risk of suicidality in children, adolescents and young adults up to age 24 years (http://www.fda.gov/Drugs/ DrugSafety/InformationbyDrugClass/UCM096273). ## Methods of our analysis These guidelines are intended for use in clinical practice by clinicians who diagnose and treat adolescents with paraphilic disorders. The aim of these guidelines is to improve the quality of care and to aid physicians in clinical decisions. Although these guidelines are based on the available published evidence, the treating clinician is ultimately responsible for the assessment and the choice of treatment options, based on knowledge of the individual subject. To achieve our aim, an extensive literature search was conducted by J.M.W. Bradford and F. Thibaut, using the English-language literature indexed on MEDLINE/PubMed (1990-2014 with the following keywords ''adolescent sexual offenders, juvenile sexual or sex offenders, paraphilia, paraphilic disorder, treatment'' supplemented by other sources, including published reviews (according to previous WFSBP guidelines, [bib_ref] World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment..., Soyka [/bib_ref]. Both controlled and uncontrolled studies were included in the review. Studies of any form of treatment were eligible for inclusion. The treatments included in the review were multisystemic therapy, cognitive-behavioural therapy, satiation therapy, vicarious sensitisation, family therapy, psychoeducational therapy, and pharmacological treatments. Most of the studies included male adolescent sexual offenders. The outcomes eligible for inclusion were recidivism, self-reported measures of deviant sexual attitudes and behaviours, and measures of arousal in relation to deviant sexual stimuli. The evidence from the literature research was summarised. Each treatment recommendation was evaluated and discussed with respect to the strength of evidence for its efficacy, safety, tolerability and feasibility. It must be kept in mind that the strength of recommendation is due to the level of efficacy and not necessarily of its importance. Four categories were used to determine the hierarchy of recommendations (related to the described level of evidence) [bib_ref] World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment..., Soyka [/bib_ref] : Level A: there is good research-based evidence to support this recommendation. The evidence was obtained from at least three moderately large (sample size equal to or greater than 50 participants), positive, randomised, controlled, double-blind trials (RCTs). Level B: there is fair research-based evidence to support this recommendation. The evidence was obtained from at least two moderately large, positive, randomised, double-blind trials or from one moderately large, positive, randomised, double-blind study and at least one prospective, moderately large (sample size equal to or greater than 50 participants), open-label, naturalistic study. Level C: there is minimal research-based evidence to support this recommendation. The evidence was obtained from at least one randomised, double-blind study with a comparator treatment and one prospective, open-label study/case series (with a sample of at least 10 participants), or at least two prospective, open-label studies/case series (with a sample of at least 10 participants) showing efficacy. Level D: evidence was obtained from expert opinions (from authors and members of the WFSBP Task Force) supported by at least one prospective, open-label study/ case series (with a sample of at least 10 participants). No level of evidence or Good Clinical Practice (GCP): This category includes expert opinion-based statements for general treatment procedures and principles. The guidelines were developed by the authors and arrived at by consensus with the WFSBP Task Force, consisting of international experts in the field. ## Limitations of our analysis Most reports on the treatments of paraphilic disorders in sexual offender adolescents are open studies. In general, treatment efficacy studies are being extremely difficult to conduct and are marked by some methodological biases for several reasons: small sample sizes leading to false-negative results; sexual offending is not socially acceptable and those who suffer from this behaviour rarely seek treatment voluntarily; ethical considerations make it difficult performing double-blind placebocontrolled studies (or no treatment studies) in potential offenders (for review, the outcome measurements are usually based on subjective measures such as self-report questionnaires of conventional and paraphilic sexual activity. Comparisons between studies are often difficult due to methodological differences: retrospective or prospective designs, heterogeneity of patients included (types of paraphilic disorders, comorbidities, types of victims, number of previous offences and/or previous convictions, etc.), durations of follow-up, outcome variables such as definitions of recidivism, types of treatment and compliance, statistical analyses, etc. ). In addition, specific problems occur when randomisation is adapted to psychological treatments [bib_ref] Drug treatment of paraphilic and nonparaphilic sexual disorders, Guay [/bib_ref]. In fact, the therapist can have a significant impact on therapeutic outcomes if, he (or she), can adapt treatment to the learning style and interpersonal approach of each subject and adjust therapy to the fluctuations in the subject's motivation and mood. Controlled study design does not allow many of the features of an effective therapist-subject relationship. # Results A search of the literature for adolescents with paraphilic disorders came to the conclusion that it is almost nonexistent and the majority of the literature relates to adolescent sexual offenders. As the studies in the bibliography included adolescent sexual offenders, this paper will refer to adolescent sexual offenders with the assumption that a substantial proportion of them would have some type of paraphilias or paraphilic disorders, which is not always specified. Effective treatments for adults who have paraphilic disorders, some of whom are sexual offenders, have clearly shown to be available in recent meta-analyses of psychological treatments and extensive reviews of pharmacological treatments [bib_ref] First report of the collaborative outcome data project on the effectiveness of..., Hanson [/bib_ref] [bib_ref] The effectiveness of treatment for sexual offenders: a comprehensive meta-analysis, Losel [/bib_ref] [bib_ref] Does sexual offender treatment work? A systematic review of outcome evaluations, Schmucker [/bib_ref] It is also quite clear that most of the research on adolescent sexual offenders has focused almost exclusively on males. This is understandable as [bib_ref] The effectiveness of sexual offender treatment for juveniles as measured by recidivism:..., Reitzel [/bib_ref] reported, in a meta-analysis of nine published and non-published studies on the effectiveness of treatment of juvenile sexual offenders, that most of them were males (n¼2986 with 2604 male juvenile offenders). The study of adolescent sexual offenders has lagged behind but, more recently, research studies on adolescent sexual offenders have been increasing [bib_ref] What is so special about male adolescent sexual offending? A review and..., Seto [/bib_ref]. In studies of adult sexual offenders there are reports that their first sexual offence occurred while they were teenagers. There are also direct reports of sexual offending behaviour occurring in adolescenceand even in childhood [bib_ref] Were adolescent sexual offenders children with sexual behavior problems?, Burton [/bib_ref]. Finally, most of the studies conducted in adolescent sexual offenders involved psychological treatment, especially cognitive behavioural therapies. ## Psychological treatments Various types of psychological treatments have been reported including cognitive behavioural treatment (CBT) as the most common form of treatment followed by psychosocial education, family system treatment, multimodal treatment and multisystemic therapy. In fact, the approaches that have been commonly used in adolescent sexual offenders, in community or residential programmes in North America (USA and Canada) were CBT in 90% of the programmes, when psycho-socio-educational and multisystemic approaches were cited in respectively 35 and 22% of the programmes (according to a survey conducted by [bib_ref] Current practices and emerging trends in sexual abuser management. The Safer Society, Mcgrath [/bib_ref]. In children, as well as in female adolescents, working on sexual abuse history was also an important component of treatments. It is noteworthy that despite the recognition of the importance of treatment engagement, therapeutic alliance and motivation [bib_ref] Managing resistance and rebellion in relapse prevention intervention, Mann [/bib_ref] , less than half the community programmes in North America reported using motivational interviewing. ## Description of the various psychological treatment approaches Classical insight-oriented approaches for the treatment of adolescent sexual offenders are of limited value (The National Task Force on Juvenile Sexual Offending, 1988, USA, https://www.ncjrs.gov/App/ Publications/abstract.aspx?ID ¼ 110827). Standard CBT, usually considered as treatment as usual for juvenile sexual offenders includes: decreasing deviant arousal, increasing victim empathy, addressing cognitive distortions especially atypical sexual interests, relapse prevention and family counselling. Key treatment objectives include: youth acceptance of responsibility for the offence(s), breaking the sexual offence cycle by increasing youth's awareness of triggers, identification and exercise of internal and external behaviour controls and development of a relapse prevention protocol to reduce the risk of recidivism. To achieve these goals, several techniques are used: (1) covert sensitisation, described as follows: the sexual abuser imagines performing the chain of behaviours that led to his sexual offending or that might lead to some high-risk situation. Prior to committing an offence or engaging in high-risk behaviour in his imagination, the abuser interrupts the chain by imagining an aversive consequence or by imagining successfully escaping the situation. This technique is currently being used in about 42% of cases in North America according to [bib_ref] Current practices and emerging trends in sexual abuser management. The Safer Society, Mcgrath [/bib_ref] (2) verbal satiation (a conditioning paradigm of extinction) is carried out in the same manner as masturbatory satiation (13% of cases) except that the client does not masturbate while verbalising his abusive sexual fantasies. This approach is used in 11% of cases in North America [bib_ref] Current practices and emerging trends in sexual abuser management. The Safer Society, Mcgrath [/bib_ref]. Some studies have used laboratory satiation with plethysmography. Imaginal desensitisation using deviant sexual stimuli extinction controlled by relaxation was also reported. Multisystemic treatment (MST) directly addresses intrapersonal (e.g., cognitive problem solving), familial (e.g., inconsistent discipline, low monitoring, family conflict), and extra-familial (e.g., association with deviant peers, school difficulties) factors that are associated with youth serious antisocial behaviour, including sexual offending ). Protocols also address youth and caregiver denial about the offence. Psycho-socio-educational approach emphasises education as a method of helping sexual abusers to change their behaviour. Group classes and social skills practice are typically included. The results of the studies using these latter therapeutic approaches will be detailed in this paper. Cognitive behavioural treatment (CBT) [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] (1) Studies of CBT started in the late 1980s with [bib_ref] Measuring the effectiveness of treatment for the aggressive adolescent sexual offender, Becker [/bib_ref] reporting on the effectiveness of CBT for aggressive adolescent sexual offenders. A sample of male sexual offenders (n¼24) participated in a multicomponent community-based outpatient treatment programme, which included various levels of CBT [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. This was a typical type of comprehensive CBT programme that was also used in adults at this time. In addition there was a detailed sexual behaviour evaluation including sexual preference testing by penile plethysmography. In this particular study, sexual arousal testing was completed at the entry point to the study and also post-treatment as an outcome measure. Results from this study showed a significant decrease in deviant sexual arousal from pretreatment to post-treatment in offenders with a sexual preference for male victims. Adolescent sexual offenders with a sexual preference for female victims did not demonstrate any significant decrease in sexual arousal. (2) [bib_ref] Resistance to treatment of adolescent sex offenders, Mcconaghy [/bib_ref] reported on a sample of six adolescent male offenders (three paedophiles) and 39 adult offenders who were randomly allocated to CBT in the form of covert sensitisation; medroxyprogesterone acetate (MPA) treatment; or imaginal desensitisation with or without the addition of MPA treatment. Results from this relatively small study indicated that the adolescents required additional treatment (either CBT or MPA) (4/6 adolescents as compared to 7/39 adults). These results suggested that adolescents might be more resistant to treatment, including MPA. Adolescents showed lower responses at first year (not significant) but the decrease became more important during the following years, 3/6 adolescents offended vs. 3/39 adults. It was suggested that their sexual drive/sexual urges were under more direct hormonal control than in adults, which may indicate more treatment resistance. However, it is important to notice that, in several cases, MPA treatment was used for a short duration (6 months) and was interrupted before recidivism occurred (for detailed information, see [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. (3) Hunter and Santos (1990) completed a study of 27 male paedophile adolescent sexual offenders (with a high comorbidity of alcohol and drug abuse). They participated in a specialised residential treatment programme, which used specific CBTs including satiation and covert sensitisation, as well as individual, group and family insightorientated psychotherapy [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. Outcome measures included deviant sexual arousal as measured by penile plethysmography. The results of the treatment programme indicated a significant decrease in deviant sexual arousal in the participants when pre-and post-treatment levels Audiotape stimuli (conventional and deviant sexual behaviour) Plethysmography: Significant differences in terms of arousal (plethysmography): Female paedophiles (15) were measured. In contrast to the previous study, in this particular study, there was no difference in outcome between offenders with a preference for female victims or male victims. (4) [bib_ref] The clinical utility of satiation therapy with juvenile sex offenders: variations and..., Hunter [/bib_ref] reported on a study of 39 male adolescent sexual offenders (including a high proportion of learning disabilities and ADHD as comorbidities), who participated in a residential treatment programme, which included a minimum of 6 months of verbal satiation treatment [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. In addition, individual, group and family psychotherapy, which was non-behavioural and insightorientated, was also used. Outcome measures included deviant sexual arousal as measured by penile plethysmographic responses. The results indicated that older adolescent sexual offenders appear to have a greater potential for learning to lower deviant sexual arousal through satiation therapy while maintaining normophilic arousal to age appropriate stimuli and to consensual sexual activity compared to younger adolescent offenders. (5) [bib_ref] The impact of verbal satiation on adolescent sex offenders: a preliminary report, Kaplan [/bib_ref] studied a sample of 15 adolescent male paedophilic sexual offenders. They were treated with verbal satiation over a period of between 8 and 13 weeks [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. Deviant sexual arousal as measured by penile plethysmography showed a decrease between pre-treatment and post-treatment phallometric testing. As previously reported, it was more difficult to decrease arousal in younger adolescents and also when the age difference between the sexual offender and the victim was low. (6) [bib_ref] Effectiveness of cognitive behavioural therapy: evaluating self-instructional training with adolescent sex offenders...., Knox [/bib_ref] studied cognitive behavioural and self-instructional training in 25 adolescent sexual offenders. The adolescents were participating in outpatient group therapy as required through a local juvenile court in Texas. This study looked at whether cognitive behavioural and self-instructional training was effective in reducing antisocial behaviour and increasing pro-social behaviour in the study sample. The study was limited but recommendations were made for future research with adolescent sexual offenders. (7) [bib_ref] Reducing deviant arousal in juvenile sex offenders using vicarious sensitization, Weinrott [/bib_ref] studied a sample of 69 male paedophile sexual offenders who were treated with sensitisation procedures similar to covert sensitisation (community-based programme) and randomly allocated in two groups (treatment or comparison group which was: 3-month waiting list) [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. The duration of treatment was 6 months. Outcome measures included pre-and post-treatment deviant sexual arousal as measured by penile plethysmography. In addition some psychological outcome measures were used. The treatment group demonstrated lower deviant sexual arousal post-treatment compared to the control group and to pre-treatment levels related to child female stimuli. For adolescent sexual offenders with a sexual preference for male children and responding to male child stimuli the only significant difference was found between the pre-and post-treatment groups with no difference found between the treated group and the control group. (8) [bib_ref] Adolescent sexual offender recidivism: success of specialized treatment and implications for risk..., Worling [/bib_ref] studied a sample of 58 adolescent sexual offenders including five females [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. The treatment group participated in a community-based outpatient treatment programme consisting of individual, group and family psychotherapy, sexual education, as well as CBT with a relapse prevention orientation for 16-24 months. The programme included: increasing insight, developing offence prevention plans, enhancing awareness of victim impact and social relationships, and reducing the impact of traumatic past-events. Two-thirds of treatment group participated in both group and family therapy in addition to individual therapy. Recidivism (sexual and non-sexual) was the outcome measure and the results indicated that the treatment group had significantly less recidivism for sexual offence (mean duration of follow-up: 6 years), violent and non-violent non sexual offences compared to the control group which consisted of 90 adolescents (including four females) who were treatment drop outs, refusals or other treatments. The comparison group may have introduced a bias even if there were no statistical differences in the variables used for comparison. In 2010 [bib_ref] 20-Year prospective follow-up study of specialized treatment for adolescents who offended sexually, Worling [/bib_ref] , the same group published the results of the same cohort with a mean follow-up duration of 16 years. Nine percent of those adolescents who have participated in at least 10 months of specialised treatment were charged with a new sexual offence during this follow-up period as compared with 21% of those adolescents who did not receive specialised treatment. In total, only 11.5% (17 of 148) of the participants were charged for sexual offences as adults. (9)studied the recidivism data of 89 convicted adolescent sexual offenders between 1985 and 1998. There was a treatment group (n¼41) who had participated in a 10-month treatment programme essentially consisting of CBT in an adolescent sexual offender programme in Canada. There was a comparison group (n¼23 adolescent sexual offenders) who were treatment drop outs and received less than 10 months of CBT and (n¼25) who were treatment refusers or did not receive any specific treatment. A follow-up period of 7 years was used to assess recidivism data based on criminal convictions. The rates of criminal convictions were significantly higher for the treatment drop outs and the treatment noncompleted as compared to the treatment group on measures of nonsexual and serious recidivism. The treatment group had a lower rate of sexual offence recidivism (2.4%) than the treatment drop outs (17.4%) and the non-completed group. The study suggested that adolescent sexual offenders who completed a specific treatment for sexual offending behaviour had less sexual recidivism as well as nonsexual and serious recidivism. (10) [bib_ref] Assessing the efficacy of treatment for adolescent sex offenders: a crossover longitudinal..., Eastman [/bib_ref] [bib_ref] Variables associated with treatment failure among adolescent sex offenders, Eastman [/bib_ref] studied, in an open study, without any comparison group, 100 male adolescent sexual offenders court-ordered, who took part in a residential treatment programme without specific information on this programme (38 additional adolescents were included in the 2005 study) [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. As, in most cases, CBT was used and we considered this programme as CBT. Three samples were examined, firstly individuals who were just entering the programme; secondly individuals who had completed the programme and were waiting to be released; and finally individuals who completed the programme and had been living in the community for a minimum of 6 months. The three samples were subjected to a number of measures in two stages with a 6monthly interval. The assessment included: cognitive distortions, sexual knowledge attitudes related to sexual behaviour, empathy and self-esteem. Significant differences between the pre-treatment group and the two other groups were observed except for the empathy scale. Interestingly, two treatment outcome variables assessing the level of offender cognitive distortions related to sexual offending behaviour and three demographic/background variables (level of intellectual functioning, history of witnessing domestic violence and history of personal victimisation) were identified as having the strongest potential to discriminate between offenders who completed treatment and those who did not. [bib_ref] Juvenile sex offender re-arrest rates for sexual, violent nonsexual and property crimes:..., Waite [/bib_ref] looked at 10-year follow-up recidivism of two adolescent sexual offender treatment programmes in 256 male adolescent sexual offenders. This study included only incarcerated adolescent sexual offenders in the state of Virginia, USA [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. There was considerable variation in the two treatment programmes both in terms of the therapeutic environment as well as the intensity of treatment. What was judged to be the more intensive treatment programme was a self-contained programme in specialised living units separated from the general incarcerated adolescent offender population (144 cases). The programme that was judged to be less intensive had adolescent sexual offenders in the general population of adolescent offenders as opposed to being in a separate environment (112 cases). Recidivism was based on arrest rates and incarceration rates due to a conviction. The outcome data looked at rearrest rates, length of time to re-arrest and type of offence (property offences, non-sexual assaults, sexual offences), using a survival analysis. The results showed that, in both groups, actual re-arrest for a non-sexual offence was more likely (31 vs. 47%, intensive versus less intensive programme), whereas for sexual offences this was less than 5% for both programmes (with no difference between both groups). The more intensive treatment programme had a longer survival time prior to rearrest for all types of offences compared to the less intensive programme. It was also reported that adolescent offenders with high levels of impulsive/antisocial behaviours were more likely to recidivate regardless of what treatment programme they went through. (12) [bib_ref] An independent evaluation of mode deactivation therapy for juvenile offenders, Thoder [/bib_ref] studied 39 male adolescent sexual offenders who participated in a CBT programme called mode deactivation therapy [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. Baseline scores were compared to posttreatment scores (at 1 year) on a number of parameters and indicated a significant decrease in antisocial behaviours and a recidivism rate of sexual offences of 7% after one year without any sexual offences. (13) [bib_ref] Adolescents who have sexually harmed: an evaluation of a specialist treatment programme, Edwards [/bib_ref] completed an evaluation of a CBT residential individual and group treatment programme in a sample of 34 male adolescents (35% paedophiles) with a repeated measures design assessing psychosexual functioning and offence related attitudes based on questionnaires (25 subjects completed the programme) [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. Results indicated improvements in overall psychosocial functioning and offence related attitudes post-treatment. A positive significant improvement of all measures except for impulsivity was observed. There were also clear behavioural and attitudinal changes. In summary: only two CBT studies were randomised [bib_ref] Resistance to treatment of adolescent sex offenders, Mcconaghy [/bib_ref] [bib_ref] Reducing deviant arousal in juvenile sex offenders using vicarious sensitization, Weinrott [/bib_ref] (in the latter study, the comparison group was a 3-month waiting list), eight had no comparison groups, three studies had comparison groups: in one case drop out and treatment refusals were included in the comparison group, in another case, individuals who were just entering the programme or who had completed the programme and were waiting to be released were compared to the treatment group, and in the latter case, CBT was less intensive in the comparison group. In total, more than 800 males and 14 females aged between 12 and 19 years old were included in these studies. Most of them were sexual offenders; comorbidities were not reported in many cases. When the past history of sexual abuse was reported, it was present in more than 50% of cases. The duration of follow-up was very heterogeneous, varying from several months to almost 20 years. Plethysmography was used in four studies published before 1998 and not after. The scales used for outcome measurements were heterogeneous and did not allow any comparison between studies. Re-arrest rates were only assessed in five studies (duration of follow-up45 years except for one study). Different CBT approaches were used such as: covert sensitisation, verbal satiation, deactivation therapy, imaginal desensitisation, sexual education, relapse prevention, and in some cases, family therapy, were used. In all studies, CBT has reduced the outcome measures considered. In two studies, CBT effectiveness was more important in older adolescents and in two studies, the victim gender preference may have interfered with treatment effectiveness. Multisystemic treatment (MST) [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] (1) [bib_ref] Multisystematic treatment of adolescent sexual offenders, Borduin [/bib_ref] were the first to describe a structured multisystemic therapy including adolescent and family systemic approach (communityand family-based, ecological model, including treatment at home). The approach included: empowering parents and adolescents deal with denial about offences, safety planning and improving relations with social peers. This first and randomised study reported its efficacy in 16 male adolescent sexual offenders (eight in the treatment group vs. eight in a comparison group receiving a combination of psychodynamic, behavioural and psychotherapeutic approaches). The mean duration of treatment was 4 months. The outcome was based on recidivism rate for sexual offences, which was 12.5% in the MST group as compared with 75% in the comparison group (p¼0.04) during a mean follow-up of 37 months. Six patients (three in each group) completed the treatment and in total four out of six were re-arrested for sexual offences [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. (2) [bib_ref] A randomized clinical trial of multisystemic therapy with juvenile sexual offenders: effects..., Borduin [/bib_ref] , have compared the same treatment (MST for a mean duration of 31 weeks) in a sample of 24 male adolescent sexual offenders as compared with 24 male adolescent sexual offenders receiving usual community services (UCS was composed of CBT, group and individual therapy, for a mean duration of 30 weeks). This was a randomised study. The mean duration of follow-up was 9 years and re-arrest was the main outcome used. MST participants had 83% fewer rearrests for sexual crimes and 70% fewer re-arrests for other crimes than did their UCS counterparts. By the end of the follow-up, 46% of UCS participants as compared to 8% of MST participants, had been arrested at least once for a sexual crime. All other psychological items were also improved in the MST group [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] in the same hospital, using community MST, have reported its efficacy in 67 adolescents (in the total sample, three were females). The mean duration of treatment was longer (7 months). In this randomised study, standard comparison treatment included group CBT (treatment as usual) (60 participants). Sexual reoffending was not examined. At 1-year follow-up, youths and parents reported significantly greater reductions of many outcome measures including sexual behaviour problems (77% decline as compared to no decline), antisocial behaviour (decreased by 60% as compared with 18%), substance use and costly out-of-home placements, in the MST group vs. usual treatment respectively [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. Treatment completion was mandatory (probation or diversion) and only six subjects in each group failed to complete treatment. MST empowered caregivers to better identified friends who were having a negative influence on juvenile sexual offenders and advised them to stop associating with such friends. At 2-year followup [bib_ref] Two-year follow-up of a randomized effectiveness trial evaluating MST for juveniles who..., Letourneau [/bib_ref] , sexual offence rearrests were examined but the number of re-arrests was too low for statistical analyses. MST positive treatment effects were maintained when sexual behaviour, self-reported delinquency, out-of-home placements were considered. In summary: This combination of well-structured CBT and family therapy seems very promising, especially for sexual offences but has only been studied by one North American group. It needs to be replicated by other groups. The studies were randomised and the comparison groups were using, in most cases, CBT as usual, a hundred adolescents (mainly sexual offenders, including three females) were receiving MST. ## Psychosocial education (1) [bib_ref] The development of a psycho-educational group program for adolescent sex offenders, Hains [/bib_ref] included 17 males who were in a state treatment facility for delinquent adolescents between 16 and 18 years of age. They participated in group-sessions, which were educational and focused on sexual education, improving psychological attitudes, problem solving and moral judgment training. Nine subjects of the sample were engaged in treatment while eight were in a waiting-list control group. Outcome measures included scores on sexual knowledge assessment, psychological attitudes, problem-solving and moral judgment. The results indicated a slight but significant difference with regards to attitudes towards sexual behaviour and social competence. (2) [bib_ref] Assessment of sexual knowledge and attitudes in an adolescent sex offender population, Kaplan [/bib_ref] studied a sample of 213 males, 12-19 years of age. However, only 19 were included in the final analysis. They took part in a programme including a small number of sessions of sexual education and a 40-week CBT programme (group format) which consisted of cognitive restructuring, covert sensitisation, social skills training, anger control training, relapse prevention. Outcome measures were based on an educational test. The results showed an improvement in scores for those who completed treatment. (3) Bremer (1992) studied a sample of 193 male sexual offenders, aged 14-16 years old, included in a juvenile sexual offender programme that specifically was an intensive programme to treat serious juvenile sexual offenders. They were released between 1982 and 1991. These psychoeducational programmes addressed issues such as personal accountability, life history, personal victimisation, sexual-assault cycle and victim empathy. There was also a long-term post-treatment follow-up focusing on recidivism rates. The results of this follow-up showed that participation in the programme produced lower recidivism rates. (4) [bib_ref] Outpatient treatment for adolescents with sexually inappropriate behavior: program description and six-month..., Mazur [/bib_ref] studied an outpatient treatment programme for adolescents that had sexually inappropriate behaviour. This programme was family-based and consisted of a 16-week group intervention protocol that included human sexuality interaction, education and relapse At 2 years: MST treatment effects were maintained for 3 of 4 measures of youth problems: sexual behaviour, self-reported delinquency, outof-home placements. The base rate for sexual offence was too low for statistical analyses and no betweengroups difference were observed for other criminal arrests prevention with a transition to follow-up. Followup for the programme (n¼10 cases) for 6 months showed no inappropriate sexual behaviour. (5) [bib_ref] Adolescent sex offenders and social skills training, Graves [/bib_ref] reported on a sample of 18 males between 12 and 19 years of age who were referred to an inpatient treatment centre and participated in an adolescent social skills affective fitness-training programme. A control group (n¼12) consisted of males 13 to 18 years of age randomly assigned. Outcome measures included social skills ratings and other psychometric rating scales. Results showed that those in the treatment group demonstrated more frequent use of social skills taught than those in the control group. There were also improvements in other areas including parent-adolescent communication. (6) Lab et al. (1993) studied a sample of 46 males with a mean age of 14.2 years who participated in a psychoeducational programme addressing sex education, victim empathy, relapse prevention, anger management and personal responsibility. A control group (n¼109) with a mean age of 14.6 years consisted of adolescents who received nonsexual specific treatment. Recidivism was used as an outcome measure and the results showed that both groups demonstrated low levels of sexual recidivism. No significant differences were found between groups, nor were there significant differences found on any further offences. (7)reported on a multifaceted empathy-training programme designed for population and adolescent sexual offenders. Analysis of preand post-treatment scores and 2-month posttreatment levels of empathy was evaluated. No significant differences were found. When pretreatment and 2-month post-treatment scores were studied, a trend in the direction of increased empathy was found. Physiological measures showed a decrease in heart rate, which has been documented as an empathic response in previous research and this showed a significant decrease. (8)completed a study on recidivism rates of 50 adolescent sexual offenders placed in a state juvenile correctional facility for committing a sexual assault against a child. The recidivism rates were assessed 2 years after the completion of a Serious Sexual Offenders programme. This programme required the offender to take responsibility for the offence, to understand the factors that led to the offence, to learn early warning signs of sexual acting out behaviour, to increase feelings of empathy, and to develop appropriate noncriminal pro-social behaviours. At follow-up, 46% had committed further criminal behaviour consisting of 20% personal injury offences and 26% property offences with only 8% being sexual offences. (9) [bib_ref] The efficacy of a serious sex offenders treatment program for adolescent rapists, Hagan [/bib_ref] reported on a sample of 50 males who were committed to a secure residential facility and who were defined as adolescent rapists. In this facility, they were involved in a group treatment programme focused on responsibility, relapse prevention and victim empathy, general and special education and sex education. Recidivism was the outcome measure and 58% of the sample was convicted of another crime with 10% convicted of a sexual offence. (10) [bib_ref] A ten-year longitudinal study of adolescent perpetrators of sexual assault against children, Hagan [/bib_ref] studied a sample of 50 males aged 12-19 years old committed to a secure residential facility and who were involved in groups geared towards responsibility, relapse prevention and victim empathy. Recidivism was the outcome measure. At 10 years of follow-up, 20% had committed another sexual offence, 46% had committed a personal injury offence and 20% property offences. (11)studied 40 participants, 14-20 years of age, admitted to a residential treatment programme for adolescent sexual offenders. They agreed to participate in an expert mental group therapy programme designed to enhance global empathy capacities. A sample of 31 completed the experimental (12 sessions of 6 weeks) global empathy group programme. The rest of the sample (n¼9) was selected as a control group and continued to receive traditional victim empathy group therapy. Various questionnaires were used to assess outcome. Overall the group receiving the experimental group treatment showed greater scores in empathy than the control group. In summary: Psychosocial education was an unclear combination of CBT and education mainly focused on sexual attitude and the improvement of victim empathy. Only four studies [bib_ref] The development of a psycho-educational group program for adolescent sex offenders, Hains [/bib_ref] [bib_ref] Adolescent sex offenders and social skills training, Graves [/bib_ref] had comparison groups receiving non-specific treatment or a waiting-list control group. Psychosocial education treatments were principally delivered in peer group settings. In total, more than 500 male adolescent sexual offenders (no females) were included in these programmes. Recidivism rates were used as outcome measures in about half of studies, 8-20% recidivism for sexual offences was observed depending on the duration of the follow-up (10 years when the recidivism rate was 20%). In the other studies different outcome measures were used and cannot be compared except for victim empathy, which was improved. Generally, due to the various and uncontrolled study designs used, the results were not convincing. [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] No controlled studies were conducted in juvenile sexual offenders using pharmacological treatments. Several case reports were published as described below and in Tables I and III [bib_ref] Assessment and treatment of sex offenders: the Prince of Wales Programme, Mcconaghy [/bib_ref]. According to the [bib_ref] Current practices and emerging trends in sexual abuser management. The Safer Society, Mcgrath [/bib_ref] , selective serotoninergic reuptake inhibitors (SSRIs) were used in 20% of adolescent juvenile sexual offenders, whereas antiandrogen treatments were used in 25% of male adolescent sexual offenders. Caution is warranted in children and young adolescents because the effects of antiandrogens on the normal growth and development of youth are not known. The American Academy of Child and Adolescent Psychiatry (AACAP; Shaw 1999) recommended the use of antiandrogens to be limited to the most severe cases and discouraged their use with youth under the age of 17. ## Pharmacological treatments ## Psychotropic drugs Several case reports and uncontrolled studies (mainly involving adults) reported the efficacy of clomipramine (one case report) and SSRIs (mostly fluoxetine and sertraline) in the treatment of paraphilic disorders. (1)has reported successful treatment with clomipramine (150 mg/day) within 2-3 weeks in a sexually obsessive-compulsive 17-year-old boy who had been referred for fetishism and pervasive lust-murder fantasies directed at 10-yearold girls. He also had a temporal lobe abnormality with EEG abnormalities. This type of lesion has been reported in sexually sadistic individuals. He had already been treated with MPA in another psychiatric centre, but discontinued it because of minor breast enlargement. He was referred for an inpatient forensic psychiatric evaluation. Violent sexual fantasies of raping and strangling or suffocating 10-years-old girls were pervasive. Phallometric testing showed a sexual preference for paedophilia and sexual sadism. Because of his reluctance to continue antiandrogen treatment, he was treated with clomipramine, 150 mg/day. Repeated phallometric testing showed almost complete suppression of sexual arousal to rape, as well as paedophilia. Follow-up over a number of years showed no recurrence of these problems. (2) [bib_ref] An adolescent male with multiple paraphilias successfully treated with fluoxetine, Galli [/bib_ref] reported the efficacy of fluoxetine (40 mg/day) over the course of 1 year in a 17-yearold male who met DSM-IV criteria for multiple paraphilias including paedophilia, frotteurism, sexual sadism, zoophilia, necrophilia and also exhibitionism and voyeurism. Bipolar type II disorder and obsessive-compulsive disorder were comorbid disorders [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. Paraphilic urges and behaviours, depression and violent obsessions improved with fluoxetine after not responding to long-term residential treatment (group therapy for 1 year and 5 months). (3) [bib_ref] Fluoxetine and compulsive sexual behavior, Aguirre [/bib_ref] reported the case of a 16-year-old male who met DSM-IV criteria for post traumatic stress disorder and paraphilia not otherwise specified. He was admitted to a residential programme where he sexually molested a number of his peers. Olanzapine 5 mg/day and sertraline up to 50 mg/day were not successful. Fluoxetine was prescribed up to 60 mg/day. Upon discharge from hospital, after 17 days of inpatient treatment, he expressed a marked decrease in symptoms. There was no follow-up after discharge. (4) In [bib_ref] A comparison of treatment of paraphilias with three serotonin reuptake inhibitors: a..., Greenberg [/bib_ref] retrospective open study, the efficacy of fluvoxamine, fluoxetine and sertraline was studied in paraphilic patients aged from 17 to 72 years. Paraphilic fantasies were significantly decreased in the three groups with no differences in efficacy between the three SSRIs but no specific focus was made on adolescents. (5) In the same way, [bib_ref] An open pilot study of sertraline in the treatment of outpatients with..., Bradford [/bib_ref] ## Conducted a 12- week open-labelled, dose-titrated study of sertraline in 18 paedophiles over 16 years of age with comorbid mood disorders. Improvement in selfreport scales and penile plethysmography measures were observed with sertraline but again the results obtained in the adolescent subgroup were not separately analysed. On the one hand we are unable to treat paraphilic disorders or sexual deviant behaviour specifically, but on the other hand we know successful treatments of some target symptoms associated to paraphilic disorders, such as serotonergic compounds which might be helpful in decreasing impulsiveness and aggressiveness [bib_ref] The effect of increased serotonergic neurotransmission on aggression: a critical meta-analytical review..., Carrillo [/bib_ref]. Pharmacological approaches for treating violent and criminal behaviour in psychopathic persons have been generally disappointing, with some, but important exceptions (for review [bib_ref] The neurobiology of psychopathy: recent developments and new directions in research and..., Cummings [/bib_ref]. The first exception regards lithium, which may reduce impulsive violence and irritability in a group of chronically aggressive adult prisoners (for review,. However, it did not alter instrumental violence or overall criminality. However, lithium has a [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. Pharmacological treatments. # Methods # Results ## References ## Characteristics of the patients treatment conditions Outcome measures Treatment efficacy [bib_ref] An adolescent male with multiple paraphilias successfully treated with fluoxetine, Galli [/bib_ref] Case report In 19/20, dosage increased: -in 9 cases: to 150 mg/day -in 11 cases: to 200 mg/day (10/11 initial benefit) but: In 6/11 cases: decreased efficacy after 3 months In 5/11 cases: ongoing benefits In total, in 15/21 cases: masturbation: 3/week and sexual fantasies: 1/day In 5/6 cases: good efficacy of leuprolide at 3.75 to 7.5 mg/month (used in more severe patients at baseline) y, years; MPA, medroxyprogesterone acetate; SSRIs, selective inhibitors of serotonin reuptake; ADHD, attention deficit and hyperactive disorder; PTSD, post-traumatic disorder; IED, intermittent explosive disorder; CBT, cognitive behaviour therapy. narrow therapeutic window and needs blood concentration monitoring. The second exception is clozapine, which reduced impulsive behavioural dyscontrol and anger, resulting in a decrease in violence incidents, in six of seven adult patients with severe antisocial personality disorders. Clozapine serum levels for six of the seven patients were in the range 150-350 ng/ml [bib_ref] Clozapine: an effective treatment for seriously violent and psychopathic men with antisocial..., Brown [/bib_ref]. However, clozapine treatment must follow a reglemented plan to monitor haematological side effects. In the same way, [bib_ref] The neuropharmacology of impulsive behaviour, Pattij [/bib_ref] published an overview of the neuropharmacology of impulsive behaviours, which might be helpful. In special populations such as children and adolescents with autism spectrum disorders or intellectually disabled juvenile sexual offenders, [bib_ref] An update on pharmacotherapy for autism spectrum disorder in children and adolescents, Ji [/bib_ref] as well as Häßler and Reis (2010) recently published updates. Among these pharmacological treatments options, SSRIs are the most interesting option for juvenile sexual offenders. Clozapine should only be used in some cases of treatment-resistant schizophrenic patients with delusional deviant sexual fantasies or behaviours and, lithium, in bipolar patients with comorbid paraphilic disorders. ## Antiandrogen treatments The pharmacological properties of the different types of antiandrogen treatments were already described [bib_ref] Pharmacologic treatment of sex offenders with paraphilic disorder, Garcia [/bib_ref]. There have only been a few case reports of antiandrogen treatments in juvenile sexual offenders. Most of the case reports involved cyproterone acetate (CPA) treatment of adolescents with mental retardation. Four additional subjects were receiving MPA, and seven subjects, gonadotrophin releasing hormone agonists (GnRHa) (in six cases, GnRHa treatment was used in naltrexoneresistant patients). There were no controlled studies. (1)published the case of a mildly mentally retarded 16-year-old adolescent with a plastic bag fetish and paedophilia. He was successfully treated using CPA. Phallometric testing had shown a clear sexual preference for paedophilia. His behaviour was potentially homicidal towards children, when he started to place plastic bags over the heads of young children. Five years of follow-up in the community showed no evidence of any recurrence of any sexual offence recidivism. (2) [bib_ref] The influence of antiandrogens on libido, potency and testicular function, Ott [/bib_ref] reported the efficacy of CPA in a sample of 26 sexual offenders, hypersexual males and psychiatrically ill subjects, as well as in patients with epilepsy and mental retardation, ranging in age from 14 to 74 years. No specific focus was made on adolescents. (3) [bib_ref] Cyproterone acetate for male hypersexuality, Davies [/bib_ref] reported the efficacy of CPA in nine juvenile patients with mental retardation who masturbated in public. He also described the efficacy of CPA in three adolescent males with severely mental retardation, who were physically aggressive to other patients and staff and who showed no response to conventional treatment. In addition, four cases of sexual hyperactivity associated with chromosomal disorders in adolescent males were treated effectively with CPA. (4) [bib_ref] Resistance to treatment of adolescent sex offenders, Mcconaghy [/bib_ref] [bib_ref] Assessment and treatment of sex offenders: the Prince of Wales Programme, Mcconaghy [/bib_ref] , randomised studies, see [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] have compared MPA alone or in combination with imaginal desensitisation or covert sensitisation in a group of 45 male sexual offenders including six adolescent sexual offenders (14-19 years old) (see [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] for methodology). Then, MPA was used as an add-on and intermittent treatment in four out of six adolescent sexual offenders when CBT was not sufficient during 2 to 5 years after completion of the study. Three of the six adolescents reoffended. In three of six cases, MPA was not successful in combination with CBT (imaginal desensitisation) (the paraphilic disorders were respectively: fetishism, exhibitionism, and homosexual paedophilia). In the latter case, recidivism occurred after 2 years of MPA treatment interruption and MPA was successful when reintroduced for 6 months (no recidivism was observed after 2 years of follow-up) [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] for clinical details of the cases). Side effects were not reported and adolescent sexual offender treatment was not the main objective of this study. (5) [bib_ref] Effect of a long-lasting gonadotrophin hormone-releasing hormone agonist in six cases of..., Thibaut [/bib_ref] reported the case of a 15-yearold adolescent exhibitionist (in public areas) with mental retardation in whom low compliance was expected. Since the age of 13, he had been preoccupied with unremitted sexual tension with compulsive masturbation (10-15 times a day) and frequent exhibitionism. The parents and patient gave their informed consent for treatment with a long lasting GnRHa. Pubertal development and growth were achieved. Cyproterone was concurrently prescribed for several months to control the initial increase in testosterone levels (flare-up effect). The patient's deviant behaviour completely disappeared and masturbatory activities decreased to zero within 4-5 weeks of GnRHa treatment. No adverse effects were reported. A 2-year follow-up confirmed this improvement then, the patient withdrew from treatment for non-medical reasons. (6) [bib_ref] Naltrexone in the treatment of adolescent sexual offenders, Ryback [/bib_ref] , in an open prospective study, has reported the efficacy of naltrexone in association with CBT in 21 male paedophile juvenile sexual offenders (in-patients) who met any of the selfreported following criteria: (1) excessive masturbation (3 times per day); (2) feeling unable to control arousal; (3) spending more than 30% of awake time in sexual fantasies; or (4) having sexual fantasies or behaviour that regularly intruded into and interfered with their functioning in the treatment programme. Naltrexone is a long-acting opioid used clinically in alcoholism or drug abuse treatments. This study investigated whether naltrexone can decrease sexual arousal in legally adjudicated adolescent sexual offenders. After having been treated for more than 2 months, 13 patients had their naltrexone administratively stopped, thus providing a before, during, after, and resumption-of-treatment design. Outcome measures were self-report daily sexual fantasies and masturbation numbers. Sexual offence recidivism was not reported. A positive result was recorded if there was more than a 30% decrease in any self-reported criterion and if this benefit lasted at least 4 months. Leuprolide (3.75 or 7.5 mg/ month, a GnRHa) was added in case of lack of naltrexone efficacy. In 15 cases, naltrexone efficacy was considered as sufficient, patients continued to respond for at least 4 months to an average dose of 160 mg/day with decreased sexual fantasies and masturbation. Dosages above 200 mg/day were not more helpful. Administrative discontinuation of naltrexone in a subset of 13 patients resulted in reoccurrence of symptoms that began when the tapered dose reached 50 mg/day. Five of six patients who did not benefit from naltrexone (the most severe cases) responded favourably to leuprolide [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. The mean duration of leuprolide treatment was 1 year. ## Failure to successfully complete psychological or pharmacological treatment In a retrospective study, [bib_ref] Factors associated with treatment compliance in a population of juvenile sexual offenders, Hunter [/bib_ref] have tried to identify variables, which were predictive of treatment response, in 121 juvenile sexual offenders who entered a community-based sexual offender treatment programme (86% were court-adjudicated or under court advisement including cases of child molestation in 76%, peer rapes in 9% and exhibitionism in 3% of the cases). Half of the youths were previously arrested for a non-sexual offence. Half of them had a previous history of sexual abuse and drug abuse. The mean duration of the treatment programme was 22 months. The treatment programme included: weekly specialised group therapy, family therapy and individual therapy based on CBT. Sixty of the 121 remained in the study at 12 months and 28 of the 121 completed the study. Two had recidivated sexually. Lower levels of denial at inclusion predicted successful programme compliance; adjudicated youths were also more motivated for treatment. In addition, youths failing to comply had higher overall levels of measures of sexual maladjustment. In the current literature, personal characteristics identified as increasing the likelihood of treatment failure include severe history of personal victimisation as well as prior sexual and nonsexual criminal history. Treatment targets identified as having a negative impact on treatment completion include extreme levels of distorted beliefs regarding sexual aggression, deficits in empathic abilities, primitive interpersonal skills, and an observable absence in personal coping skills [bib_ref] Where should we intervene? Dynamic predictors of sex offense recidivism, Hanson [/bib_ref]. Interestingly, these targets may be improved with CBT. ## Limitations of the studies Most of the current literature comes from North America. Since the development of the first comprehensive treatment programme for adolescent sexual offenders in 1975, there have been many studies but the great majority of them did not include any comparison groups, which renders difficult to ascertain the relative effects of treatment on recidivism. In addition, many studies had a short duration of follow-up, which resulted in low recidivism rates. There is a lack of research focused on pharmacological treatments in juvenile sexual offenders (several case reports and one study whose primary goal was neither youth sexual offenders nor pharmacological treatment efficacy). Concerning psychological treatments, standard treatment is based on CBT. Yet, it remains very difficult to compare the studies, due to different biases such as heterogeneity of adolescents included, different durations of follow-up, non-comparability of treatment programmes and outcome measures. In most cases, it is difficult to identify the inclusion or exclusion of treatment drop outs and refusers in the treatment group. In addition, CBT, psychoeducational and multisystemic programmes (CBT combined with family therapy) are all based on cognitive behavioural approaches and it is very difficult to disentangle the respective roles of the different approaches used. According to [bib_ref] Treatment impact of an integrated sex offender program as measured by J-SOAP-II, Rehfuss [/bib_ref] (sample of 309 adjudicated male juvenile sexual offenders), an integrated sexual offender treatment programme including both CBT and psychoeducational interventions led to a significant decrease on the scores of the J-SOAP-II but only in the moderate risk of recidivism group. Many studies do not specify the cognitions and behaviours targeted for change, nor do they monitor the areas of functioning selected for change (e.g., empathic functioning, relationship with peers), which might be different between treatment settings [bib_ref] The effectiveness of sexual offender treatment for juveniles as measured by recidivism:..., Reitzel [/bib_ref]. [bib_ref] Current practices and emerging trends in sexual abuser management. The Safer Society, Mcgrath [/bib_ref] , in an interesting survey conducted in North America, reported that 80% of programmes responding to the survey were community-based, which are less expensive than residential treatment. Their survey contained the responses of 1379 sex offence specific treatment programmes representing all 50 American states and nine Canadian provinces (involving adult and adolescent sexual offenders). During calendar year 2008, the USA respondents provided services to 53,811 male and female adult, adolescent and children sexual offenders in residential and community settings. The Canadian respondents provided services to 3020 individuals. Over half of all programmes for adolescent males and females used one or more behavioural sexual arousal control techniques. Covert sensitisation was the most common technique (40%). Community programmes for adolescent males and females showed a significant increase since 2002 in the use of minimal arousal conditioning (about 18%), a variation of covert sensitisation (except that the abuser interrupts the chain of behaviours as soon as he (or she) experiences any type of mentally or physically sexually arousing thoughts or feelings [bib_ref] A comparison of verbal satiation and minimal arousal conditioning to reduce deviant..., Gray [/bib_ref]. In addition, the use of SSRIs was reported in respectively 30% of male and 21% of female adolescent sexual offenders in community programmes and respectively 36% and 32% in residential programmes in the USA, and slightly less, around 20%, in Canada. Antiandrogens (medroxyprogesterone acetate and mostly leuprolide acetate; cyproterone acetate is only used in Canada) were used in respectively 3 and 5% of males in community and residential USA programmes as compared to 27% in Canada. Unfortunately, we found no published data concerning current trends in treatment approaches of juvenile sexual offenders in other parts of the world. ## Female juvenile sexual offenders There were few females included in the studies, which did not allow separate statistical analyses on this subgroup. ## Children with sexual behaviour problems There was only one randomised study [bib_ref] Randomized trial of treatment for children with sexual behavior problems: tenyear follow-up, Carpentier [/bib_ref] , which was beyond the scope of this paper. This study prospectively followed 135 children, 5-12 years of age, with sexual behaviour problems. The randomised trial compared a 12-session group CBT with group play therapy and followed 156 general clinic children with non-sexual behaviour problems as a comparison group. Ten-year follow-up data on future juvenile and adult arrests and child welfare perpetration reports were collected. The CBT group had significantly fewer future sex offences than the play therapy group (2 vs. 10%) and did not differ from the general clinic comparison group (3%). The recidivism rate was 1/64 in the treatment group vs. 7/71 in the comparison group (play therapy group). There were no group differences in nonsexual offences (21%). For children under the age of 13 who offended against other children, there was insufficient evidence to determine if CBT combined with parental support was more effective than standard treatment (group based play therapy and parental support) in preventing sexual offending [bib_ref] Randomized trial of treatment for children with sexual behavior problems: tenyear follow-up, Carpentier [/bib_ref]. ## Conclusion of the review Adolescent sexual offenders have not been well researched in relation to the presence of sexual deviation or paraphilias (in DSM-5 terms: paraphilic disorders) (American Psychiatric Association 2013). Adult sexual offenders have been subjected to far more studies and the presence of paraphilic disorders has been well established in various research studies. Yet, even in adult sexual offenders the question remains: how many sexual offenders have a paraphilia or a paraphilic disorder? It is quite clear that not all sexual offenders suffer from a paraphilic disorder. According to [bib_ref] Assessment of a new law for sex offenders implemented in France in..., Tesson [/bib_ref] , about 10% of adult convicted-sexual offenders were suffering from paraphilic disorders. As sexual offending behaviour is defined in terms of the criminal justice system, this is not surprising; individuals with an antisocial personality disorder may commit sexual offences as part of opportunistic behaviour when engaged in other criminal behaviours; individuals suffering from other mental disorders such as psychotic disorders or bipolar disorders could easily commit sexual offences without evidence for paraphilic disorders. Even in documented studies of individuals engaged in intra-familial child sexual abuse (incest), when tested for deviant sexual arousal and specifically paedophilic arousal, a significant percentage did not show a paedophilic sexual preference or deviant sexual arousal of any type [bib_ref] A comparison of incest offenders based on victim age, Firestone [/bib_ref]. Similarly in adolescent sexual offenders, there is a multi-causation of sexual offending behaviour including for example conduct disorders, whereas a certain percentage of adolescent sexual offenders clearly suffer from paraphilic disorders. The fact that 15% of adolescent sexual offenders have been shown to go on to adult sexual offending behaviour shows that a common characteristic with adult offenders is carried through into adult sexual behaviour. This subgroup represents most likely a subgroup with paraphilic disorders [bib_ref] What we do not know about juvenile sexual re-offence risk?, Caldwell [/bib_ref] [bib_ref] Risk of sexual recidivism in adolescence who offend sexually: correlates and assessment, Worling [/bib_ref]. The other important issue is that the actual aetiology of the paraphilic disorders remains unknown and, from a neurobiological, hormonal and familial transmission standpoint, the amount of research is relatively limited [bib_ref] The neurobiology, neuropharmacology, and pharmacological treatment of the paraphilias and compulsive sexual..., Bradford [/bib_ref] [bib_ref] The role of central and peripheral hormones in sexual and violent recidivism..., Kingston [/bib_ref] [bib_ref] Evidence for heritability of adult men's sexual interest in youth under age..., Alanko [/bib_ref] [bib_ref] Sexual offending runs in families: a 37-year nationwide survey, Langströ M [/bib_ref]. So it is very difficult to approach the pharmacological treatment of adolescents with paraphilic disorders without considerable caution. What is known is that, during adolescence, significant hormonal changes occur with an onset at puberty and these hormonal changes then progress until puberty has been completed. This process is relatively complicated when both hormonal changes and neurotransmitter changes are considered [bib_ref] The neurobiology, neuropharmacology, and pharmacological treatment of the paraphilias and compulsive sexual..., Bradford [/bib_ref]. Most significantly, pharmacological agents affecting sexual hormones, specifically antiandrogens, can have a significant impact on puberty and bone growth and can terminate puberty or delay its full presentation [bib_ref] The neurobiology, neuropharmacology, and pharmacological treatment of the paraphilias and compulsive sexual..., Bradford [/bib_ref] [bib_ref] Pharmacological treatment of the juvenile sex offender, Bradford [/bib_ref] [bib_ref] The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the..., Thibaut [/bib_ref] [bib_ref] Can sexual offenders be treated?, Bradford [/bib_ref]. From this review we may conclude that for the treatment of adolescent sexual offenders: overall, there is a low level of scientific evidence; randomised controlled trials are lacking, which can be attributed to the logistic, legal and ethical challenges faced by researchers on such sensitive social issues [bib_ref] Preventing sexual abusers of children from reoffending: systematic review of medical and..., Långströ M [/bib_ref] ; research focused on pharmacological treatment is also lacking; the effectiveness of segregated treatment units for juvenile sexual offenders has not been proven; however, it is often necessary for the juvenile to be temporarily placed outside of his family home when he has perpetrated against family members. The study results indicate the following useful trends: when pre-and post-evaluation is available, it is in favour of the treatment group (as in adults), particularly in juvenile sexual offenders at moderate risk of reoffending; drop outs of treatment programmes do worse in the long term than sexual offenders who completed the programme (as in adults); differences between ''older'' and ''younger'' adolescents are suggested [bib_ref] The clinical utility of satiation therapy with juvenile sex offenders: variations and..., Hunter [/bib_ref] ; information concerning potential adverse outcomes of treatment is not available; motivation for treatment is generally not assessed. Due to the high rate of treatment non-compliance, incorporating into pre-treatment and treatment programmes strategies that minimise attrition may be helpful [bib_ref] The effectiveness of sexual offender treatment for juveniles as measured by recidivism:..., Reitzel [/bib_ref]. In general, adjudicated youths are more motivated for treatment; and finally, the important roles that caregiver discipline and youth association with deviant peers play in the development and maintenance of antisocial behaviour have been supported consistently by an extensive correlational and longitudinal literature. The AACAP [bib_ref] Practice parameters for the assessment and treatment of children and adolescents who..., Shaw [/bib_ref] practice parameters for the assessment and treatment of children and juveniles who are sexual abusers recommend the following aims for CBT: decreasing deviant sexual arousal; facilitating nondeviant sexual interests; promoting victim empathy; enhancing interpersonal and social skills; assisting with value clarifications; clarifying cognitive distortions; teaching to recognise internal and external antecedents of sexual offending. They also recommend limiting the use of antiandrogens to the most severe cases and discourage their use with youths under the age of 17. Långströ m et al. (2013) have conducted a systematic review of one randomised controlled trial (using MST) and prospective controlled observational studies of adolescent perpetrators of adolescent or child sexual abuse. They concluded that only MST could be effective in preventing sexual reoffending among moderate risk adolescent sexual offenders (relative risk 0.18; CI: 0.04 -0.73). One limitation is that the effectiveness of this therapy seems to be reduced, when it is implemented by non-researchers outside the settings in which it was originally developed [bib_ref] Multisystemic treatment: a meta-analysis of outcome studies, Curtis [/bib_ref]. The scientific evidence was insufficient for CBT effectiveness in preventing sexual reoffending among moderate risk adolescent sexual offenders and no evidence was found in high-risk subjects. For children under the age of 13 who abuse other children (which is beyond the scope of our guidelines), there was only one high quality randomised controlled trial using a combination of CBT and parental support as compared to standard treatment (group based play therapy combined with parental support) with insufficient level of evidence, and no evidence for other preventive interventions. In the same way, in the meta-analysis conducted by [bib_ref] The effectiveness of sexual offender treatment for juveniles as measured by recidivism:..., Reitzel [/bib_ref] , the average weighted effect size concerning the effectiveness of juvenile sexual offenders treatment (any kind) was 0.43 (2,986 subjects; nine studies; CI: 0.33-0.55; p50.001), which means that for every 43 sexual offenders receiving the primary treatment who recidivated, 100 of the sexual offenders in the comparison group or in the notreatment group recidivated. The best treatment effect sizes were found in studies with the highest baseline rates of recidivism (i.e., multisystemic studies) but studies using MST were also the best-designed studies. In another meta-analysis, [bib_ref] Treatment effectiveness for male adolescent sexual offenders: a meta-analysis and review, Walker [/bib_ref] reported encouraging effects, especially in the studies utilising CBT approaches to treat male adolescent sexual offenders. Ten studies (n¼644) were included in their review (two controlled and eight uncontrolled studies). The overall average weighted effect size (r) was 0.37. In three studies using an outcome measure of sexual recidivism, the weighted average r was 0.26. Although this result is somewhat encouraging, one cannot conclude that treatment necessarily reduces the risk of recidivism, as only three of the 10 studies in this metaanalysis used recidivism as an outcome variable. In fact, effect size calculations were based on a blend of dependent variables including psychological test scores, measurements of sexual arousal, and recidivism rates. Furthermore, only two of the 10 studies included in this meta-analysis employed a comparison group. Finally, the interesting notation is that three of the four studies with effect sizes above 0.50 employed CBT or MST. [bib_ref] Sexually abusive youth: a review of recidivism studies and methodological issues for..., Fortune [/bib_ref] summarised 28 published studies of specialised treatment. They found that only seven of the studies included a comparison group, and only five investigations employed a mean follow-up period beyond 5 years. They concluded that, although recidivism rates for treated youths are typically lower than recidivism rates for those who did not receive treatment, methodological problems make it difficult to draw conclusions regarding the outcome of specialised treatments. Finally, [bib_ref] Epidemiology and treatment of juvenile sexual offending, Gerardin [/bib_ref] have reviewed studies of specialised treatments for adolescent sexual offenders and recidivism rates published between 1986 and 2000. Among 12 studies, only three had comparison groups (in one study there was no information on treatment received). CBT was used in 10 studies, MST in one study and ''Sexual abuse, family education and treatment programme'' (SAFE-T) in another study. Follow-up durations were from several weeks to 10 years. Recidivism outcome measures used were criminal charges, convictions or re-arrests (7/12 studies), penile plethysmography in one study and self-reports in other cases. Sexual recidivism rates were from 0 to 18% in the treatment groups as compared to 19 or 75% in the comparison groups (respectively observed in the comparison groups of [bib_ref] Adolescent sexual offender recidivism: success of specialized treatment and implications for risk..., Worling [/bib_ref] [bib_ref] Multisystematic treatment of adolescent sexual offenders, Borduin [/bib_ref]. They concluded that treatment must include behavioural therapy as well as family therapy and psychosocial interventions; psychiatric interventions may be indicated to manage concurrent psychiatric diseases. Pharmacotherapy cannot be a firstline treatment: SSRIs can be effective but controlled studies are necessary; in some rare situations with severe paraphilias associated with a high risk of sexual violence, hormonal interventions may be needed, subject to informed consent of the youths and their parents. ## Evaluation of a paraphilic disorder Juvenile sexual offenders are a heterogeneous group and standardised methods of assessment including risk assessment tools would probably help to facilitate treatment strategies. Such methods would include the assessment of intellectual and personality functioning or psychopathology and the assessment of sexual behaviour and minimisation or denial of the sex offence. Gathering multiple sources of information is crucial (family interviewing, getting information from teachers and peers is also important). Motivational interviewing is not mentioned in the published studies but lack of motivation is a major factor of non-compliance and it should be routinely assessed. Clinical and demographic characteristics include: demographic characteristics of the subject: age, gender, number of siblings (age and gender if any), education level, school adjustment and performances; deviant and non-deviant sexual fantasies and activity (frequency and type), exclusive or non-exclusive paraphilic disorder behaviour, age at onset of paraphilic disorder behaviour and fantasies, type and number of paraphilic disorders, gender and age of victims, intra-familial or not (known or unknown victim), internet use or video use, violence, previous convictions for sexual or non-sexual offences, family and personal history of sexual disorders, previous treatments for sexual offending and compliance, alcohol or illicit drug consumption, age of puberty, completion of growth, etc.; family background and functioning as well as peer relationships; family and personal history of psychiatric disorders or suicide attempts, history of brain trauma, previous or current psychiatric or non-psychiatric diseases, treatments and compliance, previous history of sexual or physical abuse, personality disorders, etc.; empathy, coping with stress, impulsivity, interpersonal relationships, insight, motivation for treatment, cognitive distortions, denial, degree of mental retardation if any, etc. The first step is to establish a trusting relationship with the adolescent. [bib_ref] Assessment, management, and treatment planning for male adolescent sexual offenders, Saunders [/bib_ref] recommended having different sequences of questions to determine offenders' knowledge about biological gender differences and sexual intercourses. They also suggested inquiring about understanding and experiences of normal and deviant sexual activities and experience of sexual abuse. A psychiatric interview is necessary to identify and address environment stressors and potentially treatable neuropsychiatric conditions, which may contribute to the aggressive and deviant behaviour. A medical examination is also necessary which should focus on endocrinological and neurological status. Cognitive performance has also to be measured (evaluation of specific learning or language disorders; executive dysfunctions may be assessed if necessary) [bib_ref] Epidemiology and treatment of juvenile sexual offending, Gerardin [/bib_ref]. Standardised assessment scales are interesting to evaluate potential risk of reoffending (ERASOR and J-SOAP-II are the most frequently used in North America, [bib_ref] Current practices and emerging trends in sexual abuser management. The Safer Society, Mcgrath [/bib_ref]. The use of direct measurement of sexual arousal using phallometric assessment is not recommended in adolescent sex offenders. Visual Reaction time may be used as a less intrusive objective measure of sexual preference (see also previous chapter on outcome measures). The aims of the baseline evaluation are to obtain: diagnosis and evaluation of the severity of paraphilic disorder(s); evaluation of comorbidities with personality disorders or psychiatric disorders (especially attention deficit/hyperactivity disorders (ADHD), affective disorders, addictive disorders, conduct disorders, anxiety disorders, obsessive-compulsive disorders and psychotic disorders) including assessment of suicidality, decision for treatment or referral; a neuropsychological evaluation; an evaluation of intellectual capacity (IQ) (limits to insight, self-control and CBT efficacy); status of legal responsibility, including factors of age (regulations differ by country) and IQ; assessment of treatment motivation and capacity/ need of support for treatment compliance; assessement of recidivism risk, including history of records in education (discipline)/police/justice systems; information on comorbidity with somatic diseases if any, assessment of need for treatment referral; evaluation of the youth's psychosocial environment (social support and/or risk systems including family and peers, educational status, estimate of crime rate in neighbourhood (role model) and of access to weapons and, last but not least, barriers to health care providers including lack of social security). Antiandrogens or GnRHa (when necessary, see [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] have to be prescribed by a physician specialised in paediatric endocrinology, after appropriate medical assessment including: physical examination, weight, height and body mass index (BMI) by age and gender percentiles, target height [bib_ref] Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or..., Almeida [/bib_ref] , blood pressure measurements and electrocardiogram; testosterone, testosterone-binding protein, LH, prolactin blood levels; hepatocellular, kidney and thyroid function evaluations; fasting blood glucose levels; lipid profile; calcium and phosphate blood levels ; previous history/risk of thromboembolism including smoking during therapy (e.g., acne, contraception, hirsutism, polycystic ovary syndrome, pubertas praecox/tarda) (CPA or MPA), gynaecomastia , pituitary adenoma [bib_ref] Prolonged flare-up of testosterone after administration of a gonadotrophin agonist to a..., Huygh [/bib_ref] , meningioma [bib_ref] Risk of meningioma among users of high doses of cyproterone acetate as..., Gil [/bib_ref] , hepatic disease (CPA), liver carcinoma (CPA), severe osteoporosis, tuberculosis (CPA), diabetes (CPA or MPA), cachexia (CPA), severe chronic depressive disorder including assessment of suicidality, as well as allergy to hormonal treatment must be assessed through interview of each candidate for hormonal treatment; finally, in case of personal or familial osteoporosis risk, baseline bone mineral density must be checked by using osteodensitometry but avoid unnecessary X-ray exposure; in case of any concomitant medical condition check for possible pathophysiological, metabolic or drugdrug interaction patterns; including hormone-producing tumours as well as drug-induced hypersexuality, agitation or impulsivity. informed consent from parents (or legal guardian) and patient must be obtained. ## Monitoring of the patient Deviant and non-deviant sexual activity and fantasies (nature, intensity and frequency) and risk of sex offence must be evaluated during the interview at least every month through self-reports of the patient and, if useful and possible, interview of parents and/or caregivers. In case of hormonal treatment, due to ongoing development of the adolescent, monitor more frequently than in adults: every 3 months, blood pressure, height/weight/BMI percentiles, gynaecomastia; every 3 months, fasting blood glucose levels, lipid profile, renal function, thromboembolic indicators, calcium and phosphate levels, (plus blood cell counts, hepatocellular functions if CPA is used); every 3 months, testosterone blood levels to monitor changes due to ongoing development, breaks in the therapy, or in case of risk of masked testosterone supplementation; every 2 years (or every year, if increased risk of osteoporosis), bone mineral density could be checked using osteodensitometry, consult with a paediatrician to avoid unnecessary X-ray exposure. Calcium, vitamin D or biphosphonates must be prescribed in case of osteoporosis as adolescents too may be exposed to osteoporosis. Treatment guidelines/algorithm of pharmacological treatment [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] ## General principles The paediatrician or the general practitioner, during the course of a routine evaluation, plays an important role for children, adolescents and their families in education about normal sexual development, and sometimes in early recognition of deviant sexual behaviour. Health professionals must know that not all sexual contacts between minors are harmless and they must learn to identify juvenile deviant sexual behaviour. In case of non-consent, coercion or a significant age difference, sexually abusive behaviour must be recognised and reported to the authorities. Trauma models posit that being neglected or sexually-abused as a child is a major explanatory factor as to why some sexual abusers commit their offences, in particular adolescent sexual offenders. Accordingly, helping abusers resolve their sexual trauma is considered a critical treatment component in this population. Preventing sexual trauma through media campaigns and school programmes (education of parents, teachers and youths) is also very helpful as well as creating a free hotline for people who want to anonymously seek help for their deviant sexual fantasies (as implemented in Germany). Juveniles who display psychiatric and behavioural problems may require additional therapies. In these cases, pharmacological treatments such as benzodiazepines, antipsychotics, antidepressants or other specific psychotherapies must be used according to prescription recommendations. In particular, some sexual abusers are viewed as having a sexual addiction and may require specific psychotherapies (for review of these therapies, see . Treatment in adolescents should follow the principles of the Risk Need Responsivity model developed by [bib_ref] Rehabilitation through the lens of the risks-needs responsivity model, Andrews [/bib_ref]. These authors suggested that an effective therapy has to focus on the risk of a single offender for committing new offences. The higher the risk, the more intensive the intervention should be. Specific criminogenic needs, like sexual deviance, should be considered in therapy-goals as well as responsivity factors like intellectual dysfunction. Behaviour therapy is founded on the premise that behaviour is learned and that it can be changed by a variety of methods. The family is the primary unit of treatment and the goal of family therapy is to change maladaptive relationship patterns. In addition, education (especially sexual education) may help sexual abusers to change their behaviour. In adolescents with paraphilic disorders, CBT or MST approaches should always be used as first-line treatments. Accordingly, pharmacological interventions, when necessary, should always be part of a more comprehensive treatment plan including psychological therapies. There are no licenced medications for the treatment of adolescent sexual offenders, either in Europe or in North America. In general, the treatment approaches recommended for these age groups are CBT interventions, family interventions, psycho-educational interventions and, in some cases, SSRIs. The use of antiandrogens is discouraged before 17 years of age. Research showed that they can delay onset of puberty and bone growth. It is difficult to recommend a length of follow-up as only scarce long-term studies with large samples have been conducted on adolescent sex offenders. In the same way, the duration of the therapies reported in the published studies were very heterogeneous and it is difficult to recommend a minimal duration of psychological or pharmacological treatment. Group CBT and MST have usually been described as treatments of choice, but well-designed comparative studies, conducted on large samples, are still lacking. If multisystemic approach (MST) appears the most efficient, proper systemic family therapy is not always feasible and, in this case, any kind of family intervention could be appropriate. The first step of treatment is motivation and engagement in treatment. The next step is to help the juvenile to accept the responsibility for his behaviour, which does not necessarily mean admittance of an offence. Other treatment objectives are: improvement of cognitive distortions, reduction of deviant arousal and atypical sexual interests, enhancement of impulse control and control of anger, improvement of victim empathy, knowledge of warning signals leading to offending and, of course, sexual education. Patients must also be helped with the acquisition of communication skills and social competency. Substance abuse and antisocial behaviour are also important treatment targets if present. In accordance with Andrews and Bonta's responsivity principles, treatment programmes for mentally-retarded sexual offenders should be more concrete, practical, and action-oriented, with cognitive demand minimised [bib_ref] Treatment of adolescent sex offenders with intellectual disabilities, Lindsay [/bib_ref]. Services are often provided in the home, neighbourhood, school, and community in an effort to change the individual's ''ecological context''. Home visits by social workers or psychologists, after discharge from residential treatment or during ambulatory therapies, may be interesting complements. This emphasises the importance of a multi-professional team including mental health professionals such as psychiatrists, psychologists, social workers etc. The involvement of parents and caregivers is also important as well as coordination with teachers and school health professionals. Community-based treatment may be proposed when the offence is the first one, when there is no history of violence, antisocial behaviour or psychiatric illness and when the patient accepts treatment. Residential treatment may be preferred when adolescents' maladjustment is severe and when family environment is inadequate [bib_ref] Epidemiology and treatment of juvenile sexual offending, Gerardin [/bib_ref]. Pharmacological treatment should also follow the principles of the Risk Need Responsivity model, meaning that the higher the risk, the more intensive the proposed effects of medication should be. The criminogenic needs primarily addressed by medication are: sexual deviance/ paraphilia and hypersexuality/sexual preoccupations. ## Algorithm Adolescent sex offenders with a paraphilic disorder need to be considered broadly into two groups based on age (418 and 18) and, by implication, stage of puberty (according to Tanner stages of puberty, Tanner 1973) (Annexe 1). The mean age of onset of puberty in boys is 11.6 years (range 9.5-13.5 years). For subjects older than 18, please refer to our previous guidelines .org for free download). Adolescents older than 18 years old should go through the same evaluation of severity as that proposed in the WFSBP adult guidelines and clinicians are advised to follow the guidelines for treatment of adult paraphilic subjects if pharmacological treatment is necessary in addition to psychological therapies .org for free download). The other group (12-18 years of age) may be divided into two subgroups: Group I, between 12 and 16 years of age (16 years), Group II, from 17 to 18 years of age (416 years). The first group would still be in an active developmental stage of puberty (between Tanner III and V), whereas the group 17-18 years of age is most likely having completed puberty in the majority of cases (Tanner V stage of puberty). As part of the evaluation, and prior to pharmacological treatment (especially antiandrogens), assessment of the stage of puberty needs to be completed through hormonal levels and Xray of the long bones looking at epiphyseal closure; consultation with a paediatric expert in endocrinology of adolescents is necessary in case of any doubt about completion of puberty and of bone growth (see also Annexe 1). The treatment algorithms for the two groups are different [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref]. We also have to take into account the fact that the US Food and Drug Administration (FDA) released safety warnings, stating that use of antidepressants may increase the risk of suicidality in children, adolescents and young adults up to age 24 years (http://www. fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ UCM096273). Therefore, in adolescents and young adults, initiation of antidepressant treatment may precipitate short-term increases in suicidal ideation and behaviour [bib_ref] The antidepressant quandary-considering suicide risk when treating adolescent depression, Simon [/bib_ref]. Clinicians and the public are urged to weigh the risk of using antidepressants in youths versus the risk of not treating paraphilic juveniles at-risk of sexual offending. Group I (between 12 and 16 years of age) (16 years) [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] : The treatments recommended for these age groups are MST, CBT, family interventions (Level C of evidence) and (at least if both previous therapies are not available) psycho-educational interventions including sexual education (Level D). Motivational interviewing is also recommended to prevent treatment drop outs (Level D). From a pharmacological standpoint and, as a second step, SSRIs are the most common form of pharmacological treatment prescribed in this population, in the dosage ranges recommended in the WFSBP algorithm (see [fig_ref] Table I: Cognitive Behavioural Treatment [/fig_ref] (Level D of evidence with few case reports). If stage Tanner V of puberty is not reached (especially if bone growth is not completed), antiandrogen treatment must not be used, even in severe cases. Group 2 (17 to 18 years of age; Tanner stage V of puberty) (416 years): Psychological treatments must always be used as firstline treatments. In adolescents with paraphilic disorders, MST or CBT approaches should be used. Pharmacological interventions, when necessary, should always be part of a more comprehensive treatment plan including psychological therapies. If Tanner V stage of puberty is reached and age above 17, adolescents should go through the same evaluation of severity as that proposed in the WFSBP adult guidelines and clinicians are advised to follow the guidelines for treatment of adult paraphilic subjects if pharmacological treatment is necessary in addition to psychological therapies . In case of Tanner stage IV or below, in the most severe cases, growth must be assessed (using X-ray of the long bones looking at epiphyseal closure) before antiandrogen treatment is prescribed and the advice of an expert in paediatric endocrinology is necessary. The levels of evidence for these treatments are Level C/D for MST and CBT (Level C was shown for moderate risk subjects but was not clear for high risk subjects), Level D for SSRIs and Level D for a combination of SSRIs and an antiandrogen, or an antiandrogen used alone (few case reports). If growth is not completed see above Group 1 recommendations (between 12 and 16 years of age). The question of the length of treatment needs to be constantly evaluated. Informed consent must be obtained from the youth, his parents and/or caregivers in all cases of antiandrogen treatment prescription, according to the national legal and ethical regulations. Taking into account the low level of evidence available in the literature on which we have based our guidelines, clinicians who will use these guidelines are strongly encouraged to send us their comments and feedback (to the corresponding author of this paper) in order to help us to improve these guidelines in the future. Annexe 1Because the onset and progression of puberty are so variable, Tanner has proposed a scale, now uniformly accepted, to describe the onset and progression of pubertal changes. Boys are rated on a five-point scale. Boys are rated for genital development and pubic hair growth. The same may apply for girls but there is no indication of antiandrogen treatment in female adolescents. The mean age of onset of puberty is 11.6 years in boys (range 9.5-13.5 years). Progression from Tanner stage II to V takes 2-4 years. The first physical sign of puberty is testicular enlargement in 98% of males. The stages in male pubic hair development are as follows Stage I: Prepubertal (can see velus hair over the pubes similar to abdominal wall). There is no androgen-sensitive pubic hair. Stage II: Sparse growth of long pigmented downy hair, slightly straight or curled, at base of penis. Stage III: Darker, coarser and more curled hair, spreading sparsely over junction of pubes (easy to recognise). Stage IV: Hair adult in type, but covering smaller area than in adult; no spread to medial surface of thighs. Stage V: Adult distribution in type and quantity, described in the inverse triangle. There can be spread to the medial surface of the thighs. The stages for male genitalia development are as follows Stage I: The testes, scrotal sac, and penis have a size and proportion similar to those seen in early childhood. Stage II: Enlargement of scrotum and testes; scrotum skin reddens and changes in texture. Stage III: Enlargement of penis (length at first, although with some increase in circumference); further growth of testes and scrotum. Stage IV: Increased size of penis with growth in length and circumference and development of glans penis; testes and scrotum become larger and scrotum skin darker. Stage V: Adult genitalia, testes volume420 ml. ## Boys growth Stage I: 5-6 cm/year. Stage II: 5-6 cm/year. Stage III: 7-8 cm/year. Stage IV: 10 cm/year. Stage V: No further height increase after 17 years. Based on a radiological examination of skeletal development of the left-hand wrist, bone age is assessed and then compared with the chronological age. The main clinical methods for skeletal bone age evaluation are the Greulich and Pyle (GP) method and the Tanner and Whitehouse (TW2) method. Both methods rely on radiographs taken from the left hand. Their respective use depends on the countries. [fig] . 3: Henggeler et al. (2009) andLetourneau et al. (2009), [/fig] [table] Table I: Cognitive Behavioural Treatment (CBT). [/table]	None	https://europepmc.org/articles/pmc4743592?pdf=render	Abstract The primary aim of these guidelines was to evaluate the role of pharmacological agents in the treatment of adolescents with paraphilic disorders who are also sexual offenders or at-risk of sexual offending. Psychotherapeutic and psychosocial treatments were also reviewed. Adolescents with paraphilic disorders specifically present a different therapeutic challenge as compared to adults. In part, the challenge relates to adolescents being in various stages of puberty and development, which may limit the use of certain pharmacological agents due to their potential side effects. In addition, most of the published treatment programmes have used cognitive behavioural interventions, family therapies and psychoeducational interventions. Psychological treatment is predicated in adolescents on the notion that sexually deviant behaviour can be controlled by the offender, and that more adaptive behaviours can be learned. The main purposes of these guidelines are to improve the quality of care and to aid physicians in their clinical decisions. These guidelines brought together different expert views and involved an extensive literature research. Each treatment recommendation was evaluated and discussed with respect to the strength of evidence for efficacy, safety, tolerability and feasibility. An algorithm is proposed for the treatment of paraphilic disorders in adolescent sexual offenders or those who are at risk.
3a161748e9d94264339681ef75ede2f2899912f4	pubmed	Recommendations for initial examination, differential diagnosis, and management of concussion and other head injuries in high‐level football	Recommendations for initial examination, differential diagnosis, and management of concussion and other head injuries in high‐level football Head injuries can result in substantially different outcomes, ranging from no detectable effect to transient functional impairments to life-threatening structural lesions. In high-level international football (soccer) tournaments, on average, one head injury occurs in every third match. Making the diagnosis and determining the severity of a head injury immediately on-pitch or off-field is a major challenge for team physicians, especially because clinical signs of a brain injury can develop over several minutes, hours, or even days after the injury. A standardized approach is useful to support team physicians in their decision whether the player should be allowed to continue to play or should be removed from play after head injury. A systematic, football-specific procedure for examination and management during the first 72 hours after head injuries and a graduated Return-to-Football program for high-level players have been developed by an international group of experts based on current national and international guidelines for the management of acute head injuries. The procedure includes seven stages from the initial on-pitch examination to the graduated Return-to-Football program. Details of the assessments and the consequences of different outcomes are described for each stage. Criteria for emergencyThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. # \| introduction Across all sports, special attention should be given to acute head injuries, since they may be potentially severe and may lead to a prolonged recovery or to long-term consequences. [bib_ref] The role of concussion history and gender in recovery from soccer-related concussion, Chiang Colvin [/bib_ref] The incidence of head injuries and concussions in football has been reported to be lower than in American football, ice hockey, or rugby 2 but higher than in non-contact sports. [bib_ref] Epidemiology of sports-related concussion in NCAA athletes from 2009-2010 to 2013-2014: incidence,..., Zuckerman [/bib_ref] Published incidences are higher in female than male players, [bib_ref] Injury surveillance in the World Football Tournaments 1998-2012, Junge [/bib_ref] [bib_ref] Concussions and heading in soccer: a review of the evidence of incidence,..., Maher [/bib_ref] during matches than during training, [bib_ref] Concussions and heading in soccer: a review of the evidence of incidence,..., Maher [/bib_ref] and highest during international tournaments with about one injury in every third match, and one or two concussions per tournament. [bib_ref] Injury surveillance in the World Football Tournaments 1998-2012, Junge [/bib_ref] As in other sports, the total number of concussions and other head injuries in football appears to be underreported. [bib_ref] Underreporting of concussions and concussion-like symptoms in female high school athletes, Mcdonald [/bib_ref] [bib_ref] Concussion under-reporting and pressure from coaches, teammates, fans, and parents, Kroshus [/bib_ref] [bib_ref] Concussion nondisclosure during professional career among a cohort of former national football..., Kerr [/bib_ref] Head injuries include all injuries caused by a direct or indirect blow against/transmitted to the head and can result in substantially different central and peripheral outcomes, ranging from no detectable functional effects to transient functional impairments, from absent to major structural lesions, and from clinically absent to life-threatening deficits. [bib_ref] Sideline assessment of concussion, Putukian [/bib_ref] [bib_ref] American Medical Society for Sports Medicine position statement on concussion in sport, Harmon [/bib_ref] [bib_ref] Consensus statement on concussion in sport-the 5(th) international conference on concussion in..., Mccrory [/bib_ref] [bib_ref] Diagnosis, prognosis, and clinical management of mild traumatic brain injury, Levin [/bib_ref] A differentiation between injuries of the brain, the skull, the face, the cervical spine, or the inner ear (vestibular and cochlear labyrinth) is often not possible on-pitch or off-field, [bib_ref] Brain or strain? Symptoms alone do not distinguish physiologic concussion from cervical/vestibular..., Leddy [/bib_ref] especially since combined injuries of different central and peripheral systems (eg, brain, cervical, vestibular, cochlear, and ophthalmological) are frequent. [bib_ref] American Medical Society for Sports Medicine position statement on concussion in sport, Harmon [/bib_ref] [bib_ref] Patients with chronic dizziness following traumatic head injury typically have multiple diagnoses..., Arshad [/bib_ref] [bib_ref] Post-traumatic balance disorder, Elzière [/bib_ref] In addition, an athlete may not have or may not report any symptoms immediately after the injury, nor demonstrate any pathological signs; however, he/she might develop symptoms and/or abnormalities on physical examination minutes, hours, or even days later. [bib_ref] Diagnosis, prognosis, and clinical management of mild traumatic brain injury, Levin [/bib_ref] [bib_ref] Mild traumatic brain injury, Vos [/bib_ref] [bib_ref] Advanced trauma life support((R)) update 2019: management and applications for adults and..., Galvagno [/bib_ref] Thus, the diagnosis and estimation of the severity of an injury on-pitch or off-field is a major challenge for the team physician. [bib_ref] Return to play management after concussion in football: recommendations for team physicians, Feddermann-Demont [/bib_ref] Nevertheless, an immediate, targeted assessment and diagnosis is of great importance for the return-to-play decision and the therapeutic approach. [bib_ref] American Medical Society for Sports Medicine position statement on concussion in sport, Harmon [/bib_ref] [bib_ref] Brain or strain? Symptoms alone do not distinguish physiologic concussion from cervical/vestibular..., Leddy [/bib_ref] The present paper provides practical recommendations for team physicians on the management during the first 72 hours after a head injury in high-level football, and a football-specific Return-to-Sport program. Our recommendations are based on a review of the literature with regard to the newest findings on concussion, that is, mild traumatic brain injury (mTBI), as well as peripheral injuries (eg, vestibular organ or cervical spine), and are specifically designed for high-level football. We have defined high-level football as participation in international or national competitions. The review of the literature included national and international guidelines for the management of concussion in sports by expert groups (eg, Concussion in Sports Group), [bib_ref] Consensus statement on concussion in sport-the 5(th) international conference on concussion in..., Mccrory [/bib_ref] [bib_ref] Updated guidelines for the management of sports-related concussion in general practice, Makdissi [/bib_ref] [bib_ref] What are the critical elements of sideline screening that can be used..., Patricios [/bib_ref] [bib_ref] Head injury in soccer: from science to the field; summary of the..., Putukian [/bib_ref] American Academy of Neurology,American Medical Society for Sports Medicine (AMSSM), [bib_ref] American Medical Society for Sports Medicine position statement on concussion in sport, Harmon [/bib_ref] American Association of Neurological Surgeons,and sport federations (eg, World Rugby, 25 National Football League,National Hockey League,English Ice Hockey Federation,Parachute Canada,Water Polo Canada 30 ) as well as national and international guidelines on the management of mTBI [bib_ref] Diagnosis, prognosis, and clinical management of mild traumatic brain injury, Levin [/bib_ref] [bib_ref] Mild traumatic brain injury, Vos [/bib_ref] and (other) head injuries.All authors are experienced in the management of concussion/TBI and cover different medical areas: Emergency Medicine, Neurology, Neuro-Otology and Neuro-Ophthalmology, Internal Medicine, Football and Sports Medicine, Performance Medicine and Rehabilitation Medicine. Four authors (G.C., C.C., M.P., and T.M.) are team physicians and two (E.K. and G.C.) emergency physicians in high-level football. The authors are from three continents. ## \| procedure after head injury A systematic approach for the initial examination, diagnosis, and management in the first 72 hours after head injury in high-level football has been developed . The procedure can be initiated by the team physician or his/her designee. It consists of seven post-injury phases and includes the emergency management , an initial (on-pitch) examination (phase 1), followed by off-field/quiet area (phase 2/3), post-match examinations (phases 4-6), and a detailed Return-to-Football program (phase 7). The initial (on-pitch), off-field, and quiet area examinations are not designed to make a specific diagnosis, such as a concussion, but to identify clinical signs and symptoms, which require (temporary) removal from play for a more detailed management (red flags), removal from play (orange flags), and referral to specialists for further diagnosis and treatment (persistent orange flags) are provided. The guidelines for return to sport after concussion-type head injury are specified for football. Thus, the present paper presents a comprehensive procedure for team physicians after a head injury in high-level football. examination. Due to the potential severe neurological consequences of a head injury, any suspicion of abnormal findings should result in initiation of appropriate emergency management in case of red flags , further examination in case of orange flags , and removal from match or training. If the physician is in doubt, the player should be removed from the pitch. Only players without suspected signs or symptoms of a TBI (including concussion) or other significant injury should be allowed to continue to play or train. The post-match examinations serve to establish a diagnosis to accurately initiate therapeutic strategies and a safe return to football. The physician should be aware that an emergency situation can arise at any time in the first hours and days after the head injury,and therefore, repetitive examinations are required. Ideally, the team physician knows each individual player, their characteristics, medical history, and baseline tests results, if performed, and should be able to communicate with all players appropriately. Observe and recognize (phase 0): Team physicians should observe the match (or training) with a focus on potential head injury, which often happens during aerial duels, [bib_ref] Concussions and heading in soccer: a review of the evidence of incidence,..., Maher [/bib_ref] [bib_ref] A six year prospective study of the incidence and causes of head..., Fuller [/bib_ref] [bib_ref] Time trends of head injuries over multiple seasons in professional male football..., Beaudouin [/bib_ref] and specifically the immediate red and orange flags , such as (suspected) loss of consciousness, convulsion or abnormal posturing, slowness, or imbalance. [bib_ref] American Medical Society for Sports Medicine position statement on concussion in sport, Harmon [/bib_ref] [bib_ref] International consensus definitions of video signs of concussion in professional sports, Davis [/bib_ref] The injury mechanism and player behavior are best recognized using direct observation, if possible supported by immediate video review. [bib_ref] Head injury in soccer: from science to the field; summary of the..., Putukian [/bib_ref] [bib_ref] International consensus definitions of video signs of concussion in professional sports, Davis [/bib_ref] With respect to concussion, observable signs demonstrated on video, such as lying motionless, motor incoordination, ataxia, staggering gait, no protective action (floppy, tonic), cervical hypotonia, seizure/convulsion, tonic posturing, and blank/vacant look, have been shown to be useful for clinical decision making. [bib_ref] International consensus definitions of video signs of concussion in professional sports, Davis [/bib_ref] Emergency management and red flags for referral to hospital: It is important to consider the differential diagnoses when examining a deteriorating or collapsed player. [bib_ref] Advanced trauma life support((R)) update 2019: management and applications for adults and..., Galvagno [/bib_ref] Potentially life-threatening emergency concerns after acute head injury include signs or symptoms of cardio-pulmonary arrest or of severe structural injuries to the brain, skull, face, cervical spine, or spinal cord, which have been denoted as red flags . The emergency assessment and management after any acute head injury should be performed according to clear principles and standardized practice, for example, embodied in the Advanced Trauma Life Support (ATLS™) principles. [bib_ref] Advanced trauma life support((R)) update 2019: management and applications for adults and..., Galvagno [/bib_ref] The first priority is the treatment of the greatest threat to life and the avoidance of further harm.Cardiac arrest is extremely rare and not considered to be a consequence of a head injury. It can be caused by a hit against the chest (commotio cordis) or occur spontaneously. [bib_ref] Failure of commercially available chest wall protectors to prevent sudden cardiac death..., Weinstock [/bib_ref] Full Advanced Cardiac (Life) Support procedures have to be undertaken. [bib_ref] Advanced trauma life support((R)) update 2019: management and applications for adults and..., Galvagno [/bib_ref] [bib_ref] american heart association focused update on advanced cardiovascular life support use of..., Panchal [/bib_ref] [bib_ref] Resuscitation Council Guidelines for Resuscitation 2015 Section 8. Initial management of acute..., Nikolaou [/bib_ref] Any head injury should be regarded as having a concomitant cervical spine injury until excluded by clinical examination or imaging if indicated . [bib_ref] Diagnosis, prognosis, and clinical management of mild traumatic brain injury, Levin [/bib_ref] Any suggestion of a cervical fracture or intraspinal lesion (GCS < 15 on initial assessment, neck pain or tenderness, focal neurological deficit, paresthesia, or weakness in the extremities, any other clinical suspicion of cervical spine injury) should result in immobilization and stabilization of the cervical spine, appropriate removal from pitch, and emergency transport to hospital.Similarly, all players with a suspected fracture of the skull should be removed from the pitch for further examination. This includes also players with a suspected skull fracture who are free of symptoms or have local pain only. In addition to local ocular tenderness to palpation, other significant signs and symptoms of an orbital floor fracture are periorbital hematoma, double vision (diplopia), and abnormalities in eye movements. Any deterioration of signs and symptoms can indicate intracranial bleeding and/or swelling, which can only be diagnosed by tomographic imaging (eg, computerized tomography) of the brain. Therefore, it is also important to continuously observe players even if they are initially symptom-free. Any red flag mandates removal from play, treatment on site (on-pitch/sideline/medical room) as necessary and consideration of immediate emergency transport to a hospital, if the sign or symptom is confirmed, persists, or deteriorates. Initial (on-pitch) examination (phase 1): The outcome of the initial (on-pitch) examination is the basis for the team physician´s decision on emergency management, referral to hospital, off-field/quiet area assessment, and removal from or return to match play or training. The physician´s decision should be communicated to the referee during match play and to the manager/coach during training. If no physician is present, the principles of "recognize and remove" and "if in doubt, sit them out" should be applied. [bib_ref] The concussion recognition tool 5th edition (CRT5): background and rationale, Echemendia [/bib_ref] During this initial examination, it is essential to focus on red and orange flags. The elements of the initial (on-pitch) inspection and examination are based on the latest version of the Sport Concussion Assessment Tool (eg, SCAT5™)and the NICE criteria.The inspection concentrates on visible signs (eg, loss of consciousness, vomiting), while the examination assesses core signs and symptoms of neurological impairment of different brain areas (cortical, subcortical, cerebellar, brain stem) [bib_ref] Consensus statement on concussion in sport-the 5(th) international conference on concussion in..., Mccrory [/bib_ref] [bib_ref] Clinical diagnosis of bilateral vestibular loss: three simple bedside tests, Petersen [/bib_ref] [bib_ref] Assessment of vision in concussion, Akhand [/bib_ref] and of a cervical spine or intraspinal injury. Any period of loss of consciousness or GCS < 15 indicates a concussion/mTBI or a more severe TBI. The injured player should be removed from the pitch to the off-field location for further assessments , phase 2) if (a) the outcome in one or more criteria of the initial assessment is considered or suspected to be abnormal, (b) additional time for examination is required, or (c) all tests yield normal results, but the team physician suspects that the player is suffering from functional neurological impairment. Note: Any period of loss of consciousness or GCS < 15 indicates a concussion/mTBI or a more severe TBI, and thus, the player has to be removed from match play or training, albeit he/she might not have other acute or suspected findings. The player should only be allowed to continue to play or train if all on-pitch examinations reveal no (suspected) signs or symptoms and on explicit confirmation of the player's capability to play by the team physician to the referee during match play and to the manager/coach during training. If the team physician is uncertain, the principle "if in doubt, take him/her out" applies. The team physician should continue observing the player throughout the match play or training (phase 4) and re-evaluate him/her serially to watch for the delayed onset of signs or symptoms (phase 5). All players after head injury should be observed for the first 24 hours (phase 6). ## \| 1853 FEDDERMANN-DEMONT ET Al. ## Off-field assessment (phase 2): The off-field assessment should focus on red and orange flags . Testing of ocular motor function should be included, since many of the pathways in the brain potentially affected by head injuries are involved in ocular motor control. [bib_ref] Review of vestibular and oculomotor screening and concussion rehabilitation, Kontos [/bib_ref] [bib_ref] A brief vestibular/ocular motor screening (VOMS) assessment to evaluate concussions: preliminary findings, Mucha [/bib_ref] [bib_ref] Sideline concussion assessment: the current state of the art, Yue [/bib_ref] Obvious minor injuries, such as lacerations or bruises, might be treated. Examination and treatment in a quiet area (phase 3): Players attributed with any (suspected) orange flag onpitch or off-field should be examined in a quiet area (eg, medical or locker/change room, pop-up tent) using the latest version of a sport concussion assessment tool (eg, SCAT5 TM ) 39,45 and a detailed neurological examination. The neurological examination should include an examination of cranial nerves, vestibular, balance, and coordinative functions (spontaneous nystagmus, head impulse test, [bib_ref] The video head impulse test, Halmagyi [/bib_ref] vertical eye deviation, dynamic visual acuity, 40 balance (Romberg), positioning maneuvers), [bib_ref] A brief vestibular/ocular motor screening (VOMS) assessment to evaluate concussions: preliminary findings, Mucha [/bib_ref] cervical spine (range of motion, stability, proprioception, strength, muscle tone), motor function of upper/lower extremities, and standardized neurocognitive tests. Based on the outcome of the neurological examination, the team physician decides on further examinations, as recommended by the National Institute of Health and Care Excellence (NICE) for head injuriesand by the European Federation of Neurological Societies (EFNS) guidelines for mTBI [bib_ref] Mild traumatic brain injury, Vos [/bib_ref] as well as other guidelines. [bib_ref] Diagnosis, prognosis, and clinical management of mild traumatic brain injury, Levin [/bib_ref] Players who continued playing or returned to the match or training session where they incurred the head injury, and who have no further signs or symptoms after phase 2 (or 3) can be allowed to participate as usual in the next training and match. Players who are removed from the match or training session and have signs or symptoms of a TBI (including concussion) or of other significant head injury at any time should complete the graduated Return-to-Football program (Stage 7) once their symptoms have resolved. ## Observation and serial re-examination until leaving the sports facilities (phase 4): The team physician should observe the player until the end of the match or training for worsening or additional signs or symptoms regardless of whether the player had returned to or was removed from match play or training. Medications that may mask or worsen symptoms should be avoided unless a more severe head injury has been ruled out. Any worsening or newly developed signs or symptoms should result in emergency management in the case of red flags or further examinations in the case of orange flags . Prior to leaving the sports facilities, all injured players should be re-examined for worsening of or new signs and symptoms using the latest version of a sport concussion assessment tool. Before travel without access to emergency care (eg, flight), any worsening of symptoms or concern for any form of brain, skull, or cervical spine injury should be cleared with appropriate diagnostic imaging. Driving a car should not be allowed until medically cleared,which was reported to take about 24 to 48 hours. [bib_ref] Post-concussion driving behaviors and opinions: a survey of collegiate student-athletes, Schmidt [/bib_ref] An initial computerized tomography (CT) scan is recommended on the day of injury, if risk factors for a brain injury (eg, Glasgow Coma Scale < 13 or <15 after 2 hours, suspected skull fracture, more than 1 episode of vomiting, post-injury seizure, loss of consciousness, persistent anterograde amnesia, or focal neurological deficit) are present. [bib_ref] Diagnosis, prognosis, and clinical management of mild traumatic brain injury, Levin [/bib_ref] [bib_ref] Mild traumatic brain injury, Vos [/bib_ref] Observation for 24 hours after head injury (phase 5): In general, all players after a head injury should be observed for 24 hours either by the team physician or by a reliable adult person instructed to immediately contact the team physician or the emergency department of the closest hospital in case of worsening of or new symptoms (red or orange flags, .Until re-evaluation (phase 6), physical and cognitive rest is recommended, which includes avoidance of using electronic devices. If a player was allowed to return to play on the day of injury, is free of symptoms, and has a normal neurological examination, the team physician may decide that the observation is not necessary. [bib_ref] Consensus statement on concussion in sport-the 5(th) international conference on concussion in..., Mccrory [/bib_ref] [bib_ref] Mild traumatic brain injury, Vos [/bib_ref] In any case, the injured player should be informed and instructed to report worsening or new symptoms, and the team physician should contact him/her the following morning with respect to symptom development and further steps. ## Re-evaluation within 18 to 72 hours after head injury (phase 6): A player who was removed from football and those who continued to play and developed specific signs or symptoms at any time after the head injury should be re-evaluated within 72 hours by a physician, or his/her designee, experienced in head injury assessment according to current international guidelines. [bib_ref] What domains of clinical function should be assessed after sport-related concussion? A..., Feddermann-Demont [/bib_ref] [bib_ref] Acute sport concussion assessment optimization: a prospective assessment from the CARE consortium, Broglio [/bib_ref] The time frame of up to 72 hours has been chosen, since symptoms can develop with latency, and a brief initial period of cognitive and physical rest after brain injury is currently recommended. [bib_ref] Concussion part II: rehabilitation -the need for a multifaceted approach, Schneider [/bib_ref] [bib_ref] Rest and treatment/ rehabilitation following sport-related concussion: a systematic review, Schneider [/bib_ref] Ideally, the team physician, or his/her designee, should assess the injured player daily during this period, if the number or the intensity of signs and symptoms do not improve or even worsen. In addition to the examination of cranial nerves, cervical spine, motor function of upper/lower extremities, balance, vestibular, ocular motor, vision, coordination, emotions, and neuropsychological tests, a detailed medical history (eg, previous head injuries, pre-existing headache, or sleep problems), and, if indicated, neurocognitive tests should be included. [bib_ref] What domains of clinical function should be assessed after sport-related concussion? A..., Feddermann-Demont [/bib_ref] These examinations provide valuable hints to different head injury diagnoses. [bib_ref] What domains of clinical function should be assessed after sport-related concussion? A..., Feddermann-Demont [/bib_ref] indicates which signs and symptoms might be caused by injuries of the brain, the cervical spine, and the vestibular, cochlear, visual and ocular motor systems and thus helps to choose a medical specialist for further examination and treatment in case of persistence. Results from baseline testing may be helpful for comparison of signs and symptoms in the decision-making process with respect to the most appropriate diagnostic and therapeutic approach. The aim of the examination in phase 6 is to decide whether 1. The player is medically cleared to start the graduated Return-to-Football program (phase 7) in case of no, minimal, or improving symptoms and a normal outcome of all examinations in phase 6; or 2. The player should be referred to a medical specialist for further examination and treatment in case of persistent orange flags (see . ## Graduated return-to-football (phase 7): The graduated Return-to-Football program is based on the Return-to-Sports protocol by McCrory et al [bib_ref] Consensus statement on concussion in sport-the 5(th) international conference on concussion in..., Mccrory [/bib_ref] and intended to ensure a controlled stepwise return to sport activities for high-level adult football players after concussion/mTBI. It adds football-specific detail to the more general recommendations from the Concussion in Sports Group. For players with a structural damage (such as intracranial hemorrhage or skull fracture), the return-to-football procedure should be determined on an individual basis by the physician in charge. The player should be re-examined by the physician in charge before starting symptom-limited activity (Stage 1), ideally within 18-72 hours after head injury , phase 6) and before returning to "routine/contact training" , Stage 5). The medical re-evaluations should focus on (a) the abnormal diagnostic findings on the day of injury, (b) persisting or additional signs or symptoms or changes in their character, intensity or frequency, and (c) symptom development under increasing physical and cognitive training load. [bib_ref] American Medical Society for Sports Medicine position statement on concussion in sport, Harmon [/bib_ref] [bib_ref] Physiological, vestibulo-ocular and cervicogenic post-concussion disorders: an evidence-based classification system with directions..., Ellis [/bib_ref] Current guidelines and position statements agree that a player with a (suspected) concussion should not return to sport on the same day. [bib_ref] American Medical Society for Sports Medicine position statement on concussion in sport, Harmon [/bib_ref] [bib_ref] Consensus statement on concussion in sport-the 5(th) international conference on concussion in..., Mccrory [/bib_ref] Although there is insufficient scientific evidence on appropriate duration of rest after concussion, an initial phase of cognitive and physical rest (24 to 48 hours) before the graduated return to training and match play is recommended. After this initial period of rest, lowlevel exercise that does not lead to worsening of pre-exercise intensity of symptoms or new symptoms has been identified as meaningful. [bib_ref] Earlier time to aerobic exercise is associated with faster recovery following acute..., Lawrence [/bib_ref] [bib_ref] A preliminary study of the effect of early aerobic exercise treatment for..., Leddy [/bib_ref] [bib_ref] Early subthreshold aerobic exercise for sport-related concussion: a randomized clinical trial, Leddy [/bib_ref] Allowing a player to participate in low-level exertion without exaggeration of symptoms and without the risk for contact or fall may also minimize the players' likelihood for emotional affection as psychological response to the injury. [bib_ref] Mental health in elite athletes: International Olympic Committee consensus statement (2019), Reardon [/bib_ref] [bib_ref] Mental health issues and psychological factors in athletes: detection, management, effect on..., Chang [/bib_ref] Allowing a player, with symptoms to participate in low-level exercise (as part of the treatment plan) should be differentiated from the graduated or accelerated Return-to-Football program. The duration until return to match play varies and might be influenced by player's age or his/her history. [bib_ref] American Medical Society for Sports Medicine position statement on concussion in sport, Harmon [/bib_ref] [bib_ref] Consensus statement on concussion in sport-the 5(th) international conference on concussion in..., Mccrory [/bib_ref] A multidisciplinary team approach is recommended especially with respect to return to routine/ contact training. The standard Return-to-Football program comprises six stages with a graduated increase in physical demands ("aerobic" to "anaerobic," "no resistance" to "resistance"), football-specific exercises ("simple" to "complex"), and the risk of contact ("individualized" to "team training," "non-contact" to "full contact") and head impact ("no heading" to "heading"). Each stage should include at least one training session and should last according to current guidelines for a minimum of 24 hours. [bib_ref] American Medical Society for Sports Medicine position statement on concussion in sport, Harmon [/bib_ref] [bib_ref] Consensus statement on concussion in sport-the 5(th) international conference on concussion in..., Mccrory [/bib_ref] In case of worsening or recurrence of symptoms during or after a training session of any stage, the player should rest until these symptoms have resolved (for a minimum of 24 hours) and then continue the program at the previous symptom-free stage. [bib_ref] Consensus statement on concussion in sport-the 5(th) international conference on concussion in..., Mccrory [/bib_ref] The player should only be medically cleared to return to football, when each stage has been completed without symptoms. Currently, there are no scientific data on the appropriate duration of absence from match play after a head injury. In the adult players with minimal symptoms, no prior brain or other significant head injury, and no other risk factors, an accelerated Returnto-Football program can be considered, while in younger players and players with certain risk factors, such as a history of repetitive concussive injuries, a more conservative approach is recommended. [bib_ref] What is the difference in concussion management in children as compared with..., Davis [/bib_ref] [bib_ref] Predictors of clinical recovery from concussion: a systematic review, Iverson [/bib_ref] In some leagues, there are more specific, mandated concussion guidelines and the team physician should refer to these where relevant. The accelerated Return-to-Football program should only be initiated, if (a) any acute post-injury symptoms and signs were classified as not specific for concussion, (b) the duration of these unspecific symptoms was shorter than 24 hours, and (c) the results of the re-evaluation were normal (or similar to pre-injury baseline, if performed). Persisting orange flags or one or more red flags at any time after the head injury disqualify from an accelerated return to football. The accelerated return-to-football approach concentrates on stages 2 and 5 and requires a close cooperation of the player, the coach, and a physician experienced in concussion management. Individual variations between the accelerated and the standard approach are possible; however, no scientific evidence on the effectiveness is currently available. Any individual return-to-football procedure should include a multidisciplinary approach. Detailed recommendations on Return-to-School/Work were published, for example, by the Concussion Awareness Training Tool (CATT),and are not specific for football. Medical clearance for return to football, school, work, or other physical activity should always be made by the treating physician/s and based on medical considerations only, regardless of the player's desire to play, dissimulation of symptoms, [bib_ref] At-risk populations in sports-related concussion, Kutcher [/bib_ref] and/or pressure from others including the coaching staff, parents, or media. # \| conclusion The present paper presents a standardized practical procedure for the initial examination, differential diagnosis, and first 72-hour management after head injury in high-level football and a graduated Return-to-Football program developed by an international group of experts based on review of the literature and current national and international guidelines for the management of head injuries. It should serve as recommendation for team physicians with respect to a consistent procedure after a head injury in football. ## \| perspective Head injuries can result in different outcomes, and signs and symptoms can develop or change rapidly within minutes, hours, and days after head injury. Therefore, a systematic procedure for examination and management of football players after head injuries should be implemented to support team physicians in their decision whether the player should be allowed to continue to play or should be removed from play. The presented procedure can be adapted to other sports. Awareness to the potential severity of a head injury should be raised across sports and responsible medical persons. Future research should focus on biomechanical aspects, such as severity of impact (threshold), and on the time course of pathophysiological/metabolic changes, that may eventually lead to an energy crises and delayed signs or symptoms. Further development and validation of on-pitch tests and measures to quantify signs and symptoms are needed. [fig] F: I G U R E 1 Procedure after head injury in high-level football \| 1849 EDDERMANN-DEMONT ET Al. [/fig]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/sms.13750	Head injuries can result in substantially different outcomes, ranging from no detectable effect to transient functional impairments to life‐threatening structural lesions. In high‐level international football (soccer) tournaments, on average, one head injury occurs in every third match. Making the diagnosis and determining the severity of a head injury immediately on‐pitch or off‐field is a major challenge for team physicians, especially because clinical signs of a brain injury can develop over several minutes, hours, or even days after the injury. A standardized approach is useful to support team physicians in their decision whether the player should be allowed to continue to play or should be removed from play after head injury. A systematic, football‐specific procedure for examination and management during the first 72 hours after head injuries and a graduated Return‐to‐Football program for high‐level players have been developed by an international group of experts based on current national and international guidelines for the management of acute head injuries. The procedure includes seven stages from the initial on‐pitch examination to the graduated Return‐to‐Football program. Details of the assessments and the consequences of different outcomes are described for each stage. Criteria for emergency management (red flags), removal from play (orange flags), and referral to specialists for further diagnosis and treatment (persistent orange flags) are provided. The guidelines for return to sport after concussion‐type head injury are specified for football. Thus, the present paper presents a comprehensive procedure for team physicians after a head injury in high‐level football.
bae1deaace02cb6c36355cb6660bb0ca60a9cdf7	pubmed	Best Practices in Dengue Surveillance: A Report from the Asia-Pacific and Americas Dengue Prevention Boards	Best Practices in Dengue Surveillance: A Report from the Asia-Pacific and Americas Dengue Prevention Boards Background: Dengue fever is a virus infection that is spread by the Aedes aegypti mosquito and can cause severe disease especially in children. Dengue fever is a major problem in tropical and sub-tropical regions of the world.Methodology/Principal Findings: We invited dengue experts from around the world to attend meetings to discuss dengue surveillance. We reviewed literature, heard detailed reports on surveillance programs, and shared expert opinions.Results: Presentations by 22 countries were heard during the 2.5 day meetings. We describe the best methods of surveillance in general, the stakeholders in dengue surveillance, and the steps from mosquito bite to reporting of a dengue case to explore how best to carry out dengue surveillance. We also provide details and a comparison of the dengue surveillance programs by the presenting countries.Conclusions/Significance: The experts provided recommendations for achieving the best possible data from dengue surveillance accepting the realities of the real world (e.g., limited funding and staff). Their recommendations included: (1) Every dengue endemic country should make reporting of dengue cases to the government mandatory; (2) electronic reporting systems should be developed and used; (3) at minimum dengue surveillance data should include incidence, hospitalization rates, deaths by age group; (4) additional studies should be completed to check the sensitivity of the system; (5) laboratories should share expertise and data; (6) tests that identify dengue virus should be used in patients with fever for four days or less and antibody tests should be used after day 4 to diagnose dengue; and (7) early detection and prediction of dengue outbreaks should be goals for national surveillance systems. # Introduction Dengue virus, which is most commonly transmitted by the Aedes aegypti mosquito, is the most important mosquito-borne viral disease affecting humans [bib_ref] The global emergence/resurgence of arboviral diseases as public health problems, Gubler [/bib_ref]. Caused by one of four serotypes, dengue fever (DF) produces a spectrum of clinical illness that ranges from an influenza-like illness to a fatal shock syndrome (DSS). Most patients that progress to shock first develop a more severe form of infection called dengue hemorrhagic fever (DHF). We estimate that 3.6 billion people in 124 countries are at-risk for infection and 500 million people infected each year. Over two million cases of DHF occur annually, and approximately 21,000 deaths are likely attributable to dengue. Dengue prevention is limited vector control and treatment is limited to supportive care to avoid shock. To address the need for dengue prevention, several dengue vaccines are in development. One candidate entered expanded phase 2 clinical trials in 2009. Decision making prior to vaccine introduction and monitoring for effectiveness and safety after introduction require adequate country specific disease surveillance data. To assess the status of dengue surveillance and to develop recommendation to improve surveillance data quality, two Dengue Prevention Boards convened to discuss dengue surveillance in representative countries. This report describes the results of that work. # Methods ## Prevention boards As part of its program to facilitate the development and introduction of a dengue vaccine in endemic countries, Pediatric Dengue Vaccine Initiative (PDVI)has sponsored two Boards consisting of dengue experts primarily from endemic countries, the Asia-Pacific Dengue Prevention Board (APDPB) and the Americas Dengue Prevention Board (AmDPB). These experts are in-country advocates for improved dengue prevention and control activities, most working in anticipation of dengue vaccines. The Boards meet regularly to assess various aspects of dengue prevention and control. ## Meetings on surveillance Accurate burden of disease data will be needed for informed decision making regarding vaccine introduction [bib_ref] Policymakers' views on dengue fever/ dengue haemorrhagic fever and the need for..., Deroeck [/bib_ref] ; however, often the only data available are from national surveillance. For this and other reasons, the Boards along with PDVI selected surveillance for their first topic to address. The format for their work was two working meetings of Board members and invited consultants and representatives from the Ministries of Health or other agencies involved in dengue surveillance. The objectives of the meetings were to assess the state of dengue surveillance in selected countries and reach a consensus on best practices. The Asia-Pacific Board met on ; the Americas Board, on January [bib_ref] Notifiable disease surveillance and practicing physicians, Krause [/bib_ref] [bib_ref] The underreporting of disease and physicians' knowledge of reporting requirements, Konowitz [/bib_ref]. In addition to Board members, meeting attendees included national and international experts in surveillance and dengue, representatives of ministries of health, WHO and regional offices (e.g. SEARO), PAHO and the Caribbean Epidemiology Center (CAREC). Oral presentations, facilitated discussions, and a survey of presenters were used to determine the key issues and best practices. In total, there were presentations on the surveillance programs from twenty two countries given by representatives of Ministry of Health or other agency participating in dengue surveillance in-country (e.g. Institute Pasteur) (for APDPB: Australia, Cambodia, French Polynesia, India, Malaysia, the Philippines, Sri Lanka, Singapore, Thailand, Japan, Vietnam; for AmDPB: Argentina, Brazil, Costa Rico, Colombia, Cuba, Honduras, Mexico, Puerto Rico, Nicaragua, United States (South-west border states), and Venezuela) [fig_ref] Figure 1: Countries with local dengue transmission in the last 25 years [2] [/fig_ref]. Because ensuring adequate surveillance requires participation from several disciplines, experts presented on topics of surveillance, epidemiology, entomology, and virology. Each country provided a detailed description of their national dengue surveillance system and results [fig_ref] Table 1: Characteristics of national surveillance systems [/fig_ref]. Attendees then synthesized the comments and opinions of the Board members. Full reports of each meeting are be available on the website of the Prevention Boards. # Results ## Observations on surveillance systems The core functions of a comprehensive surveillance system are detection, reporting, investigation, confirmation, analysis, interpretation, and response. Cooperation is essential between the healthcare system and the public health authority because for rapid response to emerging public health threats the public health authority is dependent on healthcare system to generate timely and accurate case reports. ## Observations on diagnosis and case definitions of dengue At the time of the meeting, WHO had published guidelines on the diagnosis of dengue including case definitions; but these guidelines were published more than 10 years ago-in 2009 WHO published new guidelines with major changes in dengue case classifications. Regional offices have also drafted guidelines. The guidelines agree on major issues with minor variations (for example, some include leukopenia or hepatomegaly in the case definitions, but not all include a ''suspected case'' category). One major difficulty with all previous guidelines is case classification [bib_ref] Severe dengue: the need for new case definitions, Rigau-Pérez [/bib_ref]. Because case fatality rates are much higher among patients with DHF, correct classification is important for triage, treatment, and prognosis. Obtaining a platelet count, hematocrit, and radiographic imaging is often not possible, too time consuming, or too expensive in many healthcare facilities in endemic countries-but the results of these tests are required diagnostic criteria for DHF. There was wide recognition of the need for a simplified classification system that is still helpful for case management [bib_ref] Severe dengue: the need for new case definitions, Rigau-Pérez [/bib_ref] [bib_ref] The WHO dengue classification and case definitions: time for a reassessment, Deen [/bib_ref]. Although meeting attendees reported using similar dengue case definition systems, surveillance methods varied between countries. Laboratory methods also vary as well as the testing algorithms and the interpretation of positives. For example, in Brazil and ## Author summary The Pediatric Dengue Vaccine Initiative organized Dengue Prevention Boards in the Asia-Pacific and the Americas regions consisting of dengue experts from endemic countries. Both Boards convened meetings to review issues in surveillance. Through presentations, facilitated discussions, and surveys, the Boards identified best practices in dengue surveillance including: (1) Dengue should be a notifiable disease in endemic countries; (2) World Health Organization regional case definitions should be consistently applied; (3) electronic reporting systems should be developed and used broadly to speed delivery of data to stakeholders; (4) minimum reporting should include incidence rates of dengue fever, dengue hemorrhagic fever, dengue shock syndrome, and dengue deaths, and hospitalization and mortality rates should be reported by age group; (5) periodic additional studies (e.g., capture/ recapture) should be conducted to assess under-detection, under-reporting, and the quality of surveillance; (6) laboratory methods and protocols should be standardized; (7) national authorities should encourage laboratories to develop networks to share expertise and data; and (8) RT-PCR and virus isolation (and possibly detection of the NS1 protein) are the recommended methods for confirmation of an acute dengue infection, but are recommended only for the four days after onset of fever-after day 4, IgM-capture enzyme-linked immunosorbent assay is recommended. Surveillance Best Practices www.plosntds.org Colombia, healthcare providers complete case reports on both ambulatory and hospitalized patients, however, in Thailand and Vietnam the majority of reported cases are hospitalized. In only 12/22 (55%) of countries represented at the meeting confirmed all officially reported cases with laboratory testing. Nearly every country includes suspected dengue cases regardless of age, but in Cambodia surveillance is conducted only among children less than 15 years of age. In Singapore and Brazil, monitoring vector indices is an integral part of the dengue surveillance system, while in Puerto Rico it is not. The attendees reported that these differences were not currently a problem for country level analyses but make inter-country, regional, and global analyses and comparisons difficult. Moreover, some difference (e.g. lack of dengue surveillance among adults in Cambodia) could be an impediment to strategic planning and implementation of a dengue vaccine since the disease also affects adults as well as children. Moreover, the vaccination of children is likely to also have an impact on adult disease burden [bib_ref] Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae, Kyaw [/bib_ref] [bib_ref] The Japanese experience with vaccinating schoolchildren against influenza, Reichert [/bib_ref] , further improving the cost-effectiveness. Since surveillance data are needed for health ministries to target control responses when outbreaks are detected, data must be collected in a timely fashion. In order to better understand the overall process, attendees reviewed the steps from infection to reporting [fig_ref] Figure 2: Timeline showing transmission cycle, clinical disease, and surveillance events [/fig_ref]. The incubation period is, on average, one week following the bite of an infectious mosquito. Several more days pass before symptoms become severe enough to cause the patient to seek medical attention, and still more time is required for the symptoms of DHF to develop. Outpatient clinic-based surveillance will detect cases earlier than inpatient facilities, potentially allowing more time for public health action. The medium for reporting ranged from paper case report forms, to hand-held computers, to internet-based systems. A case study from Nicaragua showed that hand-held computers, although initially requiring significant investment in infrastructure and training, do reduce reporting time. In Kolkata, India, special mapping of cases has been used to target control activities. In Singapore and Brazil, ministries are also using intranet-based data entry software allowing staff to directly enter data on cases and Ae. aegypti breeding sites in the field. The data are then immediately available to plan interventions and follow-up. All countries are dependent on paper forms for case reporting before any additional investigation or action. Time is required for that report to reach the surveillance office, to be entered and analyzed, and finally be reported. However, many countries are developing improved methods for data collection for targeted interventions. Another key issue is the needs of stakeholders with interests in dengue diagnosis and surveillance. These stakeholders include the general public, senior policy-makers, academics, and legislators. A diverse group, their interests range from the parents of sick children who want immediate and accurate test results-knowing the diagnosis allows them to cope better-to healthcare workers, staff in laboratories, public health and vector control authorities. All want a point-of-care test to speed accurate diagnosis and In most countries diagnostic testing and surveillance relies on healthcare practitioners and laboratory staff to report cases but they receive little benefit. Confirmatory diagnostic tests such as virus isolation or reverse transcriptase-polymerase chain reaction testing (RT-PCR) require expertise and equipment usually found only in reference laboratories. However, several attendees explained that the time required for a sample to reach and to be processed at centralized facilities often results in delays that render the results useless to the treating physician. Further delays occur if the information provide on a sample is incomplete or if batchtesting of samples is conducted. After testing, the report generated requires verification, approval and delivery (e.g. mailing). As a consequence, health care providers in most countries must treat patients empirically. The attendees concluded that simplified case reporting [bib_ref] Notifiable disease surveillance and practicing physicians, Krause [/bib_ref] , rapid turnaround of results, and training healthcare providers in reporting [bib_ref] The underreporting of disease and physicians' knowledge of reporting requirements, Konowitz [/bib_ref] can be important ways to encourage continued reporting of cases. Mandatory reporting, they explained, rarely guaranteed reporting. ## Strengths and weaknesses of existing surveillance systems Strengths. Attendees were asked to identify the strengths and weaknesses of their systems. Most indicated that their countries had adequate infrastructure and surveillance systems, and the adjectives ''dedicated'', ''committed'', ''skilled'', and ''motivated'' were widely used to describe the quality of the personnel engaged in surveillance. They reported some country-specific but effective links between the various stakeholders; especially healthcare providers, laboratory staff, and the public health and vector control authorities. However, many of these relationships are dependent on personal contacts which are affected by staff turnover. Weaknesses. A common perception among meeting attendees was that disease control is politically more important than prevention. That is, highly visible outbreak response through spraying is considered more important than outbreak prevention. Specifically, during outbreaks, public demand for action often leads to pesticide spraying [bib_ref] Worst dengue epidemic--nation-wide campaign to demand resignation of Health Minister Chua Jui, Siang [/bib_ref] which is unlikely to be effective since the pesticide released in the streets is unlikely to reach the adult mosquitoes resting and feeding inside homes [bib_ref] Behavior of resting Aedes aegypti (Culicidae: Diptera) and its relation to ultra-low..., Perich [/bib_ref]. Lack of preventive services in the provinces is seen as a further impediment to conducting adequate surveillance. Further, even when adequate infrastructure exists, data are rarely used locally; rather they are forwarded to the central ministry offices for official evaluation, missing the opportunity for an immediate local response. Diagnostic tests further complicate the situation because the results are often difficult to interpret by the healthcare providers and public health practitioners unfamiliar with the limitations of the tests [bib_ref] Dengue: a review of the laboratory tests a clinician must know to..., De Paula [/bib_ref]. Lack of funding for laboratory confirmation of cases and having those services available only at central level were reported as further weaknesses. One participant remarked that local pubic health agencies in large countries such as Brazil have their response time greatly delayed if they must wait for laboratory confirmation at the national level. Indeed, while experts agreed that staff conducting surveillance were committed, under-detection and under-reporting of dengue cases were significant and often due to the design of the surveillance system and lack of funding. Also, data sharing and full coordination of entomologic surveillance conducted by vector control units and human disease surveillance conducted by epidemiologists is needed to improve detection of increased transmission sufficiently early to prevent or control outbreaks. Finally, virological surveillance is under-utilized or in some countries, completely lacking: It's importance emphasized by the fact that large outbreaks tend to follow changes or reintroductions of serotypes. # Discussion As an outcome of the meeting, attendees agreed on best practices on laboratory practices, data gathering, analyses, reporting, and feedback for dengue surveillance. ## Guiding principles Every dengue endemic country should systematically gather data in an established dengue surveillance system, and each system should have a quality assurance mechanism. Legislation should make dengue a notifiable disease in every affected countryto improve the capture of cases by surveillance. However, even mandatory reporting is not sufficient; additional efforts are needed to improve and maintain a high level of quality reporting. All suspected cases must be reported to a central dengue unit in the health ministry as rapidly as possible and providers should be reminded that timely reporting can lead to effective response [bib_ref] The timeliness of notification of clinically suspected cases of dengue imported into..., Malcolm [/bib_ref]. Laboratory confirmation of suspected cases should always be sought, except during outbreaks. Once an outbreak is confirmed no added information is gained by testing all samples; a subset of the samples is usually sufficient to track the outbreak. That said, health providers should be informed that not all samples submitted during outbreaks will necessarily be tested. In outbreaks, data collection and analysis should be completed as rapidly as possible. Reporting should be encouraged from all levels of healthcare facilities in both the public and the private sectors. In particular, mechanisms to involve the private sector should be developed; one possible way to encourage reporting is a rapid turn around of dengue diagnostic test results which can be provided free of charge. While the turn around may not be quick enough to affect patient care, rapid return of results to submitting providers has intrinsic value for improving their diagnostic acumen. Reporting should be expanded to also include cases presenting to outpatient facilities, but staff in such settings may need further training to ensure the quality of data. To confirm and understand the burden of disease, periodic additional studies (e.g. using capture-recapture methods) should be conducted and incorporated into the system when possible. This will also determine the representativeness of the surveillance data. ## Laboratory practices Laboratory confirmation improves the specificity of surveillance [bib_ref] What does dengue disease surveillance contribute to predicting and detecting outbreaks and..., Runge-Ranzinger [/bib_ref] , but laboratory methods and protocols should be standardized. This can be achieved through national and international networking of dengue laboratories to share expertise, protocols and data. A critical element for the successful laboratory diagnosis of an acute dengue infection is the timely collection of high quality samples. Monitoring the time from case identification to receipt of blood samples in the testing facility may assist in maintaining high quality specimens. RT-PCR and virus isolation are the two recommended methods for virus identification. Monitoring serotypes and sequencing isolates can provide useful markers for outbreak prediction [bib_ref] Dengue in Southeast Asia: epidemiological characteristics and strategic challenges in disease prevention, Ooi [/bib_ref]. Detection of the non-structural protein antigen NS1 may also be useful, but it must undergoing further evaluation. For serologic testing, the hemagglutination-inhibition assay remains the gold standard of serological assays and should be maintained in those laboratories capable of performing it; however, enzymelinked immunosorbent assays for IgM and IgG are considered the minimum requirement for confirmation of cases [bib_ref] Dengue diagnosis, advances and challenges, Guzmán [/bib_ref]. Testing schedules. In the first four days after onset of fever, either RT-PCR or virus isolation are the recommended assays for confirmation of dengue infection [bib_ref] Laboratory diagnosis of primary and secondary dengue infection, Schilling [/bib_ref]. IgM antibody detection is an alternative if virus detection or isolation is negative, but may not be detectable in the early stages of the illness [bib_ref] Dengue in the early febrile phase: viremia and antibody responses, Vaughn [/bib_ref]. After day 4, serology is the method of choice [bib_ref] What does dengue disease surveillance contribute to predicting and detecting outbreaks and..., Runge-Ranzinger [/bib_ref]. Paired blood samples collected on days 0-4 of illness and days 10-21 of illness are necessary for definitive serological diagnosis by IgM seroconversion. Where possible, IgG antibody detection should also be performed, particularly on suspected secondary dengue infections due to the absence of IgM antibody in up to 30% of those cases [bib_ref] Analysis of specific IgM responses in secondary dengue virus infections: levels and..., Chanama [/bib_ref]. A four-fold increase in titer of IgG is also consistent with a recent dengue infection, but IgG antibodies are not dengue-specific and may have been caused by flaviviruses other than dengue [bib_ref] Dengue in the early febrile phase: viremia and antibody responses, Vaughn [/bib_ref]. Quality assurance and control. Support should be provided for quality control, proficiency testing and good laboratory practice at the WHO reference laboratory level, the national level and the local level. Every assay should include standards (i.e. positive, negative and cut-offs). Experience and methodologies should be shared. Financial support for reagent production and distribution to national laboratories would reduce some variability in results and reduce cost. In the past, several WHO reference laboratories provided reagents free of charge on request to national laboratories. This improved comparability of results but was not financially sustainable. ## Reporting At least weekly reporting of aggregate results was considered by the attendees as the minimum standard during peak transmission. To conserve resources, reporting could be reduced to biweekly during periods of low transmission. During an outbreak, more frequent reporting, perhaps on a daily basis, would be useful. However, it is important to note that reporting would be affected by the operating hours of the reporting facilities (e.g. facilities closed on weekends or holidays could artificially reduce reported cases and create surveillance artifacts). Reports should reach the surveillance units within 48 hours of form completion. Especially since dengue occurs frequently in young adults in Southeast Asia, it is recommended that the usual categories for reporting in health information systems should be used, namely less than 1 year, 1-4 years, 5-14 years and older than 15 years. However, reporting the median age of cases across all ages is also a useful statistic to track, and may be more useful for comparison if countries are using different age categories. Moreover, if the median age is reported by countries not including cases of all ages because the peak incidence is in children, the overall age distribution could be modeled with the available data. Electronic reporting systems should be developed and used broadly and such applications would facilitate formal reporting among countries. # Analysis and feedback Meeting attendees emphasized the need to determine the incidence of severe cases through measurement of incidence rates of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, with hospitalization rates and mortality rates broken down by age group consistently applying the WHO regional case definitions. Weekly incidence of dengue, with data stratified by age, gender, and location should also be rapidly reported to allow effective use of vector control resources and to monitor intervention programs. In addition analyses should be conducted to detect and forecast dengue outbreaks through determination of the national threshold for outbreak alert and response [bib_ref] Casta-Vélez A (1999) A deviation bar chart for detecting dengue outbreaks in..., Rigau-Pérez [/bib_ref] , to monitor the seasonality, age distribution, and transmission patterns and to evaluate and guide the introduction of potential dengue vaccines. Vector surveillance requires baseline data for comparisons. When relevant data are available, analyses should be conducted to identify locations and patterns of the vector population (species, density, and vector-control indices) and should also be used to monitor interventions (with disease reduction as a measure of impact, and house index, container index, and Breteau index as indicators of outcome). In conclusion, the two Dengue Prevention Boards met to discuss the practice and logistics of dengue surveillance. The attendees applied their practical experience and discussed the strengths and weakness for the countries represented at the meeting. They then suggested best practices in dengue surveillance in endemic countries. For PDVI, improved surveillance serves many purposes including generating more accurate estimates of disease burden, further demonstrating the need for a dengue vaccine, supporting clinical evaluations of candidate dengue vaccines and providing more robust surveillance for monitoring the impact of the eventual introduction of dengue vaccines in national immunization programs. [fig] Figure 1: Countries with local dengue transmission in the last 25 years [2]. doi:10.1371/journal.pntd.0000890.g001 [/fig] [fig] Figure 2: Timeline showing transmission cycle, clinical disease, and surveillance events. After the first infection results in clinical disease several additional infections occur before a public health response occurs in response to the index case. doi:10.1371/journal.pntd. [/fig] [table] Table 1: Characteristics of national surveillance systems. Case definition used for dengue surveillance was same as World Health Organization Region Office recommended definition: WPRO = Western Pacific Regional Office; SEARO = Southeast Asia Regional Office; Pan American Health Organization; Method of case ascertainment by national dengue surveillance system: active, passive or sentinel site surveillance;Source or location where cases are detected: OP = Outpatient clinics; IP = Inpatient or hospitalized;Reporting of dengue cases is mandated by law;Mosquito surveillance is included as part of the national surveillance system and is not just in response to outbreaks. doi:10.1371/journal.pntd.0000890.t001Surveillance Best Practices www.plosntds.org [/table] [table] Table 2: Dengue surveillance data from countries represented at the Prevention Board Meetings. USA-Mexico border only. Additional websites with current dengue data: PAHO: http://www.paho.org/english/ad/dpc/cd/dengue.htm; Asian ArboNet: http://www.nih.go.jp/vir1/NVL/ DengueNet%20Web/ToppageArboNet.htm; Caribbean Epidemiology Centre: http://www.carec.org/; WHO: http://www.who.int/globalatlas/default.asp. [/table]	None	https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0000890&type=printable	Background Dengue fever is a virus infection that is spread by the Aedes aegypti mosquito and can cause severe disease especially in children. Dengue fever is a major problem in tropical and sub-tropical regions of the world. Methodology/Principal Findings We invited dengue experts from around the world to attend meetings to discuss dengue surveillance. We reviewed literature, heard detailed reports on surveillance programs, and shared expert opinions. Results Presentations by 22 countries were heard during the 2.5 day meetings. We describe the best methods of surveillance in general, the stakeholders in dengue surveillance, and the steps from mosquito bite to reporting of a dengue case to explore how best to carry out dengue surveillance. We also provide details and a comparison of the dengue surveillance programs by the presenting countries. Conclusions/Significance The experts provided recommendations for achieving the best possible data from dengue surveillance accepting the realities of the real world (e.g., limited funding and staff). Their recommendations included: (1) Every dengue endemic country should make reporting of dengue cases to the government mandatory; (2) electronic reporting systems should be developed and used; (3) at minimum dengue surveillance data should include incidence, hospitalization rates, deaths by age group; (4) additional studies should be completed to check the sensitivity of the system; (5) laboratories should share expertise and data; (6) tests that identify dengue virus should be used in patients with fever for four days or less and antibody tests should be used after day 4 to diagnose dengue; and (7) early detection and prediction of dengue outbreaks should be goals for national surveillance systems.
0bae76a6eefd0e0dd4da2adca5aaf86be47e3b5b	pubmed	Nuclear Medicine: Guidelines for the Provision of a Clinical Service	Nuclear Medicine: Guidelines for the Provision of a Clinical Service # Introduction Purpose of this report There are no published guidelines on notional sessional commitments for consultants in nuclear medicine. Individual consultants have approached the Royal College of Physicians Nuclear Medicine Committee (RCP NMC) indicating they would find such guidelines useful in negotiations with management for example when negotiating for supporting staff, which currently many lack, and when requesting additional sessions, often in competition with larger specialties. Guidelines are also needed by management to assist them in making provision for medical cover particularly in a new specialty or when taking decisions about centralising a hitherto dispersed service. In making recommendations concerning the quantification of consultant time for nuclear medicine specialists, this report does not include discussion of the benefits for centralising departments this is an important but separate issue. The purpose of this document is to give professional guidance on levels of consultant time required for the provision of a safe and effective clinical service. While producing this guidance, the working group has been mindful of the limited resources within the NHS and has been conservative in its assessment of the level of need for medical cover. ## Definition of nuclear medicine The World Health Organisation has defined nuclear medicine as: that specialty which embraces all applications of radioactive materials in diagnosis or treatment or in medical research, with the exception of the use of sealed radiation sources in radiotherapy1. The broad range of nuclear medicine procedures includes treatment of many different disease states in both adults and children. Examples of common diagnostic procedures include ventilation-perfusion imaging for pulmonary embolism, bone scanning in benign and malignant disease, myocardial perfusion studies in ischaemic heart disease, and renal investigations in a variety of conditions (assessment of renal transplant, assessment of obstructed kidney). The most common therapeutic procedure is the use of radioiodine in the treatment of thyrotoxicosis; others include treatment in thyroid cancer, alleviating bone pain in malignancy, and the treatment of polycythaemia. The unique ability to study physiological and pathological processes by non-invasive methods means that nuclear medicine procedures are used extensively for research. This research includes the use of established techniques in the assessment of new drugs or procedures (for instance, gated blood pool scanning is used to assess the cardiotoxicity of new drugs in oncology), and also the development of new radiopharmaceuticals and procedures for assessment and therapy in specific disease processes (examples include cerebral blood flow studies and receptor, antibody or peptide imaging). Positron emission tomography (PET) scanning has been used in research for a number of years and is now making the transition into clinical practice in oncology, cardiology and neurology. Responsibilities of the nuclear medicine specialist Nuclear medicine specialists are responsible for the provision of the clinical services outlined above. Their duties include the selection, supervision and reporting of diagnostic investigations, assessing patients for therapy and providing appropriate follow up, audit, research and teaching. As heads of departments, many consultants have managerial roles and are also budget holders. However, there are unique legal responsibilities for those practising nuclear medicine, with certification required for all diagnostic, therapeutic and research procedures. The precise range of responsibilities of a nuclear medicine consultant varies due to a number of factors such as the size and type of hospital served and the hospital's commitment to teaching and research. Another important factor is the degree of centralisation of the nuclear medicine services. In some hospitals all nuclear medicine procedures are directed from one specialist department, whereas in others, individual specialists, radiologists, radiotherapists or clinicians are responsible for individual areas, either for the hospital service as a whole or for their own individual patients. For administrative, financial and legal reasons, there is a trend to centralise nuclear medicine services this trend is being seen in the UK and already exists in most of Europe, Australasia and North America2. Method A working group of the RCP NMC was appointed to make recommendations on adequate consultant staffing levels for nuclear medicine departments. The working group, one of whom had been nominated by the British Nuclear Medicine Society (BNMS), comprised four members: an academic professor, two consultants from teaching hospitals and a consultant from a district general hospital. The working group considered several ways of assessing workload, and ultimately used a system of identifying nominal time for a number of different consultant responsibilities, weighting these for different departmental models. The total time identified was then compared with sessional time in several known departments, including those thought to be adequately staffed and those perceived to be understaffed. The modelling was refined until the theoretical and practical models approximated this in fact proved much easier than anticipated. The contribution of specialist trainees to the provision of service was considered, but was excluded as many departments do not have trainees; in those that do, their numbers are small and their service commitment is balanced by the additional commitment to their training by the consultant. Time was estimated for general teaching and training duties. The final assessment has been endorsed by the RCP and the BNMS. # Results ## Status of nuclear medicine in the uk The most up-to-date survey of nuclear medicine practice in the UK was published recently2. There appear to be 235 sites undertaking procedures in nuclear medicine, the total number of procedures performed being approximately 490,000 in 1993 compared with 430,000 in 1989. There are wide variations in staffing levels, with only 22% of departments having medical cover of half-time equivalent or better, with 30% of departments having less than one consultant session per week. An annual growth rate of 7% was noted in imaging procedures. In the European Community, in terms of instrumentation (gamma cameras) per million inhabitants, Belgium leads with 22, Germany follows with 21, Italy has the median number with 10 and the UK is listed last with only 5 instruments per million population3. The UK lies 9th of 11 countries in the number of studies per head of population and 10th of 11 for studies per camera4. Whilst diagnostic procedures in nuclear medicine in the USA correspond to 5.6 per bed per annum, an equivalent figure for the UK is significantly less by at least a factor of 10. In 1988/9 the estimated annual rate of all nuclear cardiology procedures was 0.7 per thousand population in the UK. This compares with 4 per thousand in the USA over the same time period. A Council Statement from the British Cardiac Society on manpower and the need for cardiac services sets a target of approximately 2.6 nuclear cardiology investigations per thousand population per year, which once achieved, would accord with the European average5. Thus it is clear that there is an unfulfilled demand for nuclear medicine services in the UK, insufficient medical staffing levels and a significant number of regions in the country where nuclear medicine is practised with only a minimal, if not absent, medical cover. This is in clear breach of national legislation or guidance notes6-8, and together with with the high level of public concern about radiation, poses a serious risk of nuclear medicine services becoming a matter for media debate. Medical staffing for nuclear medicine Tables la and b give the minimum requirements for consultant staffing levels, in terms of workload, for five types of hospitals, ranging from a small district general hospital to a large teaching hospital: [fig_ref] Table la: Daily workload estimate of a nuclear medicine consultant for five types of... [/fig_ref] outlines the daily workload, and Table lb the weekly workload. Both tables present a varied case mix ranging from 1,500 investigations per annum in a small DGH to up to 10,000 or more investigations per annum in large teaching hospitals. One of the assumptions made by the working group is one of a notional half-day (NHD) to be equivalent to 3.5 hours. It is also assumed that cover is given by a trained consultant in nuclear medicine, and that such cover will be provided during study and annual leave. In allocating time, consideration has been given to fixed commitments such as those undertaken on a regular basis, eg special procedures, outpatient clinics, interdisciplinary meetings, teaching, ward rounds and TH: Teaching hospital Note: In all cases these figures assume cover by a trained consultant in nuclear medicine. It is also assumed that such cover will be provided during study and annual leave. No consideration has been given above for the new requirements which are a consequence of the Caiman proposals, on-call duties, cover for leave of other staff and multi-sited organisations. management, and flexible commitments, such as immediacy and continuity of care, administrative work, teaching and training. No specific consideration has been given to local circumstances such as multi-sited organisations which would entail greater time commitment in view of considerable wastage in travelling between sites, the new requirements which are a In all cases these figures assume cover by a trained consultant in nuclear medicine. It is also assumed that such cover will be provided during study and annual leave. No consideration has been given above for the new requirements which are a consequence of the Caiman proposals, on-call duties, cover for leave of other staff and multi-sited organisations. consequence of the Caiman proposals, and cover for leave of other staff. On-call duties have not been considered, although they may represent a time commitment for the larger hospital environments. The appropriate mix between fixed and flexible sessions per week has not been considered on the assumption that this should usually represent an equal mix. # Appendix Standards of delivery of a nuclear medicine service The British Nuclear Medicine Society offers purchasers of nuclear medicine services the following policy statement on standards for the safe practice of Nuclear Medicine9. 3 UK licensed products shall be used except when written authorisation on an individual patient basis is provided by the clinician holding the relevant ARSAC certificate. 4 The provider site shall hold a certificate of registration for the keeping and use of radioactive materials and be appropriately authorised to accumulate and dispose of radioactive waste in accordance with relevant current legislation, unless exempt from so doing. 5 Procedures shall be in place to ensure that the transport of radioactive materials meets relevant current legislation. 6 Measures to monitor and control the radiation exposure of patients, staff and members of the public must satisfy the requirements of relevant current legislation. 7 The policies, procedures and delivery of the service shall be subject to organisational audit at agreed intervals. 8 All investigations or therapies shall be performed only on receipt of forms signed by a medical practitioner, and these forms shall be made available by the provider unit. 9 Audit standards for the delivery of the service shall be agreed to include the range of services to be supplied, interval between request and appointment and other quality measures. 10 An adequate staff mix for the safe delivery of the service and appropriate patient care shall be in place. 11 Services shall be provided in an environment which is conducive to good patient care, with particular emphasis on cleanliness, timeliness, pleasant attitude and appearance of staff. Patient privacy, dignity and ethnic origin shall be respected. 12 All research procedures shall be performed in accordance with the terms of the Local Research Ethics Committee and the ARSAC certificate specific to that project. D Equipment and facilitiesThe service shall be delivered through safe equipment that meets current accepted standards of performance. [table] Table la: Daily workload estimate of a nuclear medicine consultant for five types of hospitals [/table] [table] Table 1 b: Weekly workload estimate of a nuclear medicine consultant for five types of hospitals [/table] [table] 2: Performance of equipment, in particular gamma cameras and dose calibrators, shall be assessed at suitable intervals. Records shall be maintained and be available on request. Radiation monitoring, imaging, counting and data processing facilities appropriate to the level of service shall be available. Advisory Committee of the DoH set up under the Medicines (Administration of Radioactive Substances) Regulations 1978 (SI 1978 No 1006) and the Medicines (Radioactive Substances) Order 1978 (SI No 1004). [/table]	None	None	None
0d1f9d483350def86c4fca3e7676a0a37cdb9601	pubmed	Management of congenital nephrotic syndrome: consensus recommendations of the ERKNet-ESPN Working Group	Management of congenital nephrotic syndrome: consensus recommendations of the ERKNet-ESPN Working Group \| Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders characterized by nephrotic-range proteinuria, hypoalbuminaemia and oedema, which manifest in utero or during the first 3 months of life. The main cause of CNS is genetic defects in podocytes; however, it can also be caused, in rare cases, by congenital infections or maternal allo-immune disease. Management of CNS is very challenging because patients are prone to severe complications, such as haemodynamic compromise, infections, thromboses, impaired growth and kidney failure. In this consensus statement, experts from the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology (ESPN) summarize the current evidence and present recommendations for the management of CNS, including the use of reninangiotensin system inhibitors, diuretics, anticoagulation and infection prophylaxis. Therapeutic management should be adapted to the clinical severity of the condition with the aim of maintaining intravascular euvolaemia and adequate nutrition, while preventing complications and preserving central and peripheral vessels. We do not recommend performing routine early nephrectomies but suggest that they are considered in patients with severe complications despite optimal conservative treatment, and before transplantation in patients with persisting nephrotic syndrome and/or a WT1-dominant pathogenic variant.PodocytesHighly specialized glomerular epithelial cells that are the main components of the glomerular filter.✉ Congenital nephrotic syndrome (CNS) is characterized by nephrotic-range proteinuria and oedema that manifest in utero or during the first 3 months of life [bib_ref] Management of congenital nephrotic syndrome of the Finnish type, Holmberg [/bib_ref]. In rare cases, CNS can be caused by congenital infections or maternal allo-immune disease, but most cases are caused by genetic defects in podocytes 2 . Several genes have been implicated in the aetiology of isolated CNS (most commonly NPHS1, which encodes nephrin [bib_ref] Positionally cloned gene for a novel glomerular protein -nephrin -is mutated in..., Kestila [/bib_ref] [bib_ref] Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome, Machuca [/bib_ref] ; NPHS2, which encodes podocin; WT1, which encodes Wilms tumour protein 1; and PLCE1, which encodes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase ε1) or in less common syndromic forms of the disease (most commonly WT1 or LAMB2, which encodes laminin subunit β-2) 5, [bib_ref] Exploring the genetic basis of early-onset chronic kidney disease, Vivante [/bib_ref]. As pathogenic variants in these genes alter the physiology of podocytes, genetic forms of nephrotic syndrome are now referred to as podocytopathies [bib_ref] Educational paper: the podocytopathies, Buscher [/bib_ref]. Patients with CNS are prone to severe complications such as haemodynamic instability, recurrent infections, thromboses and impaired growth. Most children with CNS progress to kidney failure within a few years [bib_ref] Management of congenital nephrotic syndrome of the Finnish type, Holmberg [/bib_ref] [bib_ref] The nephrotic syndrome and its complications, Cameron [/bib_ref] [bib_ref] Management of Finnish congenital nephrotic syndrome by unilateral nephrectomy, Coulthard [/bib_ref] [bib_ref] Congenital nephrotic syndrome of Finnish type. Study of 75 patients, Huttunen [/bib_ref] [bib_ref] Congenital nephrotic syndrome, Jalanko [/bib_ref] [bib_ref] Infections in infants with congenital nephrosis of the Finnish type, Ljungberg [/bib_ref]. In Finland, between 1965 and 1973, the mean survival of patients with CNS was reported to be 7.6 months (range 0-26 months) with most infants dying owing to infection or haemodynamic collapse [bib_ref] Congenital nephrotic syndrome of Finnish type. Study of 75 patients, Huttunen [/bib_ref]. In 1995, an aggressive treatment regimen including dialysis, early nephrectomy and transplantation was proposed and led to a dramatic improvement in survival [bib_ref] Management of congenital nephrotic syndrome of the Finnish type, Holmberg [/bib_ref]. With this regimen, more than 90% of patients with CNS could be transplanted with similar kidney and overall survival to other transplanted children [bib_ref] Management of congenital nephrotic syndrome of the Finnish type, Holmberg [/bib_ref] [bib_ref] Timing of renal replacement therapy does not influence survival and growth in..., Holtta [/bib_ref]. Subsequently, numerous reports have emerged of successful treatment using a conservative approach involving optimized nutrition and medications without nephrectomy [bib_ref] Management of children with congenital nephrotic syndrome: challenging treatment paradigms, Dufek [/bib_ref] [bib_ref] Treatment and outcome of congenital nephrotic syndrome, Berody [/bib_ref]. In 2018, a joint initiative of the European Reference Network for Rare Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology (ESPN) established a Work Group to develop guidelines for the clinical diagnosis, management and treatment of CNS. As evidence regarding the optimal management of CNS is frequently missing or inadequate, here we provide a consensus report based on expert opinion rather Management of congenital nephrotic syndrome: consensus recommendations of the ERKNet-ESPN Working Group than a clinical practice guideline. The genetic aspects of the hereditary forms of CNS are discussed further in a separate consensus statement [bib_ref] Genetic aspects of congenital nephrotic syndrome: a consensus statement from the ERKNet-ESPN..., Lipska-Ziętkiewicz [/bib_ref]. # Methods We followed the RIGHT (Reporting Items for practice Guidelines in HealThcare) statement for practice guidelines [bib_ref] A reporting tool for practice guidelines in health care: the RIGHT statement, Chen [/bib_ref] and used the Delphi method. Three groups were assembled: a core leadership group, an external expert group and a voting panel. The core group comprised nine members of ERKNet and ESPN, including paediatric nephrologists and kidney geneticists, as well as a neonatologist, a kidney nurse and a patient representative (Supplementary [fig_ref] Table 1 \|: Follow-up for a child with CNS [/fig_ref]. The external expert group included six paediatric nephrologists, an adult nephrologist, a kidney geneticist, a kidney pathologist, a paediatric pharmacologist, a neonatologist, a paediatric endocrinologist, an ethicist, a nurse and a patient representative, and the voting panel comprised 35 paediatric nephrologists from the ESPN nephrotic syndrome working group. The core group wrote the first draft of the consensus statement. Using an e-questionnaire, the members of the external expert group were asked to provide a level of agreement on the recommendations in the first draft using a five-point scale (strongly dis agree, disagree, neither agree nor disagree, agree, strongly agree). Recommendations that did not reach a consensus of at least 70% were revised by the Core group. The revised draft was then sent to the voting panel. Recommendations that still did not reach a consensus of at least 70% were revised by the Core group and resent to the external experts and the process was repeated until a consensus level of at least 70% was achieved. ## Pico questions We developed PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions for this consensus statement [bib_ref] GRADE guidelines: 2. Framing the question and deciding on important outcomes, Guyatt [/bib_ref]. The population was children with CNS (defined as onset of nephrotic syndrome within the first 3 months of life) before and after the initiation of dialysis or kidney transplantation. The intervention was treatment and the comparators were either no treatment or other treatment. The outcomes were recommendations for diagnosis, treatment and follow-up of children with CNS. ## Literature search The following key words were used to identify relevant studies published before 31st December 2018: nephrotic syndrome, congenital nephrotic syndrome, Galloway Mowat Syndrome, Pierson Syndrome, Frasier Syndrome and Denys Drash Syndrome. The search retrieved 1,367 results but no randomized clinical trials; 54 articles are referenced in the consensus statement. Further details and a summary of the publications used for this consensus statement are included in . ## Diagnosis Infants with CNS present with nephrotic-range proteinuria and oedema with or without kidney failure. The diagnosis and management require expertise and a combined approach that can only be guaranteed in a centre with experience in treating this condition. ## Multidisciplinary management We recommend that all patients with CNS are referred to specialized teams in tertiary paediatric nephrology centres and managed by multidisciplinary teams, including neonatologists, paediatric nephrologists, paediatric nephro logy nurses, paediatric renal dieticians, paediatric surgeons, child and/or youth psychologists and social workers (Box 1). The psychosocial pressure that is often experienced by families with a child with CNS must be taken into account to enable successful management. All members of the multidisciplinary team must be trained in child care. When children with CNS are managed outside of a transplant facility, we recommend that they are introduced to a transplant centre early in the progression of their chro nic kidney disease (CKD), with the aim of minimizing time on dialysis and facilitating the transplant process. ## Initial diagnostic work-up In infants with CNS, we recommend performing the initial diagnostic work-up as presented in Extended diagnostic work-up aimed at identification of non-kidney manifestations of hereditary forms of CNS should also be considered (such as assessment of neurological status, sight, hearing, dysmorphic features and abnormal genitalia). The possible signs and symptoms of syndromic forms of CNS are discussed further in a separate consensus statement [bib_ref] Genetic aspects of congenital nephrotic syndrome: a consensus statement from the ERKNet-ESPN..., Lipska-Ziętkiewicz [/bib_ref]. ## Genetic testing Identification of a genetic cause of CNS establishes the aetiology, informs management, particularly with regard to the potential development of Wilms tumour or neurological involvement, and enables genetic counselling of the family. We therefore recommend genetic screening as a first-line diagnostic measure in every patient with CNS. The preferred method of genetic testing is massively parallel sequencing, with rapid whole-exome sequencing being the method of choice. In countries where rapid whole-exome sequencing is not yet clinically available, use of an extended podocytopathy gene panel is recommended owing to the wide phenotypic variability and genetic heterogeneity of the disease 4,5,18-21 . The minimum set of genes to be tested should include NPHS1, NPHS2, WT1, PLCE1 and LAMB2. Screening of these genes identifies underlying genetic abnormalities in >80% of patients with CNS [bib_ref] Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome, Machuca [/bib_ref] [bib_ref] A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome, Sadowski [/bib_ref] [bib_ref] Nephrotic syndrome in the first year of life: two thirds of cases..., Hinkes [/bib_ref] [bib_ref] Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry..., Trautmann [/bib_ref] [bib_ref] Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome, Mccarthy [/bib_ref] [bib_ref] Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a..., Bierzynska [/bib_ref] [bib_ref] Genetic abnormalities and prognosis in patients with congenital and infantile nephrotic syndrome, Cil [/bib_ref]. A dozen other less commonly mutated genes account for an additional ~5% of diagnoses. A clinical presentation that is suggestive of a particular syndromic form of CNS, such as Denys Drash Syndrome or Pierson Syndrome, or Finnish ethnicity, which is associated with founder pathogenic variants in NPHS1, may lead to direct testing of the suspected causative gene. Disclosure of the results of genetic testing should involve recurrence risk counselling by a clinical geneticist or clinical counsellor. Families should be informed of the available options for prenatal testing as well as their risks to enable them to make an informed choice when considering whether to undergo such testing in subsequent pregnancies. Decisions regarding prenatal diagnostic testing, including pre-implantation diagnostics, should be discussed in light of the local financial, social and legal setting [bib_ref] ESHG Public & Professional Policy Committee. Genetic testing and common disorders in..., Van El [/bib_ref]. The gene-specific management of CNS is detailed elsewhere [bib_ref] Genetic aspects of congenital nephrotic syndrome: a consensus statement from the ERKNet-ESPN..., Lipska-Ziętkiewicz [/bib_ref]. Notably, children with the exonic WT1 pathogenic variant must be monitored for Wilms tumour by performing abdominal ultrasound every 3 months until the age of 7 years 25 . ## Histopathology As genetic screening identifies the underlying genetic abnormality in >85% of patients with CNS, non-invasive molecular diagnostic methods have largely replaced kidney biopsy in these patients [bib_ref] Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome, Machuca [/bib_ref] [bib_ref] A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome, Sadowski [/bib_ref] [bib_ref] Nephrotic syndrome in the first year of life: two thirds of cases..., Hinkes [/bib_ref] [bib_ref] Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry..., Trautmann [/bib_ref] [bib_ref] Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome, Mccarthy [/bib_ref] [bib_ref] Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a..., Bierzynska [/bib_ref] [bib_ref] Genetic abnormalities and prognosis in patients with congenital and infantile nephrotic syndrome, Cil [/bib_ref]. We do not recom mend routine kidney biopsy in patients with CNS. Kidney biopsy may be indicated in patients for whom a genetic diagnosis cannot be established or in those with a substantial reduction in eGFR (i.e. to <30 ml/min/ 1.73 m²) for whom a biopsy sample could be informative in establishing a rare diagnosis (such as congenital membranous nephropathy due to anti-neutral endopeptidase (NEP) antibodies or other glomerulopathies) and in estimating prognosis. ## Symptoms of mitochondrial disease In patients with CNS, the following findings suggest an underlying mitochondrial disease: nystagmus, retinitis pigmentosa, visual impairment or loss, sensorineural deafness, developmental delay, cognitive impairment, hypotonia, seizure, encephalopathy, cardiomyopathy, feeding difficulties, liver failure, progressive muscle weakness, diabetes mellitus, lactic acidaemia, increased serum creatinine kinase, anaemia and/or pancytopenia. A few case reports exist of remarkable improvements in kidney function, but not in neurological sequelae, with coenzyme Q10 (CoQ10) supplementation in patients with CNS owing to mitochondrial disease [bib_ref] ADCK4 deficiency destabilizes the coenzyme Q complex, which is rescued by 2,4-Dihydroxybenzoic..., Widmeier [/bib_ref] [bib_ref] Response to early coenzyme Q10 supplementation is not sustained in CoQ10 deficiency..., Eroglu [/bib_ref]. We therefore suggest initiating a therapeutic trial of CoQ10 in patients with symptoms consistent with mitochondrial disease even before receiving the results of genetic testing. This therapy should be discontinued if no improvement in kidney function or substantial decrease in proteinuria is observed after 4-6 weeks 15 . Therapeutic management CNS encompasses a wide spectrum of clinical phenotypes that should be managed with different approaches in specialized units. Some newborns and infants present with no or minimal symptoms and should not be given aggressive and potentially dangerous treatments, whereas others are critically ill with massive protein uria, anasarca and haemodynamic compromise, and may require daily albumin infusions via a central venous line (CVL) and intensive symptomatic treatments to avoid complications. Management should therefore be adapted to the clinical severity of the condition with the aim of maintaining intravascular euvolaemia and adequate nutrition, as well as preventing complications (Box 3). As is typical for such a rare disease, considerable variability exists in clinical practice, with some centres aiming to avoid intensive treatment. As no conclusive clinical data, such as the results of randomized clinical trials, are available, we propose an opinion-based management algorithm for children with CNS [fig_ref] Figure 1 \|: Opinion-based management algorithm for CNS [/fig_ref]. ## General approach We recommend rapid referral of children with CNS to a specialized paediatric nephrology unit. These children are often born prematurely and amniotic fluid may be stained with meconium but ventilator therapy is rarely needed. Pregnancy is usually uneventful. Given the wide variation in clinical findings in infants with CNS, individualized therapy is needed, with a number of key objectives: preserve all central and peri pheral arteries and veins for potential dialysis access; avoid peripherally inserted catheters and unnecessary venepunctures [bib_ref] KDOQI Vascular Access Guideline Work Group. KDOQI clinical practice guideline for vascular..., Lok [/bib_ref] administration of salt-containing fluids; prevent thrombosis, particularly in patients with a CVL or hypovolaemia; and treat infection when clinically suspected by starting empiric antibiotics before culture results are available. C-reactive protein and leuko cyte levels are not reliable indicators of septicaemia in patients with CNS 1 . ## Fluid management As no studies have investigated specific treatments for oedema in CNS, treatment should focus on assessment of volume status (that is, overfill versus underfill) and salt restriction, as recommended for adult patients [bib_ref] Over-or underfill: not all nephrotic states are created equal, Bockenhauer [/bib_ref]. Fluid restriction is advocated for hyponatraemia and in the most severe cases of oedema. Fluid prescription in patients with CNS should primarily be used to provide adequate nutrition. Intake of fluid should be limited, when feasible, by using concentrated high-calorie formulas to meet age-related energy needs, guided by the advice of expert renal dieticians. Intravenous albumin is the treatment of choice for acute symptomatic hypovolaemia (see below). ## Albumin infusions The use of albumin infusions in children with CNS varies between centres. Some centres administer intravenous albumin only when deemed clinically indicated, whereas others use regular albumin infusion protocols (1-4 g/kg/day). Potential advantages of regular albumin infusions are replacement of lost protein to support growth and psychomotor development, stabilization of intravascular volume and minimization of oedema 1 . The disadvantages of regular albumin infusions are the need for a central line, which increases the risk of infection and/or thrombosis of large vessels, which endangers future haemodialysis access, the need for prolonged hospitalization (although home administration has been reported 30 ) and the associated costs. Retrospective studies show no difference in long-term outcomes with these two strategies [bib_ref] Management of children with congenital nephrotic syndrome: challenging treatment paradigms, Dufek [/bib_ref] [bib_ref] Treatment and outcome of congenital nephrotic syndrome, Berody [/bib_ref]. As most of the infused albumin is lost in the urine within hours, the purpose of albumin infusion is not to normalize serum albumin levels but to support intravascular volume and reduce extravascular fluid retention in patients with symptomatic hypovolaemia. Symptoms that are suggestive of hypovolaemia are prolonged capillary refill time, tachycardia, hypotension, oliguria and abdominal discomfort. Impacts on quality of life and school attendance should be taken into account when considering regular albumin infusions. We acknowledge that some children with no or minimal symptoms do well without regular albumin infusions and do not need a CVL. Others may need frequent albumin infusions to prevent the clinical consequences of hypo volaemia and failure to thrive. In the latter, we recommend basing the frequency and dosage of albumin infusion on the clinical indicators of hypovolaemia listed above, rather than on serum albumin levels. In patients with severe disease, daily albumin infusions of up to 1-4 g/kg may be initiated. In stable patients or when CKD progresses, albumin dose may be reduced and infusions might subsequently be made less frequent or even stopped [bib_ref] Management of children with congenital nephrotic syndrome: challenging treatment paradigms, Dufek [/bib_ref] [bib_ref] Treatment and outcome of congenital nephrotic syndrome, Berody [/bib_ref]. ## Vascular access When possible, we recommend avoiding CVLs in children with CNS owing to the high risk of thrombosis and the need to preserve the vasculature for future haemodialysis access. However, when regular albumin infusions are inevitable, a CVL becomes necessary. In such cases we recommend administering prophylactic anticoagulation for as long as the line is in place (discussed further below). We also recommend avoiding peripherally inserted catheters and unnecessary venepunctures to preserve arteries and veins for the potential future creation of arteriovenous fistulae [bib_ref] KDOQI Vascular Access Guideline Work Group. KDOQI clinical practice guideline for vascular..., Lok [/bib_ref]. ## Box 2 \| initial work-up for a child with cns ## History - Family history: consanguinity, ethnicity, history of CNS, early infantile death and unsolved neurological and kidney diseases of infancy. - prenatal and perinatal history: enlarged prenatal nuchal translucency, increased amniotic fluid alpha-fetoprotein, fetal oedema, oligohydramnios and placental weight >25% of newborn weight. - patient history: fever episodes, pain, abdominal discomfort, swelling, fatigue. ## First-line evaluation - Growth chart: height or length, weight, head circumference if aged <2 years, calculation of Bmi and annual height velocity. - Blood pressure. - physical examination: volaemia, signs of oedema (e.g. ascites, pericardial and pleural effusions). - Blood biochemistry: blood count, levels of sodium, chloride, albumin, magnesium, creatinine, urea, protein, albumin, cholesterol, fasting triglycerides and glucose. - levels of thyroid-stimulating hormone and free thyroxine (T4). - Serum igG level. - Serum levels of ionized calcium, phosphate, alkaline phosphatase, pTH, 25(oH) vitamin D3. - ultrasound of abdomen and pleural space (kidney echogenicity and size, ascites, effusions and thrombosis). - Cardiac ultrasound (effusions and left ventricular mass). ## Extended evaluation - evaluation of dysmorphic features and skeletal abnormalities, genital examination, ophthalmological examination, hearing test. - Full neurological examination and standardized assessment of cognitive status with or without brain mri. - Serology for syphilis, toxoplasmosis, Cmv, rubella, measles, HBv, HCv, HSv1, HSv2, HZv, Hiv and Bordetella pertussis (if the mother or infant has not already been screened for these infections). - Further screening in selected patients in endemic areas or in the case of clinical suspicion: malaria, anti-nuclear antibodies, serum complement (C3 and C4), anti-neutral endopeptidase (Nep) antibodies, amino acids (for diagnosis of glutaric aciduria type i or sialic acid storage disease) and/or mercury levels). ## Genetic tests refer to the erKNet-eSpN consensus statement on genetic aspects of congenital nephrotic syndrome [bib_ref] Treatment and outcome of congenital nephrotic syndrome, Berody [/bib_ref]. ## Genetic counselling As appropriate. ## Diet Assessment and advice from a renal dietician, including advice on salt, potassium, calorie and protein intake. ## Renal histology Kidney biopsy is indicated if all other screening is negative, indicating non-infectious, non-genetic CNS. Histological examination should include light microscopy, immunofluorescence and/or immunohistochemistry and electron microscopy. ## Diuretics Diuretics should be used with caution and only in the case of intravascular fluid overload (as evidenced by good peripheral perfusion and high blood pressure), because they could induce or increase hypovolaemia and promote thrombosis (Box 4). In most children with CNS, diuretics improve oedema and fluid control and enable fluid administration to provide adequate nutrition, especially when given in conjunction with albumin infusions [bib_ref] Congenital nephrotic syndrome, Jalanko [/bib_ref]. We recommend considering an intravenous bolus of furosemide (0.5-2 mg/kg) at the end of each albumin infusion [bib_ref] Congenital nephrotic syndrome, Jalanko [/bib_ref] [bib_ref] Management of congenital nephrotic syndrome, Kovacevic [/bib_ref] in the absence of marked hypovolaemia and/or hyponatraemia. In patients with severe oedema, we recommend commencing furosemide at 0.5-2 mg/kg per dose intravenously or orally up to six times daily (maximum 10 mg/kg per day) based on the degree of oedema and diuresis achieved. Adequate monitoring is required and should involve assessment of fluid status, electrolytes (the presence of hypokalaemia or hyponatraemia), blood pressure and kidney function (diuresis and estimated glomerular filtration rate). High doses of furosemide (>6 mg/kg/day) should not be given for periods longer than 1 week and infusions should be administered over 5-30 min to avoid hearing loss [bib_ref] Ototoxic effects and mechanisms of loop diuretics, Ding [/bib_ref] [bib_ref] Avoiding furosemide ototoxicity associated with single-ventricle repair in young infants, Robertson [/bib_ref] [bib_ref] Prevalence and independent risk factors for hearing impairment among very low birth..., Wang [/bib_ref]. Furosemide must be stopped in the case of anuria. In stable patients, furosemide can be given orally at doses of 2-5 mg/kg per day in combination with a thiazide or potassium-sparing diuretic with appro priate monitoring. Experimental evidence suggests that proteases in the urine, such as plasmin [bib_ref] Plasmin in nephrotic urine activates the epithelial sodium channel, Svenningsen [/bib_ref] , directly activate the epithelial sodium channel (ENaC) and thus contribute to salt retention and formation of oedema in patients with nephrotic syndrome [bib_ref] Over-or underfill: not all nephrotic states are created equal, Bockenhauer [/bib_ref] [bib_ref] Plasmin in nephrotic urine activates the epithelial sodium channel, Svenningsen [/bib_ref] [bib_ref] Regulation of ENaCs by proteases: an increasingly complex story, Kleyman [/bib_ref]. As this direct activation of ENaC is independent of the mineralocorticoid receptor, it will not be inhibited by mineralocorticoid receptor blockers such as spironolactone. Therefore, if potassium-sparing diuretics are used, blockers of the ENaC, such as amiloride, are preferable to spironolactone. ## Anti-proteinuric agents Renin-angiotensin-aldosterone system (RAAS) antagonists (angiotensin-converting enzyme (ACE) inhibitors or angiotensin type I receptor blockers (ARBs)) reduce glomerular protein loss via a dose-dependent haemodynamic effect (i.e. preferential dilatation of the efferent arteriole) [bib_ref] Reduction of proteinuria by angiotensin converting enzyme inhibition, Heeg [/bib_ref]. In adults and older children with proteinuric nephropathies, a 30-50% reduction in proteinuria can typically be achieved with these drug classes [bib_ref] Strict blood-pressure control and progression of renal failure in children, Trial Group [/bib_ref]. In patients with CNS, the clinical effect of RAAS inhibition is usually moderate. A retrospective study reported that serum albumin levels were moderately increased (by a median of 6 g/l) and albumin infusion frequency was reduced in some, but not all, children with CNS who were treated with RAAS inhibitors [bib_ref] Management of children with congenital nephrotic syndrome: challenging treatment paradigms, Dufek [/bib_ref]. When possible, RAAS inhibition should not be used before a post-term age of 4 weeks to avoid interfering with physiological RAAS functions in early postnatal tissue growth [bib_ref] Angiotensin converting enzyme inhibition decreases cell turnover in the neonatal rat heart, Choi [/bib_ref] and/or long-lasting hypotension and oliguric acute kidney injury (AKI) [bib_ref] Side effects of angiotensin converting enzyme inhibitor (captopril) in newborns and young..., Gantenbein [/bib_ref] (Box 5). The short-lasting ACE inhibitor captopril is preferred in young infants owing to its short half-life. RAAS inhibition should be started at a very low dose and gradually increased with frequent monitoring of proteinuria, urine output, serum creatinine and potassium to the maximally effective and tolerated dose. The recommended captopril-dosing scheme for infants younger than 3 months is 0.01-0.5 mg/kg per dose, with a maximum daily dosage of 2 mg/kg. Older infants should receive 0.15-3 mg/kg per dose, with a maximum daily dosage of 6 mg/kg. If a therapeutic effect is observed, children who are in a stable condition may be switched to a long-acting ACE inhibitor (e.g. ramipril 0.1-0.2 mg/kg once daily) or ARB (e.g. candesartan 0.2-0.4 mg/kg once daily). There is no evidence to suggest that combined ACE inhibition and AT1 receptor blockade is more effective in reducing proteinuria than maximized ACE inhibitor or ARB monotherapy in children with CNS. We do not recommend use of such combinations owing to the increased risk of hypotension and AKI [bib_ref] Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of..., Makani [/bib_ref] [bib_ref] Should ACE inhibitors and ARBs be used in combination in children?, Stotter [/bib_ref]. Prostaglandin inhibitors (also called cyclooxygenase inhibitors) can reduce proteinuria by decreasing kidney perfusion and reducing intraglomerular pressure via suppression of renin production in the juxtaglomerular apparatus [bib_ref] Participation of prostaglandins in the control of renin release, Jackson [/bib_ref]. The efficacy of prostaglandin inhibitors in children with CNS is unclear because they are commonly administered in combination with other interventions such as ACE inhibitors, ARBs and/or unilateral nephrectomy. A retrospective study reported that combined treatment with an ACE inhibitor and the prostaglandin inhibitor indomethacin resulted in increased serum protein levels and sufficient growth and development in 4 of 5 children with CNS [bib_ref] A stepwise approach to the treatment of early onset nephrotic syndrome, Licht [/bib_ref]. However, a subsequent study reported similar increases in serum albumin levels in 7 children who received combined ACE inhibitor and indomethacin therapy and 35 children who received ACE inhibitor monotherapy [bib_ref] Management of children with congenital nephrotic syndrome: challenging treatment paradigms, Dufek [/bib_ref]. To avoid adverse effects, such as oliguric AKI and erosive gastritis, non-selective prostaglandin inhibitors, such as indomethacin, should be started after the end of the neonatal period (post-term (adjusted) age >4 weeks) and dosed incrementally from 0.5 mg/kg/day to a maximum of 3 mg/kg/day. Prostaglandin inhibitors should be stopped in patients with advanced CKD (stage 4-5). Co-treatment with H2 blockers and/or proton pump inhibitors is recommended. Alternatively, ## Box 3 \| recommendations for fluid and albumin administration - We recommend rapid referral of children with CNS to a specialized paediatric nephrology unit due to the complexity of the disease and fluid management. - We recommend avoiding intravenous fluids and saline. oral fluid intake should be concentrated if necessary to avoid marked oedema. - We recommend using albumin infusions based on clinical indicators of hypovolaemia (including oliguria, acute kidney injury, prolonged capillary refill time, tachycardia, hypotension and abdominal discomfort) or upon failure to thrive. We do not recommend administering albumin infusions in children with CNS based on serum albumin levels. - When possible, we recommend avoiding central venous lines in children with CNS owing to the high risk of thrombosis. if central venous access is required for repeated albumin infusions, we recommend administering prophylactic anticoagulation for as long as the line is in place (Box 7). volume 17 \| April 2021 \| 281 NATure revieWS \| NEpHROlOGy selective prostaglandin G/H synthase 2 (also known as COX2) inhibitors such as celecoxib can be considered to minimize gastrointestinal adverse effects. Treatment with diuretics, RAAS inhibitors and NSAIDs should be stopped in patients with or at risk of hypovolaemia (for example owing to gastrointestinal symptoms or worsening of hypoalbuminaemia) because they increase the risk of AKI and thrombosis in these patients [bib_ref] AKI in children hospitalized with nephrotic syndrome, Rheault [/bib_ref]. Parents must be informed of the need to stop diuretics, RAAS inhibitors and NSAIDs if their child has vomiting or diarrhoea. ## Nephrectomies In a commonly used treatment protocol for CNS, bilateral nephrectomy is performed and dialysis initiated when the infant weighs around 7-9 kg (6-12 months of age) followed by kidney transplantation a few months later (upon attainment of 10 kg body weight). The mortality of these infants on dialysis is low (6-11%) [bib_ref] Infants with congenital nephrotic syndrome have comparable outcomes to infants with other..., Dufek [/bib_ref] [bib_ref] Peritoneal dialysis in children under two years of age, Laakkonen [/bib_ref] and the risk of thrombotic events and septic infections is reduced after nephrectomy. However, many clinicians provide conservative therapy without nephrectomies and retrospective studies show no apparent difference in outcomes between these different treatment approaches [bib_ref] Management of children with congenital nephrotic syndrome: challenging treatment paradigms, Dufek [/bib_ref] [bib_ref] Treatment and outcome of congenital nephrotic syndrome, Berody [/bib_ref]. An individualized, stepwise approach with prolonged conservative management is therefore an appropriate alternative to early bilateral nephrectomies and dialysis in many children with CNS (Box 6). We suggest considering unilateral or bilateral nephrectomy in patients with severe complications including failure to thrive, thrombosis and/or difficulties in maintaining intravascular euvolaemia, despite optimization of conservative treatment. We recommend performing bilateral nephrectomies before kidney transplantation in patients with persisting nephrotic syndrome and/or a WT1 dominant pathogenic variant. ## Ambulatory management When possible, we recommend ambulatory management of children with CNS to increase their quality of life, decrease their risk of nosocomial infections and reduce treatment costs. Patients with CNS are at risk of sudden deterioration, especially with acute infections. However, a retrospective study demonstrated no apparent difference in complications and long-term outcomes for patients treated in hospital or as outpatients [bib_ref] Treatment and outcome of congenital nephrotic syndrome, Berody [/bib_ref]. Home administration of regular albumin infusions by parents following training by medical staff has been shown to be feasible and safe [bib_ref] Domiciliary administration of intravenous albumin in congenital nephrotic syndrome, Reynolds [/bib_ref]. ## Treatment of non-genetic cns As CNS is most frequently caused by genetic abnormalities that are not targeted by immunosuppressive agents, we do not recommend using these agents to treat children with CNS (Box 7). Anecdotal reports exist of improvements in proteinuria in patients who received steroids and/or ciclosporin. However, these therapies were usually given in combination with ACE inhibitors, which likely explains the reduction in proteinuria [bib_ref] Patients with mutations in NPHS2 (podocin) do not respond to standard steroid..., Ruf [/bib_ref] [bib_ref] Rapid response to cyclosporin A and favorable renal outcome in nongenetic versus..., Buscher [/bib_ref] [bib_ref] Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant..., Hinkes [/bib_ref]. Moreover, spontaneous remission has been reported in some patients with CNS 51 and could potentially explain reports of seemingly beneficial effects of immunosuppressive agents. Negative genetic testing, negative infection screening results and a kidney biopsy sample excluding diffuse mesangial sclerosis should be obtained before considering immunosuppression [bib_ref] Rapid response to cyclosporin A and favorable renal outcome in nongenetic versus..., Buscher [/bib_ref] [bib_ref] Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome, Buscher [/bib_ref]. If comprehensive genetic testing and screening for secondary forms of CNS yield negative results, a trial of immunosuppressive therapy may be considered. ## Congenital membranous nephropathy due to anti-nep antibodies. A small number of infants presenting with a clinical picture of CNS may have congenital membranous nephropathy due to a maternal variant in the MME gene, which encodes the podocyte protein NEP. During pregnancy, the mother becomes sensitized by fetal NEP and produces anti-NEP antibodies that can damage the podocytes of the fetus, leading to nephrotic proteinuria [bib_ref] Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal..., Debiec [/bib_ref] The IgG anti-NEP titres become more elevated in subsequent pregnancies, resulting in a clinical picture ranging from either a miscarriage of the first pregnancy or no symptoms in the first child, to non-nephrotic transient proteinuria or severe CNS with kidney failure in subsequent children. Anti-NEP antibody [bib_ref] Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies, Debiec [/bib_ref] [bib_ref] Genetic homogeneity but IgG subclass-dependent clinical variability of alloimmune membranous nephropathy with..., Vivarelli [/bib_ref] screening should be carried out in patients with CNS who have kidney failure at presentation or transient proteinuria at birth that spontaneously resolves within a few weeks; those who have a family history of siblings with congenital membranous nephropathy or transient proteinuria at birth; and those who have membranous nephropathy on kidney biopsy (Box 7). In all of these cases the mother should also be tested for NEP antibodies. Patient management is mainly symptomatic. Congenital syphilis has re-emerged in many countries after years of declining incidence [bib_ref] Congenital syphilis, Cooper [/bib_ref]. Kidney involvement in untreated newborns and infants can vary from mild proteinuria to nephrotic syndrome, haematuria or AKI, and might be the only presentation of the disease 59 . However, non-kidney features such as anaemia, jaundice, hepatosplenomegaly, cutaneous lesions and neurological symptoms are more frequent symptoms than kidney involvement. Diagnosis is based on the detection of antibodies against Treponema pallidum and T. pallidum haemagglutination assay. Treatment consists of penicillin G (50,000 U/kg intravenously every 12 h in patients aged ≤1 week, every 8 h in those aged >1 week and every 6 h in those aged >1 month) or benzathine penicillin G (50,000 U/kg, intramuscularly, every 24 h for 10-15 days) [bib_ref] Congenital syphilis, Cooper [/bib_ref]. Although >90% of congenital cytomegalovirus (CMV) infections are asymptomatic, CNS has been reported in infected patients. CMV-related CNS is extremely rare; more common presentations of CMV infection are convulsion, paraplegia, sensorineural hearing loss, absence of light reflexes and pulmonary and cutaneous lesions. Diagnosis is based on a positive PCR reaction showing the presence of viral DNA in urine and/or saliva. Treatment consists of ganciclovir (6 mg/kg, every 12 h for 15-21 days) followed by valganciclovir (15 mg/kg, every 12 h for 6 weeks). Of note, plasma concentrations of ganciclovir show large variations in newborns and the standard dose frequently fails to achieve the recommended target area under the concentrationtime curve over 24 h (AUC 0-24 ) of 40-50 µgh/ml 60 . If possible, we suggest measuring ganciclovir AUC in cases of treatment failure and increasing the dose if the AUC is below this target. Rare cases of infection-associated CNS have also been described in patients with congenital toxoplasmosis, hepatitis B and rubella [bib_ref] The etiology of congenital nephrotic syndrome: current status and challenges, Wang [/bib_ref]. Although HIV infection frequently causes nephropathy with proteinuria or nephrotic syndrome in children and adults, no patients with HIV-related CNS have been described to date. ## Complication monitoring and prevention We recommend regular monitoring for and prevention of complications of CNS, including acute complications (such as hypovolaemic and hypervolaemic crisis, intermittent hypertensive and thromboembolic events, and bacterial and viral infections) and chronic consequences of the disease (including hypertension, dyslipidaemia, hypothyroidism, hypomagnesaemia, hypocalcaemia, vitamin D deficiency, bone disease, growth failure and progressive CKD) as well as adverse effects of medications and complications of prematurity (such as hyperbilirubinaemia) (TaBle 1, Box 8). ## Thrombosis prophylaxis Patients with CNS are at risk of developing potentially life-threatening venous or arterial thromboembolic complications, including of the kidney, cerebral and/ or pulmonary vessels [bib_ref] Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease, Kerlin [/bib_ref]. In CNS, the thrombotic risk is ## Box 4 \| recommendations for the use of diuretics - if albumin infusions are given, we suggest administering a dose of furosemide (0.5-2 mg/kg) at the end of each infusion, unless the patient has marked hypovolaemia and/or hyponatraemia. - We recommend using diuretics in patients with signs of intravascular fluid overload (as evidenced by good peripheral perfusion and high blood pressure in combination with oedema) and preserved kidney function. - We recommend using furosemide (0.5-2 mg/kg per dose, intravenously or orally up to six times daily; maximum 10 mg/kg per day) dependent on the degree of oedema and achieved diuresis unless the patient has evidence of intravascular hypovolaemia. Dosages >6 mg/kg per day should not be given for periods longer than 1 week. We recommend administering infusions over 5-30 min to minimize ototoxicity. - if a potassium-sparing diuretic is preferred, we recommend epithelial sodium channel (eNaC) inhibitors such as amiloride over mineralocorticoid inhibitors such as spironolactone. ## Box 5 \| recommendations for antiproteinuric therapy - We recommend administering rAAS-blocking therapy such as ACe inhibitors or ArBs in children with CNS aged >4 weeks. - ACe inhibition should be started with the short-acting ACe inhibitor captopril, escalating the dosage from 0.01 to 0.5 mg/kg per dose in children younger than 3 months (maximum dosage of 2 mg/kg/day). older infants should receive 0.15-3 mg/kg per dose (maximum dosage of 6 mg/kg/day). - We do not recommend combining ACe inhibitors and ArBs owing to the potentially increased risk of acute kidney injury (AKi). - in the case of poor responsiveness to rAAS blockade, we suggest considering the use of prostaglandin inhibitors as an add-on treatment (indomethacin dosed incrementally from 0.5 to 3 mg/kg/day). - We recommend stopping prostaglandin inhibitors if no clinical benefit (that is, increase in serum albumin levels and/or reduction in oedema) is apparent after 2-4 weeks. - in the case of non-kidney volume losses such as vomiting and diarrhoea, routine treatment with rAAS inhibitors, prostaglandin inhibitors and diuretics must be discontinued owing to the high risk of intravascular volume depletion and AKi. volume 17 \| April 2021 \| 283 NATure revieWS \| NEpHROlOGy multifactorial and includes a disease-related hypercoagulability, underlying thrombophilic predisposition and risks related to treatment (such as CVLs or diuretics). An inserted CVL is a strong pro-thrombotic risk factor in the nephrotic state and should be avoided whenever possible. In CNS, hypercoagulability is related to an imbalance between procoagulant and anticoagulant factors [bib_ref] Current and future management of pediatric venous thromboembolism, Kerlin [/bib_ref] [bib_ref] Comprehensive study of haemostasis in nephrotic syndrome, Panicucci [/bib_ref] [bib_ref] Cerebral infarction as a complication of nephrotic syndrome: a case report with..., Yun [/bib_ref]. Urinary leakage of anticoagulant circulating factors (antithrombin III and plasminogen) and low molecular weight procoagulant factors (factor IX and factor XI) results in compensatory liver synthesis of high molecular weight procoagulant factors (fibrinogen, factor V, factor VII, factor VIII and factor X) resulting in hypercoagulability [bib_ref] Nephrotic syndrome. A hypercoagulable state, Kendall [/bib_ref]. Moreover, patients with CNS are deficient in pituitary adenylate cyclase-activating polypeptide, which is a major inhibitor of megakaryopoiesis and of platelet activation, owing to urinary losses of pituitary adenylate cyclase-activating polypeptide bound to ceruloplasmin [bib_ref] Pituitary adenylate cyclase-activating polypeptide (PACAP) in zebrafish models of nephrotic syndrome, Eneman [/bib_ref]. These findings theoretically justify the administration of platelet aggregation blockers in patients with CNS. We suggest that preventive anticoagulation should be considered in all children with CNS and/or a prior thrombosis and during states of increased thrombosis risk (i.e. acute illness, risk of dehydration, inserted central lines and/or thrombocytosis >750,000/ml) (Box 8). The general goal of antithrombotic therapy is to prevent the formation, local extension and recurrence of thrombosis, embolism, and long-term complications. Infusion of antithrombin III (ATIII; 50 units/kg) before the placement of a central venous catheter is recom mended [bib_ref] Congenital nephrotic syndrome, Jalanko [/bib_ref]. Agents that have been used for antithrombotic prophylaxis in nephrotic syndrome include heparin, vitamin K antagonist and aspirin [bib_ref] Comprehensive study of haemostasis in nephrotic syndrome, Panicucci [/bib_ref] [bib_ref] Cerebral infarction as a complication of nephrotic syndrome: a case report with..., Yun [/bib_ref]. Anticoagulation with low molecular weight heparins may be ineffective owing to reduced antithrombin III levels. In Finnish patients with CNS and CVLs, long-term warfarin prophylaxis (target international normalized ratio 2-2.5) has been routinely used for decades and no substantial increase in the risk of bleeding has been observed (T. Hölttä, unpublished data) [bib_ref] IPNA clinical practice recommendations for the diagnosis and management of children with..., Trautmann [/bib_ref]. However, the clinical benefit of warfarin has not been substantiated in a controlled trial. Although early reports suggest that anticoagulation might prevent cerebral thromboses in children with CNS 1 , a recent retrospective outcome study reported that anti-thrombotic prophylaxis with warfarin, heparin or aspirin did not change the incidence of thrombotic events [bib_ref] Management of children with congenital nephrotic syndrome: challenging treatment paradigms, Dufek [/bib_ref]. As aspirin might induce AKI 69 , when considered for patients with CNS it should be used with caution and high doses should be avoided. Case reports exist of successful use of direct-acting oral anticoagu lants that inhibit factor Xa as thromboprophylaxis in adults with nephrotic syndrome [bib_ref] Direct-acting oral anticoagulants as prophylaxis against thromboembolism in the nephrotic syndrome, Sexton [/bib_ref]. Magnesium and calcium supplements should be given to children with CNS when necessary to avoid very low levels that may promote thromboses [bib_ref] Mechanisms involved in the antiplatelet activity of magnesium in human platelets, Sheu [/bib_ref]. ## Infection prophylaxis and management Antibiotics. Infections are a major concern and the primary cause of death in children with CNS 1,10,13,14 . These children are prone to infections caused by encapsulated bacteria such as pneumococci because of urinary losses of IgG and complement opsonins. However, prophylactic antibiotics are not routinely indicated as several studies have shown that they are not associated with a significant reduction in the rate of sepsis [bib_ref] Management of congenital nephrotic syndrome of the Finnish type, Holmberg [/bib_ref] [bib_ref] Infections in infants with congenital nephrosis of the Finnish type, Ljungberg [/bib_ref] [bib_ref] Treatment and outcome of congenital nephrotic syndrome, Berody [/bib_ref]. Appropriate therapeutic antibiotics should be started promptly in patients with proven or suspected acute bacterial infection 1 (Box 8). ## Immunoglobulin infusions. As mentioned above, patients with CNS can have extremely low levels of circulating IgG owing to urinary losses. However, the use of prophylactic intravenous immunoglobulins (IVIGs) is much debated. Arguments against systematic infusions include rapid urinary loss (up to 50% of infused IgG is lost in 30 h) [bib_ref] Altered immunoglobulin status in congenital nephrotic syndrome, Harris [/bib_ref] ; the fact that commercial immunoglobulin preparations contain low titres of IgG against the bacteria that are most commonly responsible for septic episodes (staphylococci, streptococci and Gram-negative bacteria) 1,10 and the high cost of immunoglobulin preparations. IVIG in combination with parenteral antibiotics may be useful to treat septic episodes in children with low plasma IgG levels [bib_ref] Congenital nephrotic syndrome, Jalanko [/bib_ref]. Preventive IVIG infusions may also be considered in the case of low plasma total IgG levels and recurrent and/or severe infections, similar to the management of secondary hypogammaglobulinaemia owing to causes other than CNS. Vaccination. Vaccination should follow the recommended schedule for healthy children, including vaccinating against encapsulated bacteria (especially meningococcal, Haemophilus influenzae and pneumococcal) and varicella-zoster virus (VZV) [bib_ref] Influenza vaccination among children with idiopathic nephrotic syndrome: an investigation of practices, Klifa [/bib_ref] [bib_ref] Prospective study of live attenuated vaccines for patients with nephrotic syndrome receiving..., Kamei [/bib_ref]. We also recommend annual vaccination against influenza. ## Box 7 \| recommendations for management of non-genetic cns - We do not recommend using immunosuppressive drugs to treat children with CNS. - if comprehensive genetic testing and screening for secondary forms of CNS yield negative results, kidney biopsy and a trial of immunosuppressive therapy may be considered in selected cases. - We suggest considering congenital membranous nephropathy owing to anti-Nep antibodies in patients who have kidney failure at presentation, transient proteinuria that resolves spontaneously or siblings with transient proteinuria at birth. - We recommend treating patients with infection-related CNS with specific antimicrobial agents and performing genetic screening in these patients. ## Box 6 \| recommendations for nephrectomies - We do not recommend performing routine early nephrectomies in children with CNS. - We suggest considering unilateral or bilateral nephrectomy in patients with severe complications, including failure to thrive, thrombosis and/or difficulty in maintaining intravascular euvolaemia despite optimization of conservative treatment. - We recommend performing bilateral nephrectomies before kidney transplantation in patients with persisting nephrotic syndrome and/or a WT1-dominant pathogenic variant. ## Megakaryopoiesis The process by which megakaryocytes develop from haematopoietic stem cells. ## Prevention and treatment of vzv infection. In the case of exposure to chickenpox, we recommend treating susceptible patients (i.e. those with hypogammaglobulinaemia who are not immunized against VZV and do not have a history of chickenpox) with VZV immunoglobulins (VZIGs) as soon as possible (Box 8). This strategy may be effective for reducing the severity of chickenpox symptoms when VZIGs are given up to 10 days after exposure. If VZIGs are not available, we recommend prophylactic treatment with oral acyclovir (10 mg/kg four times a day for 7 days) within 7-10 days of exposure to chickenpox [bib_ref] IPNA clinical practice recommendations for the diagnosis and management of children with..., Trautmann [/bib_ref] [bib_ref] Oral acyclovir prophylaxis of varicella after intimate contact, Lin [/bib_ref] [bib_ref] Acyclovir prophylaxis of varicella in children with renal disease receiving steroids, Goldstein [/bib_ref]. Diagnosis of VZV infection relies on clinical features with or without the use of PCR to detect the virus in vesicle samples from the skin. Of note, specific antibody titres are not informative in children with CNS who have nephrotic-range proteinuria and are unreliable in those who are receiving IVIG infusions. We recommend treatment of VZV infection with intravenous high-dose acyclovir for 7-10 days. ## Nutrition, growth and metabolism We recommend a diet with high energy (130 kcal/kg per day) and protein content (4 g/kg per day) but low salt content (<0.5 g per day in babies aged <6 months, <1 g per day in infants aged 7-12 months, <2 g per day in children aged 1-3 years and <3 g/day in children aged >3 years) 81 (Box 8). Patients should be followed by an expert dietician and enteral tube feeding or gastrostomy should be considered in those with insufficient oral intake. Fluid restriction should not compromise caloric intake. There is no evidence that pervasive growth hormone deficiency and growth failure in CNS is likely related to nutritional deficiencies and CKD. If nutritional deficiencies have been excluded, growth hormone (0.045-0.05 mg/kg/day subcutaneously) may be administered from the age of 6 months in children whose height is <3rd percentile, height velocity is <25th percentile and eGFR is ≤60 ml/min/1.73 m 2 (reF. [bib_ref] Clinical practice recommendations for growth hormone treatment in children with chronic kidney..., Drube [/bib_ref]. As a persistently reduced growth rate ultimately results in short stature, growth hormone therapy may also be considered in children with height below the 10th percentile who have a low height velocity (<25th percentile) that persists beyond 3 months in infants and beyond 6 months in children with growth potential, provided that other potentially treatable risk factors for growth failure such as malnutrition or metabolic acidosis have been adequately addressed [bib_ref] Clinical practice recommendations for growth hormone treatment in children with chronic kidney..., Drube [/bib_ref]. Hypothyroidism in CNS occurs as a result of urinary loss of thyroxine-binding proteins. We recommend measuring free thyroxine and thyroid-stimulating hormone (TSH) at disease onset and treating hypothyroidism as indicated by laboratory testing 1 . Children with nephrotic syndrome have low 25-hydroxyvitamin D3 (25-OH-D3) levels owing to urinary loss of vitamin D-binding protein. As total serum calcium levels underestimate calcium content in the presence of hypoalbuminaemia, estimation of vitamin D deficiency is not accurate in these children. We recommend close monitoring of ionized calcium, 25-OH-D3 and parathyroid hormone (PTH) levels in children with CNS and supplementing with oral D3 vitamin (cholecalciferol) or 25-OH-D3 vitamin (calcifediol) and calcium (250-500 mg/day) in those with low 25-OH-D3 and/or low ionized calcium and/or elevated PTH levels. Reduced levels of ionized calcium and elevated PTH levels indicate the need for vitamin D and [bib_ref] Congenital nephrotic syndrome, Jalanko [/bib_ref]. Vitamin D supplementation has been shown to correct vitamin D deficiency in children with nephrotic syndrome [bib_ref] Vitamin D in incident nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study, Selewski [/bib_ref]. We suggest considering use of statins when fasting LDL cholesterol is persistently >160 mg/dl (4.1 mmol/l) [bib_ref] Management of childhood onset nephrotic syndrome, Gipson [/bib_ref] [bib_ref] Evidence-based clinical practice guidelines for nephrotic syndrome, Nishi [/bib_ref] or >130 mg/dl (3.4 mmol/l) in patients with additional cardiovascular risk factors such as hypertension and obesity [bib_ref] Dyslipidemia and cardiovascular health in childhood nephrotic syndrome, Hari [/bib_ref]. ## Anaemia prevention and management Successful correction of anaemia in patients with nephrotic syndrome depends on the underlying cause, which may be one of or a combination of the following: urinary losses of erythropoietin (EPO), iron, transcobalamin and transferrin (transferrin saturation and ferritin level are unreliable in CNS); vitamin B12 and/or copper deficiency; and ACE inhibitor toxicity [bib_ref] Therapy-resistant anaemia in congenital nephrotic syndrome of the Finnish typeimplication of EPO,..., Toubiana [/bib_ref]. Iron deficiency anaemia should be treated with iron supplementation. As massive urinary losses of EPO are expected in CNS, a trial of EPO therapy should be considered in patients with anaemia after correction of iron deficiency. Recombinant human EPO has been reported to be safe and efficacious for the treatment of anaemia in children with nephrotic syndrome [bib_ref] Therapy-resistant anaemia in congenital nephrotic syndrome of the Finnish typeimplication of EPO,..., Toubiana [/bib_ref] [bib_ref] Anemia in nephrotic syndrome: approach to evaluation and treatment, Iorember [/bib_ref]. Increased doses of EPO are often required owing to urinary losses [bib_ref] Therapy-resistant anaemia in congenital nephrotic syndrome of the Finnish typeimplication of EPO,..., Toubiana [/bib_ref] and subcutaneous administration of EPO might be superior to IV administration. We recommend close monitoring of the reticulocyte count as a marker of erythropoiesis and response to therapy (Box 8). Persistent anaemia after 4 weeks of iron and EPO therapy requires further evaluation for other possible contributing factors, such as copper, ceruloplasmin or vitamin B12 deficiency, followed by appropriate treatment. ## Management of kidney failure A retrospective case note review by members of the ESPN Dialysis Working Group reported that infants with CNS who require dialysis have rates of peritonitis, dialysis technique survival, growth and transplantation that are comparable with those of infants with other primary kidney diseases [bib_ref] Infants with congenital nephrotic syndrome have comparable outcomes to infants with other..., Dufek [/bib_ref]. Peritoneal dialysis is the modality of choice for children with CNS because it pre serves central venous access; however, haemodialysis is an alternative with comparable outcomes (Box 9). In patients with autosomal recessive disease, parental kidney donation is usually accepted. [bib_ref] Genetic aspects of congenital nephrotic syndrome: a consensus statement from the ERKNet-ESPN..., Lipska-Ziętkiewicz [/bib_ref] Mild proteinuria after kidney transplantation is not rare and can be related to several conditions including graft rejection, recurrence of primary glomerulopathy, de novo glomerulopathy, infection or drug tox icity [bib_ref] Post-transplantation nephrosis in congenital nephrotic syndrome of the Finnish type, Laine [/bib_ref]. Recurrence of nephrotic-range proteinuria has also been described in patients with CNS after kidney transplantation [bib_ref] Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after..., Chaudhuri [/bib_ref] [bib_ref] Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations..., Bertelli [/bib_ref] [bib_ref] NPHS2 mutation associated with recurrence of proteinuria after transplantation, Billing [/bib_ref]. Almost all children with CNS who have recurrence of nephrotic range proteinuria after kidney transplantation have a homozygous NPHS1 p.Leu41Aspfs variant (known as Fin-major) that leads to an early stop codon and total absence of nephrin in the native kidney. Post-transplant de novo glomerulopathy occurs in 25-35% of these patients and at least 70% of those with post-transplant glomerulopathy have detectable anti-nephrin antibodies caused by allo-immunization against the nephrin molecule in the kidney graft. Recurr ence can occur at any time after transplantation, kidney function is initially normal despite heavy proteinuria, and kidney biopsy samples show only mild histological changes with negative immunofluorescence [bib_ref] Post-transplantation nephrosis in congenital nephrotic syndrome of the Finnish type, Laine [/bib_ref] [bib_ref] Congenital nephrotic syndrome and recurrence of proteinuria after renal transplantation, Holmberg [/bib_ref] [bib_ref] Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic..., Patrakka [/bib_ref] [bib_ref] Plasma exchange and retransplantation in recurrent nephrosis of patients with congenital nephrotic..., Kuusniemi [/bib_ref]. Recurrence of nephrotic-range proteinuria in children of other genetic backgrounds is very rare and only one patient with anti-nephrin antibodies has been reported outside ## Box 8 \| recommendations for monitoring and prevention of complications Thrombosis prophylaxis - We suggest that preventive anticoagulation should be considered in patients with CNS during states of increased thrombosis risk (owing to acute illness, risk of dehydration, inserted central lines and/or thrombocytosis >750,000/ml) and/or in patients with a previous thrombosis. ## Infection prophylaxis and management - We do not suggest routinely administering antibiotic prophylaxis in children with CNS; however, prompt antibiotic treatment should be started in the case of a suspected bacterial infection. - We suggest that immunoglobulin infusions should be considered in patients with low serum igG levels and recurrent or severe infections. - We recommend following the vaccination schedule that is recommended for healthy children, including vaccinating against encapsulated bacteria and varicella-zoster virus (vZv), and administering the influenza vaccine annually. - in the case of exposure to chickenpox in children who have not been immunized against vZv, we recommend prophylactic treatment with specific vZv intravenous immunoglobulins or oral acyclovir for 5-7 days starting within 7-10 days of the exposure. - We recommend treatment of vZv infection with intravenous high-dose acyclovir for 7-10 days. ## Nutrition, growth and metabolism - We recommend provision of a diet with a high energy (130 kcal/kg/day) and protein (4 g/kg/day) content but low salt content (<0.5-3 g/day depending on the age of the patient). - We recommend initiating growth hormone treatment in patients with persistent height growth failure despite adequate nutrition. - We recommend supplementing with levothyroxine (T4) in the case of hypothyroidism. - We recommend close monitoring of ionized calcium, 25-oH-D3 and pTH levels in children with CNS and supplementing with oral D3-vitamin (cholecalciferol) or 25-oH-D3-vitamin (calcifediol) and calcium (250-500 mg/day) in the case of low 25-oH-D3 and/or low ionized calcium and/or elevated pTH levels. - We suggest considering use of statins when fasting lDl cholesterol is persistently elevated in patients with additional cardiovascular risk factors. ## Anaemia prevention and management - We recommend monitoring and treating iron deficiency and administering erythropoietin in patients who have anaemia despite iron supplementation. - We recommend close monitoring of the reticulocyte count as a marker of erythropoiesis and response to therapy. persistent anaemia after 4 weeks of iron and erythropoietin therapy requires further evaluation for other possible contributing factors, such as copper, ceruloplasmin or vitamin B12 deficiency, and appropriate treatment. ## Box 9 \| recommendations for kidney failure - We recommend that use of dialysis in children with CNS follows the general guidelines for kidney replacement therapy in infants and children. - in children with post-transplant proteinuria, we recommend considering antibody-mediated disease and antibody reduction strategies (i.e. plasmapheresis and immunosuppressive drugs). Finland; this patient carried a homozygous NPHS1 truncating variant (p.Glu189Ter) [bib_ref] Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after..., Chaudhuri [/bib_ref]. Successful treatment outcomes have been reported after treatment with daily plasma exchanges, methylprednisolone pulses and oral cyclophosphamide or rituximab [bib_ref] Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after..., Chaudhuri [/bib_ref] [bib_ref] Congenital nephrotic syndrome and recurrence of proteinuria after renal transplantation, Holmberg [/bib_ref]. Early or late recurrence of nephrotic range proteinuria has also been reported in 1-2% of patients with homozygous or compound heterozygous pathogenic variants in the podocin gene (NPHS2, especially p.Arg138Ter and p.Arg138Gln variants) [bib_ref] Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations..., Bertelli [/bib_ref]. The pathophysiology of post-transplant de novo glomerulopathy in patients with NPHS2 pathogenic variants is unclear (causative antibodies have not been identified) and might be multifactorial [bib_ref] NPHS2 mutation associated with recurrence of proteinuria after transplantation, Billing [/bib_ref]. ## Primary outcome measures Patients with CNS are prone to developing severe complications, including growth failure, cognitive delay, thromboses, hypothyroidism, infections, hypertension and anaemia, which may require frequent hospitalizations and considerably impair their quality of life. We recommend aiming for normal growth, nutritional status and cognitive and motor development; preservation of vascular access (patent central veins and peripheral vessels for fistulae); absence of thrombotic complications, severe infections, oedema and anaemia; normal blood pressure; euthyroidism; minimized hospitalizations and good quality of life (that is, absence of pain and the ability to perform normal age-appropriate daily activities) in these patients. These goals should be regularly monitored as primary outcome measures. # Ethical considerations A number of ethical issues should be considered when taking care of a child with CNS. Decisions about intensive versus palliative treatments in neonates with severe and life-threatening disease should be made by a team of professionals in a family-centred shared decision-making framework led by the primary responsible physician [bib_ref] Sustaining life or prolonging dying? Appropriate choice of conservative care for children..., Dionne [/bib_ref] [bib_ref] Best interests decisions: professional practices in health and social care, Williams [/bib_ref]. In patients with severe comorbidities and/or under circumstances with limited medical resources, the decision to withhold treatment can be taken by the medical team after discussion with the family. Specific literature on offering genetic testing to siblings of children with autosomal dominant CNS (which results in phenotypic heterogeneity in disease expression) is lacking. In general, genetic counselling of the family should precede genetic testing [bib_ref] The challenge of consent in clinical genome-wide testing, Burke [/bib_ref]. Genetic testing of asymptomatic siblings for the known pathogenic causative variant in a patient with CNS should be considered only in the case of WT1-associated glomerulopathy as this is the only autosomal dominant disorder with variable expressivity and incomplete penetrance that can manifest as CNS [bib_ref] Genotype-phenotype associations in WT1 glomerulopathy, Lipska [/bib_ref]. # Future research We recognize the paucity of scientific evidence in the field of CNS. Indeed, during our literature search we identified 54 relevant articles but no randomized controlled trials. Compelling clinical questions remain unanswered and we propose a number of research themes to address these questions (Box 10). # Conclusions In these recommendations, we provide guidance to multidisciplinary teams for the initial diagnostic work-up and monitoring of complications in children with CNS. We recommend prompt genetic screening in all children with CNS and genetic counselling of their families. Routine kidney biopsy is not recommended but may be considered in patients with sporadic, non-syndromic disease if comprehensive genetic testing has not yielded a molecular diagnosis. Therapeutic management should be adapted to the clinical severity of the condition with the aim of maintaining intravascular euvolaemia and adequate nutrition, preventing complications such as infections, thrombosis, psychomotor delay and failure to thrive, and preserving the vasculature. We recommend basing the use of albumin infusions on clinical indicators of hypovolaemia or on failure to thrive, rather than on serum albumin levels. When possible, we recommend avoiding CVLs owing to the high risk of thrombosis. We provide guidance for symptomatic treatment of CNS, including use of ACE inhibitors or ARBs, diuretics, anticoagulation during states of increased thrombosis, vaccination and IVIG infusions in selected patients. We do not recommend performing routine early nephrectomies but suggest that they are considered in patients with severe complications, despite optimization of conservative treatment, and before transplantation in patients with persisting nephrotic syndrome and/or WT1-dominant pathogenic variants. ## Box 10 \| future research - Develop a comprehensive registry for children with CNS to evaluate the variations in treatment and natural history of the disease, including rare complications. - evaluate the impact of CNS on schooling, social life and professional activity. - evaluate phenotype-genotype correlations in CNS. - Define the optimal indications, dose and frequency of albumin infusions to use once patients have achieved a stable disease state. - evaluate the risk versus benefit ratio of approaches to preventing and/or treating CNS complications, such as use of anticoagulation, immunoglobulin infusion and vaccinations. [fig] Figure 1 \|: Opinion-based management algorithm for CNS. At presentation with congenital nephrotic syndrome (CNS), a clinical and biological assessment including screening for congenital infections and genetic analysis is recommended. Initial treatment should be based on the results of these assessments. Patients should be managed at diagnosis by a specialized paediatric nephrology team. Blood volume should be assessed and symptomatic treatments instituted to maintain blood volume and prevent complications. Follow-up must be managed by a multidisciplinary team. Nephrectomy can be considered for children with persistent, severe CNS despite optimal management. Stable children can be managed on an outpatient basis with spacing or even stopping of albumin infusions. All children should be referred promptly to a kidney transplant team. Bilateral nephrectomy is recommended at the time of kidney failure (chronic kidney disease (CKD) G5) if nephrotic syndrome persists and/or if the patient has a WT1 pathogenic variant. Preventive measures: prophylaxis for thrombosis, infection and anaemia, adequate nutrition and growth hormone substitution. RAS, renin-angiotensin system, CVL, central venous line. [/fig] [table] Table 1 \|: Follow-up for a child with CNS [/table]	None	https://www.nature.com/articles/s41581-020-00384-1.pdf	None
2d881020bae027a66a8c4929b7ed0f245b51cf82	pubmed	The APOSTEL recommendations for reporting quantitative optical coherence tomography studies	The APOSTEL recommendations for reporting quantitative optical coherence tomography studies Objective: To develop consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results.Methods: A panel of experienced OCT researchers (including 11 neurologists, 2 ophthalmologists, and 2 neuroscientists) discussed requirements for performing and reporting quantitative analyses of retinal morphology and developed a list of initial recommendations based on experience and previous studies. The list of recommendations was subsequently revised during several meetings of the coordinating group.Results: We provide a 9-point checklist encompassing aspects deemed relevant when reporting quantitative OCT studies. The areas covered are study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition data analysis, recommended nomenclature, and statistical analysis.Conclusions: The Advised Protocol for OCT Study Terminology and Elements recommendationsinclude core items to standardize and improve quality of reporting in quantitative OCT studies. The recommendations will make reporting of quantitative OCT studies more consistent and in line with existing standards for reporting research in other biomedical areas. The recommendations originated from expert consensus and thus represent Class IV evidence. They will need to be regularly adjusted according to new insights and practices. Neurology ® 2016;86:2303-2309 GLOSSARY APOSTEL 5 Advised Protocol for OCT Study Terminology and Elements; GEE 5 generalized estimating equation models; IMSVISUAL 5 International Multiple Sclerosis Visual; MS 5 multiple sclerosis; OCT 5 optical coherence tomography; ON 5 optic neuritis. Optical coherence tomography (OCT) utilizes near infrared light to generate high-resolution cross-sectional images of biological tissue. [bib_ref] Optical coherence tomography, Huang [/bib_ref] Since its development, OCT has been used for the diagnosis and monitoring of numerous primary ocular diseases. With ongoing enhancement of resolution in newer devices and the development of powerful and reliable image processing algorithms, OCT is being increasingly employed to measure the effects of axonal and neuronal damage caused by retinal diseases and optic neuropathies. In recent years, such a quantitative approach has extended the application of OCT to many neurologic disorders with known damage to the visual pathway with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders being the most important. OCT is a sensitive tool for tracking structural changes of the retina, including the macula and optic nerve head, in inflammatory, 2-7 degenerative, [bib_ref] Retinal ganglion cell analysis using high-definition optical coherence tomography in patients with..., Cheung [/bib_ref] [bib_ref] Venturing into the no-man's land of the retina in Parkinson's disease, Bodis-Wollner [/bib_ref] [bib_ref] Photoreceptor layer thinning in idiopathic Parkinson's disease, Roth [/bib_ref] [bib_ref] Temporal retinal nerve fiber loss in patients with spinocerebellar ataxia type 1, Stricker [/bib_ref] [bib_ref] Subtle retinal pathology in amyotrophic lateral sclerosis, Ringelstein [/bib_ref] vascular, [bib_ref] Retinal pathology in idiopathic moyamoya angiopathy detected by optical coherence tomography, Albrecht [/bib_ref] [bib_ref] Retinal pathology in Susac syndrome detected by spectral-domain optical coherence tomography, Ringelstein [/bib_ref] and metabolic [bib_ref] Retinal neurodegeneration in Wilson's disease revealed by spectral domain optical coherence tomography, Albrecht [/bib_ref] diseases of the CNS. AIMS AND USE As the number of quantitative OCT studies in neurology rapidly increases (more than 500 articles reported in PubMed to date) and varying devices and image processing technologies have come into play, there is a need for the development of consistent and coherent standardized reporting recommendations. Harmonious reporting is important for a critical assessment of the strengths and weaknesses of a study. In previous studies, ambiguous reporting has led to uncertainty about different methodologic aspects, such as scan protocols, the use of quality control criteria, and inclusion or exclusion of patients or eyes. The lack of more detailed information on such topics limits the ability to compare data and to apply and generalize findings from these studies. Herein, we present the Advised Protocol for OCT Study Terminology and Elements recommendations (APOSTEL recommendations). They have been developed to outline core information that should be provided when reporting quantitative OCT studies. As such, the recommendations will be instructive for researchers reporting OCT studies that quantitatively assess retinal layer thicknesses and related data. Adhering to these recommendations will improve interstudy interpretability and comparability, ultimately helping to advance research and the clinical application of OCT in the study of neurologic diseases. The APOSTEL recommendations are designed to complement existing and well-established reporting guidelinesopenly available through the equator network (http://www.equator-network.org), but add specific parameters for the reporting of OCT data. We encourage authors to consider the APOSTEL recommendations when quantitative OCT data are to be reported in a study. Likewise, we invite reviewers and journal editors to support adherence to these recommendations when considering OCT studies for publication. In table 1, we provide a quick and easy-to-use checklist of the APOSTEL recommendations. The APOSTEL recommendations were conceived during convened meetings of the authors at the 2015 European Academy of Neurology meeting in Berlin, Germany. In these meetings, the aims and scopes of the recommendations were discussed and working groups were established. A preliminary version of the manuscript and the checklist was generated by the working groups, discussed and approved during a joint telephone conference, and then circulated to the members of the International Multiple Sclerosis Visual (IMSVISUAL) consortium (http://www.imsvisual.org) in several rounds for comments and revisions. The members of the consortium approved the final manuscript in person during the 2015 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) convention in Barcelona, Spain, or by e-mail in the case of those who could not attend the meeting. APOSTEL RECOMMENDATIONS Describe the study protocol. The study design including the inclusion and exclusion criteria and the demographics of the study participants should be described according to established reporting guidelines as may already be applicable to the study, e.g., the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), Consolidated Standards of Reporting Trials (CONSORT), or Case Reports (CARE) guidelines.Additional information is required for OCT studies, which generally include information regarding both eyes of each participant. With respect to inclusion and exclusion criteria, authors should define if these were applied at the eye or patient level. In OCT studies, coexisting ocular pathologies represent potential confounders, which can have profound impact on results. Therefore, the patient history and examinations performed to exclude confounding ocular pathologies such as glaucoma or macular degeneration, e.g., funduscopy, tonometry, or slitlamp examinations (for a complete list see reference 17), should be described. We also advise reporting whether patients were tested for refractive errors as well as the cutoff for exclusion based on refraction (typically 66 D). [bib_ref] Retinal nerve fiber layer measurements in myopia: an optical coherence tomography study, Leung [/bib_ref] The numbers of eyes and patients excluded should be reported, as well as the criteria leading to such exclusions. In studies comparing OCT examinations to other assessments, e.g., clinical scores or other imaging modalities, it is important to report the time interval between assessments. For OCT studies of neuroinflammatory diseases, reporting the history of and time span from a previous optic neuritis (ON), as well as the number of ON episodes, is of major importance. The authors should clearly define how history of ON was assessed. We strongly recommend the use of standardized definitions of ON [bib_ref] The investigation of acute optic neuritis: a review and proposed protocol, Petzold [/bib_ref] including information on whether previous ON diagnoses were arrived at based on clinical, 20 electrophysiologic, or structural assessments. [bib_ref] The investigation of acute optic neuritis: a review and proposed protocol, Petzold [/bib_ref] State the acquisition device type, name, and version. OCT technology has greatly advanced in recent years. Commercially available OCT devices differ in their optics, data acquisition characteristics, and image analysis algorithms. [bib_ref] The impact of utilizing different optical coherence tomography devices for clinical purposes..., Warner [/bib_ref] It is important to provide detailed information on the devices used (manufacturer, model, interferometric technique), especially in the case of multicenter studies. In addition, detailed information on the software (type, version) used for the acquisition should be provided, if applicable. Wavelength should be specified, particularly for studies using prototype OCT devices, as different OCT wavelengths may have different imaging characteristics. Define the acquisition setting. The conditions under which OCT measurements were performed should be standardized and reported. First, the number of individual operators and OCT devices should be reported (sites with more than one operator might describe the intraoperator and interoperator reproducibility of OCT measurements at their sites). Second, there has been some debate over the necessity of pupil dilation. There is concern that pupil dilation might decrease reliability due to higher beam placement variation. [bib_ref] A simple sign for recognizing off-axis OCT measurement beam placement in the..., Balk [/bib_ref] However, the actual effects of pupil dilation have not yet been definitively determined and may in fact be ambiguous. [bib_ref] Reproducibility of optical coherence tomography retinal nerve fiber layer thickness measurements before..., Alizadeh [/bib_ref] For example, some patients, especially with severe visual or cognitive impairment, might only be assessable by OCT after pupil dilation. [bib_ref] Effect of pupillary dilatation on glaucoma assessments using optical coherence tomography, Smith [/bib_ref] Handling of pupil dilation should therefore be reported. Finally, several OCT devices offer differing methods for correcting eye movement or position change during acquisition and follow-up measurements. If such a method was used, its application should be reported. Define OCT scanning protocol. Different OCT scanning protocols influence volumetric imaging and morphometric results. [bib_ref] Quality issues in interpretation of optical coherence tomograms in macular diseases, Domalpally [/bib_ref] Often, an OCT imaging session consists of several scan acquisitions per eye. Thus, it is essential to report relevant acquisition parameters of the full measurement protocol, including all scan types employed in a study. The target structure for each scan should be defined and named (e.g., retinal nerve fiber layer, macula, optic nerve). Each scan's shape (e.g., ring, line, volume, radial), orientation (e.g., horizontal, vertical), and size (in degrees or millimeters), as well as other relevant scan-specific parameters, should be reported. For all scans, the authors should provide information on the number of total B-scans, the number of A-scans used for each B-scan, and the number of B-scans averaged. Define funduscopic imaging. Many OCT devices offer additional fundus imaging modalities such as confocal scanning laser ophthalmoscopy, retinal angiography, and autofluorescence imaging. If included in the analysis, these should be described and the acquisition protocol including the excitation wavelength, filter sets, and the number of frames averaged (if applicable) indicated. Describe postacquisition data selection. Many OCT image postprocessing algorithms (either included within the device or as external software) have high demands in terms of image contrast and quality. To improve the reliability of results, studies often employ some form of image selection process. A common strategy for increasing image and data quality includes the averaging of several images or obtained values. Likewise, some studies record several images of the same target and subsequently use the optimal image based on defined selection criteria. If such strategies were applied, they should be described in detail, including the selection criteria. In order to ensure a high quality of scans, the use of quality control criteria is recommended. For example, an extensive set of quality control criteria has been published in the form of the OSCAR-IB criteria. [bib_ref] The OSCAR-IB consensus criteria for retinal OCT quality assessment, Tewarie [/bib_ref] [bib_ref] Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB..., Schippling [/bib_ref] Any postacquisition discard should be reported including the number and criteria leading to exclusion of the respective scans. Cutoffs of quantifiable variables such as signal strength should be clearly defined and stated. Numerical values for signal strength are provided in different units and scaling by the different devices so separate cutoffs should be given if more than one device type is used. Depending on the statistical approach (see below), it might be necessary to exclude eyes from the analysis. If this is the case, the strategy of eye selection for statistical analysis should also be reported. Describe postacquisition data analysis. After acquisition, images have to be further processed and analyzed. Since processing of images is not only device-specific but also dependent on software-implemented algorithms, the name of the software package and its version should be indicated. Authors should report whether the postprocessing performed (e.g., intraretinal layer segmentation) was fully automated, semiautomated with manual correction of obvious errors, or fully manual. In the case of manual postprocessing, authors should report the number of graders, and indicate whether they were masked. Currently, the main postprocessing analysis for retinal OCT data is the generation of volume or thickness data derived from the retinal layers. While data derived from line and ring scans are commonly reported in micrometers, the results derived from volume scans can be reported as mean thickness in mm or volume in mm [bib_ref] Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome, Oberwahrenbrock [/bib_ref]. We advise against the use of other units for thickness and volume measurements unless explained in the study objectives. To obtain such measurements, differently sized or shaped areas can be used, such as the ring-shaped grid defined for the Early Treatment of Diabetic Retinopathy Study.As a matter of fact, values derived from different areas or scans are not necessarily comparable and might also show differences with regard to reliability. [bib_ref] Reliability of intra-retinal layer thickness estimates, Oberwahrenbrock [/bib_ref] Thus, area shape and size, as well as the source scan used for analysis, should be reported. Use common nomenclature and abbreviations. The authors should clearly define and describe all structures analyzed. We recommend the nomenclature and abbreviations in table 2 and the figure. Adherence to the nomenclature is especially important when referring to composite structures. Authors should additionally indicate in which scale structure measurements are provided (e.g., volume or thickness). If authors need to define additional composite structures, the exact definition should be reported. Define the statistical approach with exact model description. For reporting statistical analyses, authors should adhere to the recommendations in the applicable reporting guidelines.Regarding the statistical features of OCT studies, the following additional information should be provided. As OCT scans are usually acquired for both eyes in one participant, it is important to describe any strategy applied to account for intereye within-patient dependencies. This latter usually includes either randomly selecting one eye or estimating the mean for non-ON eyes or applying statistical methods able to account for these dependencies, such as general mixed effects models or generalized estimating equation models (GEE). Different strategies might be required for specific questions. [bib_ref] Application of advanced Statistics in ophthalmology, Fan [/bib_ref] When advanced statistical models are used, authors should report them in sufficient detail, i.e., the model composition and relevant model configurations such as the working correlation matrix in GEE. # Implications and limitations The aim of the APOSTEL recommendations is to provide a consistent basis for assisting authors in composing conclusive reports of studies utilizing quantitative retinal OCT, allowing relevant comparisons across and between studies, and helping readers, reviewers, and editors to evaluate these findings. Furthermore, by emphasizing details that are of importance in such reports, we hope to generally improve the quality of future investigations in this area. Defining the relevant parameters for reporting may prompt researchers to thoroughly consider these criteria during the initial stages of study design. Such an approach could help facilitate OCT research in centers intending to incorporate OCT for clinical trials or other research purposes. Adherence to the recommendations can help avoid common pitfalls in the design and reporting of OCT studies. These recommendations are not intended to impose a rigid format on reports of OCT-based research, but rather to provide suggestions and guidance on which reporting standards to prioritize. As such, the APOSTEL recommendations are intended to complement existing reporting guidelines for clinical studies. The recommendations should be considered level of evidence IV. They are not based on a systematic review of the literature, but instead rely on the experience of IMSVISUAL's authors and members in conducting, reviewing, and reporting OCT studies. For most of the aspects deemed relevant, formal experimental evidence on their influence on OCT results is lacking, preventing a meta-analytical approach or even a comprehensive review of literature. The recommendations were not derived from a formalized consensus-building procedure like that of a Delphi process, where anonymized questionnaires are circulated and evaluated in several rounds to achieve consensus. The number of participating individuals was therefore naturally limited and was influenced by existing networks or collaborations of the authors. We acknowledge that this approach can only generate a limited level of evidence (Class IV). However, given the multiple dimensions of the topic and initial heterogeneity of opinions, it was necessary to establish consensus and standardization first. We therefore purposefully chose the term recommendation over guidelines. In order to increase the level of evidence, we plan to refine, evaluate, and validate these recommendations by means of a more formal approach involving a larger forum of researchers to develop more evidence-based guidelines. Apart from validation, several other concerns need addressing. For example, a limitation of the current recommendations is that they were established by a consortium dominated by neurologists and mainly pertain to the quantitative detection and analysis of retinal changes. Furthermore, the IMSVISUAL consortium is predominantly focused on MS research. However, several of the authors are involved in OCT research well beyond MS [bib_ref] Photoreceptor layer thinning in idiopathic Parkinson's disease, Roth [/bib_ref] [bib_ref] Subtle retinal pathology in amyotrophic lateral sclerosis, Ringelstein [/bib_ref] [bib_ref] Retinal pathology in idiopathic moyamoya angiopathy detected by optical coherence tomography, Albrecht [/bib_ref] [bib_ref] Retinal pathology in Susac syndrome detected by spectral-domain optical coherence tomography, Ringelstein [/bib_ref] [bib_ref] Retinal neurodegeneration in Wilson's disease revealed by spectral domain optical coherence tomography, Albrecht [/bib_ref] [bib_ref] Optical coherence tomography in parkinsonian syndromes, Albrecht [/bib_ref] and the recommendations have been designed to also apply to studies on patients with other neurologic or ophthalmologic conditions that are increasingly being performed with similar methodology. Further development incorporating these potentially different points of view will be crucial for the broader application and success of the recommendations. We therefore consider the APOSTEL recommendations as a preliminary but urgently needed step towards further improving the overall quality and utility of quantitative OCT research in neurologic disorders. These recommendations constitute an expert consensus statement and their value will be assessed in the future through use in studies related to visual outcomes in ocular and neurologic disease. The recommendations will require ongoing refinement to increase the level of evidence and to accommodate the continuous evolution of OCT technology. We will update these recommendations in the future, taking into account user comments, criticism, new evidence, and experience. We therefore welcome suggestions for improvement and further development of the criteria, as well as additional areas of application, and invite readers to submit their comments via the IMSVISUAL Web site. Recommendation updates and current checklist versions will be available on the IMSVISUAL Web site (www.imsvisual.org). # Author contributions Andrés Cruz-Herranz: study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Lisanne J. Balk: study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Timm Oberwahrenbrock: analysis and interpretation, critical revision of the manuscript for important intellectual content. Shiv Saidha: analysis and interpretation, critical revision of the manuscript for important intellectual content. Elena H. Martinez-Lapiscina: analysis and interpretation, critical revision of the manuscript for important intellectual content. Wolf A. Lagreze: analysis and interpretation, critical revision of the manuscript for important intellectual content. Joel S. Schuman: analysis and interpretation, critical revision of the manuscript for important intellectual content. Pablo Villoslada: analysis and interpretation, critical revision of the manuscript for important intellectual content. Peter Calabresi: analysis and interpretation, critical revision of the manuscript for important intellectual content. Laura Balcer: analysis and interpretation, critical revision of the manuscript for important intellectual content. Axel Petzold: analysis and interpretation, critical revision of the manuscript for important intellectual content. Ari J. Green: analysis and interpretation, critical revision of the manuscript for important intellectual content. Friedemann Paul: analysis and interpretation, critical revision of the manuscript for important intellectual content. Alexander U. Brandt: analysis and interpretation, study concept and design, acquisition of data, critical revision of the manuscript for important intellectual content, study supervision. Philipp Albrecht: analysis and interpretation, study concept and design, acquisition of data, critical revision of the manuscript for important intellectual content, study supervision. # Acknowledgment The authors thank IMSVISUAL and its members for their input into the development of these reporting guidelines. # Study funding No targeted funding reported. [fig] Figure: The consensus nomenclature for retinal structures The different layers (and the borders of these) specified in table 2 are illustrated in a central vertical scan through the middle of the foveola. BM 5 Bruch membrane; ELM 5 external limiting membrane; GCIP(L) 5 ganglion cell and inner plexiform layer; GCL 5 ganglion cell layer; ILM 5 inner limiting membrane; INL 5 inner nuclear layer; IPL 5 inner plexiform layer; IRL 5 inner retinal layer; ISOS 5 inner and outer segments; ONL 5 outer nuclear layer; OPNL 5 outer plexiform and nuclear layer; OPL 5 outer plexiform layer; OPT 5 outer photoreceptor tips; RNFL 5 retinal nerve fiber layer; RPE 5 retinal pigment epithelium. [/fig] [table] Table 1: Nine-point Advised Protocol for OCT Study Terminology and Elements checklistQuality control criteria (i.e., OSCAR-IB 17 or other criteria) ❑ Software used for processing scans and segmentation (may be different from acquisition software) ❑Which individual retinal layers were segmented/included ❑Method of segmentation (automated, semiautomated, or manually) ❑How potential bias was addressed in the case of manual segmentation (masking) ❑ Statistical models used for the analyses of OCT data ❑ Whether data were analyzed by eye or by patient ❑ Abbreviation: OCT 5 optical coherence tomography. [/table]	None	https://n.neurology.org/content/neurology/86/24/2303.full.pdf	Objective: To develop consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results. Methods: A panel of experienced OCT researchers (including 11 neurologists, 2 ophthalmologists, and 2 neuroscientists) discussed requirements for performing and reporting quantitative analyses of retinal morphology and developed a list of initial recommendations based on experience and previous studies. The list of recommendations was subsequently revised during several meetings of the coordinating group. Results: We provide a 9-point checklist encompassing aspects deemed relevant when reporting quantitative OCT studies. The areas covered are study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition data analysis, recommended nomenclature, and statistical analysis. Conclusions: The Advised Protocol for OCT Study Terminology and Elements recommendations include core items to standardize and improve quality of reporting in quantitative OCT studies. The recommendations will make reporting of quantitative OCT studies more consistent and in line with existing standards for reporting research in other biomedical areas. The recommendations originated from expert consensus and thus represent Class IV evidence. They will need to be regularly adjusted according to new insights and practices.
403bec1e0c73719e9b93199a25df2501337b3fca	pubmed	Mobilization and Exercise Intervention for Patients With Multiple Myeloma: Clinical Practice Guidelines Endorsed by the Canadian Physiotherapy Association	Mobilization and Exercise Intervention for Patients With Multiple Myeloma: Clinical Practice Guidelines Endorsed by the Canadian Physiotherapy Association Objective. Individuals with multiple myeloma (MM) often have reduced functional performance due to the cancer itself or as a direct side effect of cancer treatments. Physical therapy is a part of cancer rehabilitation; however, no guidelines are available to provide information and direction for physical therapists managing patients with MM. The goal of this guideline is to provide recommendations based on a systematic review and consensus process that physical therapists can use to manage patients with MM.Methods.A systematic review of the literature published until August 2018 was performed in 8 databases with 2 independent reviewers assessing quality. Seventeen articles were identified as relevant, and a draft guideline was developed in the form of action statements. A total of 10 physical therapists with hematology experience and 10 patients with MM were recruited for consensus process. A priori threshold of 80% agreement was used to establish a consensus for each statement. The draft guidelines were reviewed externally by 4 methodologists using the AGREE II tool and a stakeholder representing OH (Cancer Care Ontario) Program in Evidence Based Care, McMaster University. The final guideline was reviewed and officially endorsed by the Canadian Physiotherapy Association.Results.A total of 30 action statements were developed that achieved consensus, indicating physical therapy recommendations based on physiological markers (ie, hemoglobin, platelet count), complete patient presentation, and the stage of medical treatment.Conclusion.These clinical practice guidelines were developed to aid physical therapists in implementing evidence-based and best-practice care for patients with MM to optimize rehabilitation outcomes. Impact. These guidelines fill an important knowledge gap and are the first to provide information specifically for physical therapist management of patients with MM. # Introduction Patients with multiple myeloma (MM) may experience anemia, thrombocytopenia, pancytopenia or neutropenia, bony lesions, or fractures at some point due to the cancer itself or as a direct side effect of cancer treatments.Patients with this presentation are typically admitted to hospitals for supportive treatments such as high-dose chemotherapy, autologous stem cell transplantation, antibiotics, blood transfusions, radiation therapy, and surgical interventions for pathologic and impending fractures. Unfortunately, the side effects of these medical treatments can negatively impact these individuals with symptoms such as increased fatigue, muscle weakness, reduced muscle mass, reduced quality of life (QOL), and increased sleep fragmentation. [bib_ref] Fatigue and physical activity in patients undergoing hematopoietic stem cell transplant, Danaher [/bib_ref] [bib_ref] Recommended exercise protocol to decrease cancer-related fatigue and muscle wasting in patients..., Strong [/bib_ref] Many of these symptoms can potentially be targeted with individualized exercise programs, which may aid in reduced cancer-related fatigue and muscle wasting, [bib_ref] Recommended exercise protocol to decrease cancer-related fatigue and muscle wasting in patients..., Strong [/bib_ref] better sleep patterns, and better QOL. [bib_ref] The influence of daytime inactivity and nighttime restlessness on cancer-related fatigue, Berger [/bib_ref] [bib_ref] Effects of exercise on fatigue, sleep, and performance: a randomized trial, Coleman [/bib_ref] [bib_ref] Quality of life changes following peripheral blood stem cell transplantation and participation..., Hayes [/bib_ref] Provided that patients receiving treatment typically become physically inactive, 2-3 it would be imperative to mobilize these patients before, during, and after medical therapy to target any resulting deconditioning. However, there is a lack of specific information to guide safe mobilization and safe activity levels in patients with MM. A scoping review revealed that there are no physical therapyspecific guidelines available for exercise prescription before, during, and after chemotherapy and stem cell transplantation. Thus, the objectives of this study were to (1) develop a set of consensus-based recommendations to help physical therapists make decisions on mobilization and exercise intervention of patients with MM in acute care settings, particularly based on laboratory values (hemoglobin, platelet, and white blood cell counts) and bony lesions; and (2) develop evidence-based recommendations for physical therapy management before, during, and after chemotherapy and stem cell transplantation to improve strength, endurance, functional mobility, fatigue, increased nighttime sleep, and QOL in patients with MM. # Methods ## Design A combination of systematic review, critical appraisal, and expert opinion was used for guideline development. ## Guideline development process The guideline development steps recommended by the American Physical Therapy Association were followed when drafting recommendations and determining levels of evidence.Recommendations for research questions with inadequate evidence were developed based on a consensus process. [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] Recommendations were made in the form of action statements (AS), and levels of evidence and grades of AS were determined using the recommendations of Kaplan and colleagues. [bib_ref] Developing evidence-based physical therapy clinical practice guidelines, Kaplan [/bib_ref] Tables 1 and 2 outline the levels of evidence and grades of recommendations. Refer to the study protocol for further information about the guideline development process. 7 ## Review of literature A literature search strategy was developed and performed by 2 research assistants (M.L. and Z.M.), as outlined in the study protocol, to understand the research evidence around the physical therapy management of MM. [bib_ref] Evidence-based guidelines for physiotherapy management of patients with multiple myeloma: study protocol, Jeevanantham [/bib_ref] In brief, a reviewer (Z.M.) systematically searched databases and retrieved 48,060 articles with EndNote software, and 28,679 articles were recovered after removing duplicates. Two independent reviewers (Z.M. and M.L.) carefully screened abstracts for inclusion, and 124 potential articles were selected for fulltext review. A total 109 articles were excluded (ie, abstracts only, correlational studies, and irrelevance to guideline), and the remaining 15 articles plus 2 additional articles (grey literature) were included for final guideline development . Each article was critically appraised (Z.M. and M.L.) using the standardized methodological assessment tool outlined in the study protocol. [bib_ref] Evidence-based guidelines for physiotherapy management of patients with multiple myeloma: study protocol, Jeevanantham [/bib_ref] Supplementary [fig_ref] Table 1: Levels of Evidence a There is an absence of research on the... [/fig_ref] shows the study characteristics and the critical appraisal scores of each included article. # Drafting action statements Completed in 2 parts: The initial draft AS were developed by 2 experienced oncology/hematology physical therapists after reviewing supporting articles and guidelines (AS1-6). The second set of AS (AS7-10) was based on data from the 17 included articles. Recommendations were made in the form of AS, along with levels of evidence and grades, as outlined in the study protocol. [bib_ref] Evidence-based guidelines for physiotherapy management of patients with multiple myeloma: study protocol, Jeevanantham [/bib_ref] An a priori threshold of 80% agreement was used to establish a consensus for each AS, and a quality cut score of greater than 70% was set for AGREE II domains for consideration of the guidelines. 8 ## Expert panel Two groups of participants (physical therapists and patients with MM) were recruited for this study. The consensus process was conducted in 2 phases. Phase I involved feedback from physical therapists and Phase II involved feedback from patients with MM. A total of 10 registered physical therapists working in the public sector across Canada who were experienced with oncology populations and able to read, understand, and write in English were recruited for Phase I of the consensus process. Of these, 4 physical therapists were from Ontario, 2 from Winnipeg, 2 from Québec, and 1 from British Columbia and 1 from Alberta. The physical therapists' work experience ranged from 4 to 27 years with tremendous experience working with patients with MM. A total of 10 patients diagnosed with MM admitted to 1 Ontario hospital for cancer treatment and able to speak, read, write, and understand English were recruited for phase II of the consensus process. Participants (physical therapists) for phase I were recruited by 1 investigator (V.R.) through a college of physiotherapy public registry. V.R. contacted potential participants, explained the study, answered questions, and obtained consent through email. One physical therapist and 1 patient withdrew from the study after initially consenting to participate in the study. Phase I consensus process included 3 rounds of email conversation, whereas Phase II involved only 1 round of feedback from patients. Participants were asked to mark either agree or disagree to the proposed statements and to provide their comments for each statement. ## Results of the consensus process A total of 32 AS including sub-statements were sent for Phase I of the consensus process to receive feedback from physical therapists. In the first round, 16 items (item nos. 4c, 4d, 4e, 5b, 7, 8, 8d, 9, 9a, 9b, 9c, 9d, 10, 10a, 10b, and 10c) received 100% consensus to include, 9 items (item nos. 1, 2, 4, 4a, 4f, 5a, 8a, 8b, and 8c) received 89% consensus to include, 3 items (item nos. 3, 5c, and 4b) received 78% consensus to include, and 1 item (item no. 6) received only 67% consensus to include. The focus group recommended rewording some sentences and including additional precautions for a few of the items. Accordingly, the statements were revised based on the feedback from the physical therapists. The research team decided to include item numbers 3, 5c, and 4b, which received 78% consensus. One item (no. 6) was completely revised that received only 67% consensus and sent for a second round of consultation. The item was revised based on feedback and was sent for a third round and received 89% consensus for inclusion in the final guideline. Our research team decided to eliminate 1 AS (acupuncture for pain relief during or after medical treatment) during the first round because the majority of the physical therapists reported that they did not have expertise in acupuncture treatment. A total of 30 AS were developed that achieved consensus (Suppl. . The revised guideline was sent for Phase II of the consensus process to receive input from patients with MM. The participants were asked to read each statement and provide their input in the comment box beside each statement. All 10 patients "agreed" with the recommended statements and provided positive comments. None of the patients gave negative comments or recommended to modify the statements. ## Agree ii review As per recommendation, 4 methodologists were identified to review these clinical practice guidelines to increase the reliability of the assessment. [bib_ref] AGREE II: advancing guideline development, reporting and evaluation in healthcare, Brouwers [/bib_ref] These methodologists have clinical and research experience, with 3 having a physiotherapy background and 1 with a nursing background. All methodologists recommended this guideline for use (Tab. 3). ## Stakeholder involvement Methodological feedback on a draft document was provided by a stakeholder representing the OH (Cancer Care Ontario) Program in Evidence Based Care, McMaster University. The final guideline was reviewed and officially endorsed by the Canadian Physiotherapy Association. # Discussion Hemoglobin Physical therapist intervention is generally contraindicated in patients with hemoglobin values less than 8 g/dL. [bib_ref] The impact of low hemoglobin on the percentage of adverse events during..., Peterson [/bib_ref] It is recommended to take precautionary measures but not to withhold physical therapy for patients with hemoglobin levels lower than 8 g/dL. [bib_ref] The impact of low hemoglobin on the percentage of adverse events during..., Peterson [/bib_ref] Evidence shows that patients with levels as low as 7 g/dL (HgB level) can tolerate physiotherapy, but those patients with cardiac and respiratory conditions are at a higher risk of compromised cardiac output and desaturation. [bib_ref] The CRIT study: Anemia and blood transfusion in the critically ill-current clinical..., Corwin [/bib_ref] Stiller and Phillips 11 recommend withholding mobilization for patients with levels lower than 7 g/dL. Therefore, while providing care for patients with lower hemoglobin levels (<8 g/dL), physical therapists should monitor vital signs and signs of adverse events (ie, chest pain, pallor, leg cramps, dizziness, arrhythmias, shortness of breath, respiratory distress, SBP > 200 mmHg or DBP > 110 mmHg, drop in SBP > 10 mmHg from the baseline, heart rate increases >120 bpm with activity, SpO 2 levels <88% with activity, and/or a positive orthostatic response). Lastly, it is strongly recommended that physical therapists liaise with physicians before delivering physical therapist interventions and discuss any additional signs to monitor during therapy sessions. ## Blood transfusion Patients with MM typically receive a transfusion of red blood cells (RBC) when the Hb concentration is lower than 7 g/dL in stable adults or lower than 8 g/dL in those with cardiac issues. Patients may receive a transfusion for approximately 2 to several hours depending on the number of units of RBCs. Withholding physical therapy solely on the basis of an RBC transfusion might affect patients' mobility and functional status. It is reported that patients' receiving physical therapist intervention during RBC transfusion did not have any adverse events. [bib_ref] Safety aspects of mobilising acutely ill inpatients, Stiller [/bib_ref] It is recommended that patients be monitored closely for abnormal vital signs and other events (ie, dislodging of intravenous site, syncope, and reaction to blood products). [bib_ref] Physical therapy intervention during a red blood cell transfusion in an oncologic..., Rosenfeldt [/bib_ref] Platelets Typically, platelet counts may drop following chemotherapy with the lowest count occurring 7 to 10 days post chemotherapy and take 2 to 3 weeks to recover. While bed rest is important in preventing bleeding, multiple weeks of bed rest may cause significant functional decline in older patients with O v e r a l l q u a l i t y o f g u i d e l i n e 7 6 6 6 8 7 . 5 Recommended for use Yes Yes Yes Yes a Quality of guideline score ranges from 1 (lowest possible quality) to 7 (highest possible quality). b Domain scores were calculated as per the scoring criteria outlined in the AGREE II tool. 8 c Domain scores of ≥70% considered a high-quality guideline. [bib_ref] AGREE II: advancing guideline development, reporting and evaluation in healthcare, Brouwers [/bib_ref] MM. Therefore, it is important to consider the benefits and harms of exercise to prevent functional decline. There is not a low limit cut-off for suspending all physical activity in patients with thrombocytopenia, particularly in patients undergoing chemotherapy. 14 The Leukemia/Bone Marrow Transplant Program of British Columbia (L/BMT program of BC) recommends limited physical activity when platelet counts are <15,000/μL; however, Sekhon and Roy 13 reported risk of bleeding with counts <10,000/μL. Interestingly, these authors also report that platelet count is an imprecise predictor of bleeding risk. Overall, given that platelets are typically transfused when the platelet count is <10,000/μL, we recommend only essential ambulation (ie, bathroom) with counts <10,000/μL. Assistance/supervision and gentle range of motion (ROM) in sitting or lying are recommended to prevent bleeding due to a fall. The L/BMT program of BC recommends gentle exercises without resistance for patients having platelet counts between 15,000 to 20,000/μL. The Seattle Cancer Care Alliance recommends strength training and cardiovascular exercises without resistance and strain for patients with platelet levels between 10,000 and 19,999/μL.Neal et al 16 conducted a retrospective cross-sectional study in 119 patients with cancer admitted to an acute inpatient rehabilitation facility with at least 1 with a platelet count of <150,000/μL. Of the 119 patients, 49 had hematologic cancer and there were 56 bleeding events. Interestingly, a higher number of bleeding events (35/56) occurred when the platelets were 51,000/μL or greater, and these events were not associated with very low counts (<11,000 or 11,000-20,000/μL), all of which suggest that patients with cancer can safely undergo inpatient rehabilitation even with low platelet counts.Therefore, we recommend gentle ROM and strength-training exercises without resistance and without strain for patients with platelet levels between 10,000 and 20,000/μL to avoid bleeding from high exertional blood pressure. Exercise in standing and ambulation is recommended for platelet levels between 10,000 and 20,000/μL only if the patient is steady on his/her feet with or without assistive devices and has no signs of bleeding. The L/BMT program of BC recommends light resistance exercises for patients with platelet levels between 20,000 and 40,000/μL.However, the Seattle Cancer Care Alliance 38 and the American College of Sports Medicine (ACSM) (exercise recommendations for persons with chronic diseases and disabilities) [bib_ref] Thrombocytopenia and physical activity among older adults: the tenuous line between bleeding..., Lucelia [/bib_ref] recommend exercises using elastic bands in patients with platelet counts between 20,000 and 50,000/μL. Given the variation of the population for which the above guidelines are recommended, we suggest light resistance exercises using elastic bands if no signs of bleeding without strain for patients with MM with platelets between 20,000 and 40,000/μL. It is also recommended that exercises be performed without strain to avoid bleeding due to possible spikes in blood pressure. We recommend gentle aerobic activity, including stationary cycling in patients with platelets >40,000/μL in compliance with the L/BMT program of BC. In addition, we recommend avoiding vigorous exercises in patients with levels <50,000/μL in compliance with ACSM and proper use of clothing and equipment to prevent bleeding from trauma. Therefore, we recommend that physical therapists monitor for signs of bleeding and educate patients about these signs and precautions for prevention. It would be ideal to liaise with physicians as well regarding physical therapist interventions as only a slender line exists between bed rest for preventing bleeding and exercise/physical activity to prevent functional decline in adults with MM admitted in acute care settings. It is recommended physical therapists use their discretion and clinical judgment in this decision making. ## Neutropenia Neutropenia is often present in patients with MM and is an expected side effect following chemotherapy. Although asymptomatic neutropenia is not a medical emergency, neutropenia increases the risk of infection.Febrile neutropenia is an oncologic medical emergency, and patients with febrile neutropenia are often hospitalized for treatment. There are no specific exercise recommendations for patients with leukopenia and neutropenia; therefore, we recommend the following for physical therapy in this population to prevent infection. Patients with MM with neutropenia or leukopenia are immunocompromised, and the use of face masks (barrier for microorganism entry) and regular hand hygiene can reduce their risk of infection. We recommend that patients with MM wear a face mask when ambulating in the hallways and to wash hands properly before and after sessions. Physical therapy equipment and assistive devices should be routinely [bib_ref] Quality of life changes following peripheral blood stem cell transplantation and participation..., Hayes [/bib_ref] Physical Therapy Management of Multiple Myeloma sanitized before and after use by patients, and physical therapist intervention should be conducted individually in the patient's room to avoid infection and the consequences associated with it. [bib_ref] Infections in patients with multiple myeloma in the era of high-dose therapy..., Anaissie [/bib_ref] ## Bony lesions Patients with MM present with myeloma bone disease affecting any part of the skeleton, resulting in bony pain and increased risk of fractures. Bone destruction is primarily mediated by osteolytic metastasis, [bib_ref] Bone metastases: an overview, Macedo [/bib_ref] and it is estimated that 70% to 80% of patients with MM suffer from bone pain, 50% to 60% have fractures, and 2% to 3% have spinal cord compression leading to increased morbidity, poor mobility, and decreased QOL. [bib_ref] EORTC quality of life group. An international field study of the reliability..., Cocks [/bib_ref] Evidence supports that exercise improves physical function in patients with cancer, but additional precautions and modifications are necessary in developing an exercise regimen in this population. Bony lesions are not absolute contraindications to physical therapy intervention; however, components of exercise prescription should be modified and additional precautions should be followed to minimize the risk of fractures (ie, avoiding high-impact activities, end range movements, ie, hyper-and rotational movements, that increase compressive and shearing forces, follow back care principles, and use appropriate mobility aids and braces). [bib_ref] Clinical oncology Society of Australia Exercise and Cancer Group, Cormie [/bib_ref] Physical therapists should be cautious in designing exercises as twisting movements, forward bending, overhead reaching, pushing, pulling, and lifting weights can cause or worsen vertebral fractures in patients with bony lesions. It is also recommended that physical therapists use their clinical judgment and expertise to modify components of programs to fit patient needs. ## Psychosocial benefits (sleep, fatigue, qol) Exercise for patients with MM may be important and beneficial before, during, and after medical treatment given that exercise, for those with and without cancer, can reduce fatigue and muscle wasting and increase QOL. [bib_ref] Recommended exercise protocol to decrease cancer-related fatigue and muscle wasting in patients..., Strong [/bib_ref] [bib_ref] Quality of life changes following peripheral blood stem cell transplantation and participation..., Hayes [/bib_ref] The first phase (peri-transplant) may be an opportunistic period before deconditioning as the benefits of increased fitness may reduce treatment-related recovery time, [bib_ref] Personalized homebased interval exercise training may improve cardiorespiratory fitness in cancer patients..., Wood [/bib_ref] creating a platform for better sleep, less fatigue, and better QOL. Unfortunately, limited research is available during this phase. [bib_ref] Personalized homebased interval exercise training may improve cardiorespiratory fitness in cancer patients..., Wood [/bib_ref] [bib_ref] Optimized patient-trajectory for patients undergoing treatment with high-dose chemotherapy and autologous stem..., Bartels [/bib_ref] The next phase of the treatment pathway is medical therapy, another critical period for patients with MM both for combating the disease symptoms as well as treatment-related symptoms (poor sleep, increased fatigue, and physical/mental health declines). 3-6 A limited number of research articles report on exercise programs for patients with MM during treatment. [bib_ref] Effects of exercise on fatigue, sleep, and performance: a randomized trial, Coleman [/bib_ref] [bib_ref] Optimized patient-trajectory for patients undergoing treatment with high-dose chemotherapy and autologous stem..., Bartels [/bib_ref] [bib_ref] Exercise compliance among patients with multiple myeloma undergoing chemotherapy: a retrospective study, Shallwani [/bib_ref] [bib_ref] Inpatient rehabilitation in persons with multiple myeloma-associated fractures: an analysis of 8..., Cheng [/bib_ref] [bib_ref] Multimodal exercise training during myeloablative chemotherapy: a prospective randomized pilot trial, Oechsle [/bib_ref] [bib_ref] Feasibility of exercise during treatment for multiple myeloma, Coleman [/bib_ref] The last phase, or post-treatment phase, is again a different but critical recovery period. The treatmentrelated deconditioning, increased fatigue, and reduced QOL could all negatively impact the patient physically and mentally. Multiple studies have assessed the effects of mixed training programs during this phase. [bib_ref] Effects of exercise in combination with epoetin alfa during high-dose chemotherapy and..., Coleman [/bib_ref] [bib_ref] Telephone-delivered nutrition and exercise counselling after auto-SCT: a pilot randomised controlled trial, Hung [/bib_ref] [bib_ref] Strength training to enhance early recovery after hematopoietic stem cell transplantation, Hacker [/bib_ref] Provided that therapyrelated deconditioning may result in worsened sleep, fatigue, and QOL, it is important to implement guidelines that may reduce the psychosocial impact. Standard treatment guidelines typically call for bedrest during this phase; however, a more physical activity-based routine may be required to reduce recovery time and aid with these psychosocial aspects. ## Sleep and fatigue benefits The research regarding sleep and fatigue outcomes involves strictly home-based, individualized exercise programs during medical therapy. [bib_ref] Effects of exercise on fatigue, sleep, and performance: a randomized trial, Coleman [/bib_ref] [bib_ref] Feasibility of exercise during treatment for multiple myeloma, Coleman [/bib_ref] The results suggest that these exercise interventions (low-intensity aerobic/strengthening exercise) during treatment can decrease fatigue and increase total minutes and percentage of sleep. This highlights that exercise may aid with deconditioning and recovery time, [bib_ref] Effects of exercise on fatigue, sleep, and performance: a randomized trial, Coleman [/bib_ref] [bib_ref] Exercise compliance among patients with multiple myeloma undergoing chemotherapy: a retrospective study, Shallwani [/bib_ref] [bib_ref] Multimodal exercise training during myeloablative chemotherapy: a prospective randomized pilot trial, Oechsle [/bib_ref] which may positively impact psychosocial well-being of these patients. [bib_ref] Inpatient rehabilitation in persons with multiple myeloma-associated fractures: an analysis of 8..., Cheng [/bib_ref] [bib_ref] Feasibility of exercise during treatment for multiple myeloma, Coleman [/bib_ref] Fatigue and QOL Benefits Multiple studies have explored psychosocial factors during or after medical therapy. [bib_ref] Effects of exercise in patients treated with stem cell transplantation for a..., Persoon [/bib_ref] [bib_ref] Telephone-delivered nutrition and exercise counselling after auto-SCT: a pilot randomised controlled trial, Hung [/bib_ref] [bib_ref] Strength training to enhance early recovery after hematopoietic stem cell transplantation, Hacker [/bib_ref] The research supporting this guideline for during medical treatment periods tends to incorporate supervised, multimodal, low-intensity aerobic and/or strength/resistance-training regimens, all tailored to individual needs. Although the studies were review based 25 or had a mixed hematological cancer sample, [bib_ref] Multimodal exercise training during myeloablative chemotherapy: a prospective randomized pilot trial, Oechsle [/bib_ref] the results identify that patients undergoing medical treatment who are exercisecompliant tend to experience reduced fatigue and better QOL, particularly in physical functioning. After medical treatment, these patients embrace deconditioning and enter the recovery phase. Multiple studies met the criteria for inclusion. [bib_ref] Effects of exercise in patients treated with stem cell transplantation for a..., Persoon [/bib_ref] [bib_ref] Telephone-delivered nutrition and exercise counselling after auto-SCT: a pilot randomised controlled trial, Hung [/bib_ref] [bib_ref] Strength training to enhance early recovery after hematopoietic stem cell transplantation, Hacker [/bib_ref] These programs utilized a combination of high-or lowintensity exercise with both supervised and/or unsupervised sessions to understand the impact on psychosocial well-being. Although no significant differences were identified, all studies highlight decreased fatigue and better QOL than usual care. With little to no adverse events, it would be recommended to follow a tailored exercise program during and after treatment to aid with recovery and deconditioning by improving psychosocial aspects of the patients' lives. The results of the studies above highlight the importance of exercise during and after medical therapy to positively influence the mental well-being of the patient. Although some of the research obtained above involves mixed MM and hematological samples, the similar treatment pathways suggest that the results may be applicable to patients with MM. Of note, study limitations (mixed and small samples, contamination of control group, etc.) must be considered prior to prescribing exercise to patients with MM during and post-medical therapy. However, given the benefits described above, along with a low risk of harm to the patient, the results suggest that clinicians may prescribe exercise to reduce sleep, fatigue, and QOL issues, pending individualized considerations are met. Further, it was identified that patients with skeletal issues can exercise safely but may ultimately require supervision and thoughtful modifications to their exercise regimen. ## Physical benefits (exercise adherence, and functional mobility and performance) Exercise before, during, and after medical treatment may be difficult due to the disease process and/or the aggressive debilitating side effects. As such, a limited number of articles reported physical outcomes of mixed exercise programs for patients with MM before, [bib_ref] Optimized patient-trajectory for patients undergoing treatment with high-dose chemotherapy and autologous stem..., Bartels [/bib_ref] during, 5,25-30 and after medical therapy. [bib_ref] Effects of exercise in patients treated with stem cell transplantation for a..., Persoon [/bib_ref] [bib_ref] Telephone-delivered nutrition and exercise counselling after auto-SCT: a pilot randomised controlled trial, Hung [/bib_ref] [bib_ref] Strength training to enhance early recovery after hematopoietic stem cell transplantation, Hacker [/bib_ref] Exercise Adherence Before undergoing medical therapy may be the most opportune time to increase aerobic capacity and strength, thereby aiding with the impending deconditioning and recovery process. The research for patients with MM in this phase is limited, but the results suggest that it is safe and feasible as an unsupervised program; however, compliance with strength training was minimal. [bib_ref] Personalized homebased interval exercise training may improve cardiorespiratory fitness in cancer patients..., Wood [/bib_ref] [bib_ref] Optimized patient-trajectory for patients undergoing treatment with high-dose chemotherapy and autologous stem..., Bartels [/bib_ref] Aerobic training in the form of walking may be the preferred modality yet may not provide enough benefit, compared with resistance and high-intensity training, for these patients. [bib_ref] Optimized patient-trajectory for patients undergoing treatment with high-dose chemotherapy and autologous stem..., Bartels [/bib_ref] More research is required in this phase to understand the impact of exercise in the later stages of the treatment pathway. ## Functional mobility and performance benefits Many studies highlight the physical benefits of exercise during and after medical treatment. Functional mobility during and after deconditioning is an important aspect of recovery, as these patients need the strength and aerobic capacity to function with all activities of daily living. During treatment, these patients will typically become inpatients, and supervised exercise or rehabilitation may be implemented at this time. The evidence suggests that this is feasible as no adverse events for either aerobic or strength training exercises were reported, [bib_ref] Optimized patient-trajectory for patients undergoing treatment with high-dose chemotherapy and autologous stem..., Bartels [/bib_ref] [bib_ref] Exercise compliance among patients with multiple myeloma undergoing chemotherapy: a retrospective study, Shallwani [/bib_ref] [bib_ref] Inpatient rehabilitation in persons with multiple myeloma-associated fractures: an analysis of 8..., Cheng [/bib_ref] with potential for functional mobility and selfcare improvements to aid with repatriation to the home environment. [bib_ref] Inpatient rehabilitation in persons with multiple myeloma-associated fractures: an analysis of 8..., Cheng [/bib_ref] Multiple studies have reviewed more specific performancerelated outcomes for exercise during the treatment phase, both with full MM samples [bib_ref] Effects of exercise on fatigue, sleep, and performance: a randomized trial, Coleman [/bib_ref] [bib_ref] Feasibility of exercise during treatment for multiple myeloma, Coleman [/bib_ref] [bib_ref] Effects of exercise in combination with epoetin alfa during high-dose chemotherapy and..., Coleman [/bib_ref] and mixed hematological cancer samples. [bib_ref] Feasibility of exercise during treatment for multiple myeloma, Coleman [/bib_ref] [bib_ref] Effects of exercise in patients treated with stem cell transplantation for a..., Persoon [/bib_ref] These studies incorporate homebased or supervised, tailored exercise programs on physical performance benefits (aerobic capacity, muscular strength, and physiological changes). As expected, all patients typically experienced declines in physical performance, yet the trends suggest that exercise, if adhered to, reduces this impact, allowing patients to maintain close to baseline scores. [bib_ref] Effects of exercise on fatigue, sleep, and performance: a randomized trial, Coleman [/bib_ref] [bib_ref] Effects of exercise in combination with epoetin alfa during high-dose chemotherapy and..., Coleman [/bib_ref] [bib_ref] Effects of exercise in patients treated with stem cell transplantation for a..., Persoon [/bib_ref] Specifically, these programs may allow for an increase in aerobic capacity and muscular strength compared with usual care [bib_ref] Multimodal exercise training during myeloablative chemotherapy: a prospective randomized pilot trial, Oechsle [/bib_ref] and, not surprisingly, support a higher rating of good overall condition, more physical activity, and better integration into daily life. The last phase of the treatment pathway, post-therapy, incorporates 2 accepted studies. [bib_ref] Telephone-delivered nutrition and exercise counselling after auto-SCT: a pilot randomised controlled trial, Hung [/bib_ref] [bib_ref] Strength training to enhance early recovery after hematopoietic stem cell transplantation, Hacker [/bib_ref] Home-based, tailored programs can benefit patients in terms of strength, body composition, and physical activity. The clinically important trends highlighted that more patients had maintenance of body composition and higher rate of weekly physical activity, again with aerobic training (walking) as a preference. In terms of strength, all patients experienced a decline from baseline, but those who exercised had a less severe decline. The research for post-treatment exercise suggests benefits of early intervention for stable, mixed hematological patients to support early recovery. The evidence for physical benefits of exercise before, during, and after treatment exists for patients with MM. These mixed, individualized exercise programs may create a stronger physical base prior to treatment and reduce the impact during the deconditioning phase, possibly reducing recovery time. With multiple articles suggesting this patient population can adhere to a tailored regimen, we recommend that physical therapists utilize these guidelines to develop physical activity-based treatment plans at all stages of the medical therapy pathway. It is clear however, that they must take into consideration all aspects of the patient's health when determining these plans in order to avoid unnecessary injury or complications during an already complex health situation. Further, those with skeletal issues can still exercise but may require supervision and motivation to follow through with any program. Overall, these studies have limitations (ie, retrospective design, small/mixed sample sizes), but the trends support both supervised/unsupervised and tailored exercise for this population during all stages of the treatment protocol, and, generally speaking, this can be inexpensive and require minimal resources while potentially providing multiple physical and mental benefits. ## New and current research A quick scoping review was conducted in June 2020 by 1 of the original investigators (Z.M.) to identify any new evidence supporting or conflicting with the current views of this guideline. The review uncovered 8 articles that met the inclusion criteria set for the current guideline. Of note, these articles were not included in the current guideline development process but will be included in the 2025 guideline update. In terms of interventional studies, the results highlight similar trends as mentioned throughout this guideline. With regards to feasibility, multiple studies deemed exercise pretreatment and during medical treatment to be successful (excellent adherence rate, no adverse events), particularly as a positive emotional impact prior to the deconditioning. [bib_ref] Supervised and home-based physical exercise in patients newly diagnosed with multiple myeloma-a..., Larsen [/bib_ref] [bib_ref] Physical exercise prior to hematopoietic stem cell transplantation: a feasibility study, Van Haren [/bib_ref] [bib_ref] Effects of partly supervised and home-based exercise program in patients undergoing hematopoietic..., Kabak [/bib_ref] Other studies assessing exercise during and post medical treatment focused highly on individualized exercise in which daily laboratory values were utilized to make exercise adjustments. With outcomes focused on fatigue, fitness, and QOL, the trends suggest that exercise can be beneficial, supporting the current guideline in that exercise may have a multimodal positive or neutral effect throughout the deconditioning process. [bib_ref] Fatigue, quality of life and physical fitness following an exercise intervention in..., Koutoukidis [/bib_ref] [bib_ref] Safety and feasibility of inspiratory muscle training for hospitalized patients undergoing hematopoietic..., De Almeida [/bib_ref] [bib_ref] Effects of partly supervised and home-based exercise program in patients undergoing hematopoietic..., Kabak [/bib_ref] These recent findings further extend our understanding that this patient population requires highly individualized exercise to optimize their treatment pathway. In terms of new research, a study found that inspiratory muscle training plus conventional physical therapy may aid with reduced negative symptoms (ie, less need for oxygen therapy) compared with conventional physical therapy alone. [bib_ref] Safety and feasibility of inspiratory muscle training for hospitalized patients undergoing hematopoietic..., De Almeida [/bib_ref] The current guideline does not explore inspiratory breathing specifically, and thus these results pose an interesting new pathway for future research. The results of the 2 meta-analyses [bib_ref] Aerobic physical exercise for adult patients with haematological malignancies, Knips [/bib_ref] [bib_ref] Exercise for physical fitness, fatigue and quality of life of patients undergoing..., Liang [/bib_ref] suggest that exercise has a neutral or positive effect on most outcomes studied in the literature thus far, with more possible positive effects on muscle strength, [bib_ref] Exercise for physical fitness, fatigue and quality of life of patients undergoing..., Liang [/bib_ref] fatigue, [bib_ref] Aerobic physical exercise for adult patients with haematological malignancies, Knips [/bib_ref] [bib_ref] Exercise for physical fitness, fatigue and quality of life of patients undergoing..., Liang [/bib_ref] and QOL. [bib_ref] Aerobic physical exercise for adult patients with haematological malignancies, Knips [/bib_ref] [bib_ref] Exercise for physical fitness, fatigue and quality of life of patients undergoing..., Liang [/bib_ref] A subgroup analysis also suggests pre-transplant exercise has a favorable effect on upper/lower body muscle strength, fatigue, and QOL, but there were no effects on anything except QOL for all other treatment stages. [bib_ref] Exercise for physical fitness, fatigue and quality of life of patients undergoing..., Liang [/bib_ref] Interestingly, the results from Knips and colleagues 42 suggest no clear evidence on the majority of outcomes but indicate that the number and size of trials need to increase significantly. Unfortunately, there is still minimal literature in this field, and this limits the results of both of these meta-analyses. In addition, Mohammed et al [bib_ref] Physical therapy pathway and protocol for patients undergoing hematopoietic stem cell transplantation:..., Mohammed [/bib_ref] conducted a literature review and developed a protocol for patients undergoing hematopoietic stem cell transplantation, and it supports the recommendations proposed by our group. Since August 2018, the published studies generally support the evidence for individualized exercise throughout the treatment process in this patient population. The current guideline has evidence to suggest that exercise is important throughout the treatment process to combat deconditioning, of which the most recent research furthers our understanding. As most of the newly published research are feasibility studies, there is a need for large, randomized, and multicenter studies for strictly patients with MM. This said, the topic of individualized exercise across the treatment pathway for patients with MM is continuously moving forward, and the results suggest that it is feasible, safe, and effective for this patient population. ## Implementation recommendations These guidelines included a physical therapist intervention in multiple settings, such as acute care, outpatient department, and home environment, and these variables may affect the translation of evidence into practice. Physical therapists should assess their own practice environment and use their clinical skills to implement the AS based on patients' needs. We recommend that the following strategies be implemented in practice: (1) keep a copy of these guidelines at your practice; (2) share these guidelines with your peers (physical therapists) and patients, and with the physicians, oncologists, and hematologist of your patients who are interested in learning about physical therapy for MM; and (3) build relationships with referral sources to encourage early referrals of patients with MM. We are planning to revise these guidelines in 2025 based on the feedback from physical therapists and their patients and findings from updated literature reviews. # Strength and limitations This guideline was developed with a combination of systematic review and critical appraisal as well as with expert opinion. In this sense, the guideline may lack adequate evidence, particularly with the latter. However, to increase the merit of this guideline, a multidisciplinary team was utilized. This team consisted of researchers, physical therapists (with oncology/hematology experience), an exercise physiologist, a physician, and a direct consultation with a hematologist. The ASs were also reviewed by physical therapists with specific experience in treating patients with MM, which further strengthens the validity of the guideline. Furthermore, this guideline was reviewed and rated by methodologists with clinical and research experience in oncology. [fig] Figure: Preferred Reporting Items for Systematic Reviews (PRISMA) flow diagram. [/fig] [table] Table 1: Levels of Evidence a There is an absence of research on the topic, or higher-quality studies conducted on the topic disagree with respect to their conclusions. The recommendation is based on these conflicting or absent studies. with permission of Wolters Kluwer Health Inc. The Creative Commons license does not apply to this table. Use of the material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health, Inc. Please contact permissions@lww.com for further information. [/table] [table] Table 3: AGREE II Domain Scores and Recommendations for Use of This Guideline a [/table]	None	https://academic.oup.com/ptj/article-pdf/101/1/pzaa180/36187248/pzaa180.pdf	Abstract Objective Individuals with multiple myeloma (MM) often have reduced functional performance due to the cancer itself or as a direct side effect of cancer treatments. Physical therapy is a part of cancer rehabilitation; however, no guidelines are available to provide information and direction for physical therapists managing patients with MM. The goal of this guideline is to provide recommendations based on a systematic review and consensus process that physical therapists can use to manage patients with MM. Methods A systematic review of the literature published until August 2018 was performed in 8 databases with 2 independent reviewers assessing quality. Seventeen articles were identified as relevant, and a draft guideline was developed in the form of action statements. A total of 10 physical therapists with hematology experience and 10 patients with MM were recruited for consensus process. A priori threshold of 80% agreement was used to establish a consensus for each statement. The draft guidelines were reviewed externally by 4 methodologists using the AGREE II tool and a stakeholder representing OH (Cancer Care Ontario) Program in Evidence Based Care, McMaster University. The final guideline was reviewed and officially endorsed by the Canadian Physiotherapy Association. Results A total of 30 action statements were developed that achieved consensus, indicating physical therapy recommendations based on physiological markers (ie, hemoglobin, platelet count), complete patient presentation, and the stage of medical treatment. Conclusion These clinical practice guidelines were developed to aid physical therapists in implementing evidence-based and best-practice care for patients with MM to optimize rehabilitation outcomes. Impact These guidelines fill an important knowledge gap and are the first to provide information specifically for physical therapist management of patients with MM.
3fdee5f1c9eb501baefe6834fd704f0be69398b4	pubmed	Evidence-based clinical practice guidelines for Crohn’s disease, integrated with formal consensus of experts in Japan	Evidence-based clinical practice guidelines for Crohn’s disease, integrated with formal consensus of experts in Japan Crohn's disease is a disorder of unknown etiology and complicated pathogenesis. A substantial amount of evidence has accumulated recently and has been applied to clinical practice. The present guidelines were developed based on recent evidence and the formal consensus of experts relevant to this disease. Here we provide an overview of these guidelines, as follows. These guidelines were intended primarily to be used by practitioners in Japan, and the goal of these guidelines is to improve the outcomes of patients with Crohn's disease. # Introduction Crohn's disease (CD) is a complicated disorder of unknown etiology and pathogenesis, involving mainly the small intestine and the colon, but possibly the entire gastrointestinal tract, as well as other organs. Owing to the substantial amount of newer knowledge relevant to the care of CD, the diagnostic and therapeutic strategies for CD have significantly changed, and guidelines to provide appropriate clinical indicators have become necessary. The Japanese Society of Gastroenterology, in collaboration with the Research Group of Intractable Inflammatory Bowel Disease subsidized by the Ministry of Health, Labour and Welfare of Japan, established committees to develop clinical guidelines for CD. The first edition of the guidelines was published in 2010, and an updated version with minor modifications, adding newer therapeutic modalities, was published in 2011. This English version was produced and edited based on the existing updated guidelines. ## Purpose and focus The purpose of developing these guidelines was to provide appropriate clinical indicators for CD to contribute to improved outcomes for patients with CD. The statements in these guidelines cover the standard concept of this disease, as well as describing interventions for diagnosis, treatment, and follow up. The guidelines include descriptions of and interventions for gastrointestinal lesions, complications, extra-intestinal complications, and special situations in adults with CD. Special considerations for children or elderly patients are not included. ## Users and settings The target users of these guidelines are practitioners who provide care for CD patients in clinical settings. The guidelines are intended not only for the use of gastroenterologists, but also for the use of internists, surgeons, and general practitioners who may have the opportunity to care for patients with CD. Although the present guidelines are not intended for the use of patients, patient information may be developed from the guidelines with minor modifications, as clinical questions are extracted from the patient's point of view. ## Features The clinical questions (CQs) have been extracted from the patient's point of view. The basic process was carried out according to the international standardization of guideline development, with particular emphasis on the existing clinical evidence. When evidence was insufficient or inappropriate for practice in Japan, expert opinions were incorporated. In other words, these guidelines aim to provide clinical indicators, with scientific validity as well as applicability and flexibility. The guidelines were developed by the collaborative efforts of the Japanese Society of Gastroenterology and the Research group of Intractable Bowel Disease subsidized by the Ministry of the Health, Labour and Welfare of Japan. The major differences from the corresponding existing clinical practice guidelines formulated by the Research Group of the Ministry of Health, Labour and Welfare of Japan are: (1) the present guidelines place emphasis not only on the healthcare provider's point of view but also on the patient's;the statements are based on literature evidence with review by an expert group; (3) each indicator is accompanied by a strength of recommendation, defined according to the level of relevant evidence and the expert consensus; (4) not only specialists but all practitioners were intended as potential users, and (5) the scope and limitations of these guidelines are explicitly presented. [bib_ref] Crohn's disease in Japan: diagnostic criteria and epidemiology, Yao [/bib_ref]. Methods for developing the guidelines Independent Committees for developing clinical indicators (Development Committee) and for assessment (Assessment Committee), each of which consisted of experts in gastroenterology, general internal medicine, surgery, and clinical epidemiology, were established according to the methods provided by the Guideline Supervision Committee of the Japanese Society of Gastroenterology. The basic process of development was carried out by repeated correspondence between these two committees by which they prepared, evaluated, and modified statements, eventually creating the most appropriate statements for the guidelines. The Development Committee extracted CQs in the clinical practice field from the patient's point of view, and an external media center collected literature published up to 2007 relevant to these CQs, mainly through MEDLINE, the Cochrane Library, and the Japan Medical Abstracts Society. In addition, the members of the Development Committee manually added important literature published up to 2008 to the references in their respective areas. The members of the Development Committee examined the levels of evidence [fig_ref] Table 1: Evidence levels of literature-based information [/fig_ref] for the literature items. Literature items with an evidence level of III or higher were adopted initially, but those with lower levels of evidence were also adopted if relevant to clinical practice. Original articles, as well as reviews and existing guidelines, were selected, with consideration given to clinical interventions that improved patient outcomes, irrespective of the health insurance coverage in Japan. For multiple articles with different levels of evidence, the higher level was adopted. Randomized controlled trials with unwarranted quality were regarded as level III. If a statement was based on an unclear citation, it was considered to be the author's opinion and was regarded as level VI. Statements of recommendation and the corresponding comments were created on the basis of the selected literature, or, for issues without existing evidence, the statements of recommendation and the corresponding comments were created based on the opinions of the members of the Development Committee. The original statements and comments were evaluated by the Assessment Committee, and repetitive modifications were made by the collaborative work of both committees. The Assessment Committee and three external members evaluated the appropriateness of the statements of recommendation on a 1-to 9 scale (from 1 equaling ''most inappropriate'' to 9 equaling ''most appropriate'') according to the Delphi method. The final results after three Delphi rounds were reflected in the adoption of the statements of recommendation and the determination of the grades of recommendation. As there are some therapeutic modalities that were approved for clinical use after the publication of the Japanese Society of Gastroenterology's Clinical Practice Guidelines for Crohn's Disease (published by Nankodo Co., Ltd., Tokyo, Japan), additional searches of the literature relevant to these therapies were performed, and the same process as that described above was employed to create statements of recommendation for these therapies. ## Criteria for setting recommendation grades and interpretations The grade of a recommendation is usually determined parallel to the quality of the evidence on which the statement of recommendation is based, but there are some difficult issues with this process. The level of evidence does not assure the quality of the results of clinical studies, but is defined by the study design. There are some timehonored clinical practices without high evidence; on the other hand, there are some novel modalities in the recent literature with a high level of evidence but whose clinical usefulness is yet to be determined. In addition, a clinical intervention directly affecting human life is not a subject for a randomized controlled trial. For these issues, an expert opinion is essential. We were concerned about the possibility of biased consensus formation owing to the opinions of the dominating expert in the group and the lack of clarity of the impact of the consensus on the recommendations. In these guidelines, the Delphi method was used to form a sound consensus. In addition, the relationship of the consensus to the recommendation grade was clearly defined [fig_ref] Table 2: Criteria for setting recommendation grades Level of evidence Consensus [/fig_ref]. As a rule, the recommendation grades presented in these guidelines were determined following the above-mentioned principles; however, some statements of recommendation that were considered to be obvious by the consensus of the experts even without good evidence were graded as B rather than C1: they are indicated as B. The meanings of the grades thus determined are described in [fig_ref] Table 3: Interpretations of recommendation grades [/fig_ref]. Note that the clinical indicators that were evaluated by the consensus of the experts as not being appropriate (a Delphi median value of 6 or less) were not recommended, as a rule (i.e., those graded as C2 or D), regardless of the quality of the related literature-based evidence. ## Internal review of the guidelines The final drafts of the Clinical Practice Guidelines for Crohn's Disease (published by Nankodo Co., Ltd., Tokyo, Japan) were put up on the website of the Japanese Society of Gastroenterology for 2 months to invite opinions from the members of the Society. They were also distributed to a total of 68 research group members and collaborators of the Research Group of Intractable Inflammatory Bowel Disease subsidized by the Ministry of Health, Labour and Welfare of Japan (who represent experts on inflammatory bowel disease in Japan) for their evaluation of the validity of the guidelines. Minor modifications, made by the adoption of some comments, were made by the collaboration of the Assessment and Development Committees. ## Applicability of the guidelines The literature articles that were used as the basis for creating the statements of recommendation were selected considering their feasibility in clinical practice in Japan. Accordingly, theclinical indicators in these guidelines can be applied to daily clinical practice without any change of current systems/organizations, and therefore they probably do not require any notable additional medical resources. Examining whether these clinical indicators would be covered by the Japanese health insurance system, it appeared that the great majority of them would fall within the coverage of the insurance system. The exceptional indicators that fall outside the range of insurance coverage are accompanied by a note. ## Benefits and risks of applying the guidelines The statements of recommendation in these guidelines are standard clinical indicators for CD. They support the decision-making of practitioners, but they neither regulate nor restrict their clinical practice. They are not intended to be a basis for legal judgments. With the support of specialists as needed, and with the flexible use of the guidelines giving sufficient consideration to the patients' values, we believe the guidelines will contribute to the improved quality of clinical practice and patient outcomes. In actual clinical practice, the patients' values and practitioners' sound judgment are paramount, and it would be inappropriate for these guidelines to be used to control clinical practice, to provide a legal basis for clinical practice, or to restrain practitioners' discretion, and these guidelines would, rather, be considered harmful if used in such manner. [bib_ref] Novel pathophysiological concepts of inflammatory bowel disease, Hibi [/bib_ref]. Independence of the guidelines These guidelines were developed for common objectives by members of the Japanese Society of Gastroenterology and by the Research Group of Intractable Inflammatory Bowel Disease subsidized by the Ministry of Health, Labour and Welfare of Japan. The guidelines were developed independent of any other funding sources and without the cooperation or coordination of any other academic organization, healthcare-providing organization, or patient organization. [formula] I A A C 2 D II A B C2 D III B B C2 D IV B C1 C2 D V C1 (B) C1 C2 D VI C1 (B) C1 C2 D [/formula] A comprehensive list of potential conflicts of interest between health/medical industries and members of the various committees and institutions/organizations who developed the guidelines is provided (see . Such relationships are related to the individual members or the institutions, and no funding has been provided for the development of these guidelines. ## Future issues For these guidelines, the statements of recommendation were created with an emphasis on literature-based evidence in response to the CQs raised from the patients' point of view, and the statements were reviewed and modified by a group of experts. The recommendation grades were determined on the basis of the levels of evidence and then clearly integrated by formal consensus. As a result, we believe that these guidelines would possess internal validity, and clinical applicability and flexibility. They have not, however, been evaluated for their effectiveness, in terms of actual contribution to the improved quality of clinical practice for CD, and this is an issue to be addressed later. With the accumulation of newer evidence, a process of revision of the guidelines will be necessary. These guidelines may need to be revised and supplemented by 3 years or so after their publication. Assessment by the users should be considered for revision, and therefore constructive criticisms are invited. Disclosure of conflicts of interest 1. Disclosure of potential conflicts of interest in relation to health/medical industries The health/medical industry entities from which members of the committees for developing the guidelines were provided with remuneration according to medical professional contracts, or for lectures, written contributions, supervision of publications, etc., or from which they have received research funding, are listed in on their own declaration, regardless of their relationships with the makers of products used for CD. The names of the health/ medical industry entities are those as of June 2011. Publishers and non-profit organizations that adopt a position of neutrality are excluded. ## Means of minimizing conflicts of interest. The statements of recommendation were created on the basis of literature-based evidence. The consensus of the Assessment Committee was formally generated according to the Delphi method to avoid the domination of any particular members. The recommendation grades were determined on the basis of the levels of evidence with integration by formally developed consensus, as clearly indicated by the median values of Delphi rounds. In general, these guidelines were developed in accordance with the proposed Conference on Guideline Standardization (COGS) standard [bib_ref] Standardized reporting of clinical practice guidelines: a proposal from the Conference on..., Shiffman [/bib_ref]. ## How to read the guidelines In the text, CQs are presented according to clinical categories, and each CQ is followed by one or more corresponding statements of recommendation. Each of the statements is accompanied by a recommendation grade that indicates the strength of the recommendation. The recommendation grade, which is defined in [fig_ref] Table 3: Interpretations of recommendation grades [/fig_ref] , is followed by the levels of evidence of the literature articles that are the basis for the recommendation (in Japan and overseas) and the value of the expert group consensus (i.e., the Delphi evaluation median value). The comments provide a general description of the clinical practice related to each CQ. The lists of references are presented after the text. Clinical questions (CQs) and statements I. Disease concept I-1. Definition CQ1: What is CD?- CD is a chronic disease of unknown causes that mainly presents as granulomatous inflammatory lesions of the gastrointestinal tract. C1 (Japan VI, overseas VI; 8). ## Comments CD is a chronic inflammatory disease of the gastrointestinal tract characterized by discretely distributed transmural granulomatous inflammations and fistulas. Lesions of CD may occur throughout the entire gastrointestinal tract, but they occur most commonly in the small intestine, the colon (especially the ileocecal region), and the perianal region. The disease occurs at a young age, and lasts chronically, with remissions and relapses of symptoms and signs such as abdominal pain, diarrhea, hematochezia, fever, perianal symptoms, and weight loss, resulting in a reduced quality of life for the patients. Also, CD may cause extra-intestinal complications in the joints, the skin, the eyes, and other parts of the body. CD and ulcerative colitis (UC) are together referred to generically as inflammatory bowel disease (IBD). Although they have common and/or similar features, they are considered to be mutually distinct. ## I-2. epidemiology CQ2: How common is CD, in what age group does it occur, and in Japan, are there any differences from other countries? [bib_ref] Incidence and prevalence of inflammatory bowel disease in Japan: nationwide epidemiological survey..., Morita [/bib_ref] [bib_ref] Crohn's disease in Japan: diagnostic criteria and epidemiology, Yao [/bib_ref] [bib_ref] Age at the onset of intractable disease: based on a clinical database..., Ohta [/bib_ref] [bib_ref] Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences, Loftus [/bib_ref] [bib_ref] The epidemiology and natural history of Crohn's disease in population-based patient cohorts..., Loftus [/bib_ref] - The number of CD patients in Japan is steadily increasing, with a current estimate of more than 30,000. CD is more prevalent among men than women, at an approximate ratio of 1.8: 1.0. B (Japan V; 9). - CD occurs at comparatively young ages, more commonly from the late teens to the early 30s. B* (Japan V; 9) - The prevalence and incidence of CD in Europe and North America are higher than those in Japan, and female preponderance in those areas is noted. C1 (overseas V; 8). ## Comments A Japanese nationwide epidemiological survey in 1991 reported that the prevalence of CD was 5.85 per 100,000 (7.94 among men and 3.83 among women) and that the incidence of CD was 0.51 per 100,000 (0.71 among men and 0.32 among women) [bib_ref] Incidence and prevalence of inflammatory bowel disease in Japan: nationwide epidemiological survey..., Morita [/bib_ref]. The figures were clearly lower than those in Europe and North America. Although no such survey has been conducted since then, the estimated number of CD patients has steadily increased in Japan [bib_ref] Crohn's disease in Japan: diagnostic criteria and epidemiology, Yao [/bib_ref] , and more than 30,000 patients received registered medical services for CD in 2009. The onset of CD is usually in young people, commonly in the early third decade among men and in the late second decade among women [bib_ref] Incidence and prevalence of inflammatory bowel disease in Japan: nationwide epidemiological survey..., Morita [/bib_ref] [bib_ref] Crohn's disease in Japan: diagnostic criteria and epidemiology, Yao [/bib_ref]. According to the Japanese national registration record for medical services, it is estimated that CD occurs more commonly in the third and early fourth decades among men and in the late second decade among women [bib_ref] Age at the onset of intractable disease: based on a clinical database..., Ohta [/bib_ref]. The incidence in countries overseas is usually higher than that in Japan, although it varies from region to region; there are a substantial number of regions with a CD incidence rate of around 10 per 100,000 in Europe and North America. It has been shown that the prevalence of this disease has been increasing globally from year to year [bib_ref] Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences, Loftus [/bib_ref]. In general, CD is more common in women in Europe and North America, unlike in Japan [bib_ref] The epidemiology and natural history of Crohn's disease in population-based patient cohorts..., Loftus [/bib_ref]. At present, Japan is ranked in the middle for the prevalence and incidence rates of CD, together with South Korea, Oceanic countries, and South Africa [bib_ref] Crohn's disease in Japan: diagnostic criteria and epidemiology, Yao [/bib_ref]. ## I-3. etiology CQ3: What causes CD? Is it inherited? What are the risk factors? [bib_ref] State of the art: IBD therapy and clinical trials in IBD, Isaacs [/bib_ref] [bib_ref] Novel pathophysiological concepts of inflammatory bowel disease, Hibi [/bib_ref] [bib_ref] Inflammatory bowel disease: past, present, and future, Sands [/bib_ref] [bib_ref] Familial occurrence of inflammatory bowel disease, Orholm [/bib_ref] [bib_ref] Familial aggregation in Crohn's disease: increased age-adjusted risk and concordance in clinical..., Peeters [/bib_ref] [bib_ref] Consumption of refined sugar by patients with Crohn's disease, ulcerative colitis, or..., Jarnerot [/bib_ref] [bib_ref] Dietary habits as risk factors for inflammatory bowel disease, Tragnone [/bib_ref] [bib_ref] Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in..., Sakamoto [/bib_ref] [bib_ref] Crohn's disease patients who quit smoking have a reduced risk of reoperation..., Ryan [/bib_ref] [bib_ref] Predictors of response to infliximab in patients with Crohn's disease, Parsi [/bib_ref] [bib_ref] Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study, Felder [/bib_ref] [bib_ref] Increased risk of inflammatory bowel disease associated with oral contraceptive use, Boyko [/bib_ref] - The causes of CD have not been identified. C1 (Japan VI, overseas VI; 8). - A tendency for familial occurrence is noted. B (overseas IVa; 8). - Some causal relationships between diet and CD have been reported, though the evidence is not conclusive. B (Japan IVb, overseas IVb; 8). - Smoking is a risk factor for CD. B (overseas III; 8). - Nonsteroidal anti-inflammatory drugs (NSAIDs) and oral contraceptives are potential factors for the exacerbation of CD. C1 (overseas IVb; 7). ## Comments The causes of CD have not yet been identified. The current international consensus is that the intestinal inflammation is caused by a disordered immunomodulatory mechanism, with exposure to various environmental factors in an individual with genetic susceptibility [bib_ref] State of the art: IBD therapy and clinical trials in IBD, Isaacs [/bib_ref] [bib_ref] Novel pathophysiological concepts of inflammatory bowel disease, Hibi [/bib_ref] [bib_ref] Inflammatory bowel disease: past, present, and future, Sands [/bib_ref]. A somewhat higher incidence of CD is reported among relatives [bib_ref] Familial occurrence of inflammatory bowel disease, Orholm [/bib_ref] [bib_ref] Familial aggregation in Crohn's disease: increased age-adjusted risk and concordance in clinical..., Peeters [/bib_ref] , and reports of familial clustering indicate the presence of a genetic mechanism. Studies are underway to find the disease susceptibility genes for CD. Regional differences in the incidence of CD suggest a causal relationship between diet and CD, and many clinical and epidemiological studies have been reported. Some overseas reports found a causal relationship between CD and high intakes of carbohydrates (particularly sugar) [bib_ref] Consumption of refined sugar by patients with Crohn's disease, ulcerative colitis, or..., Jarnerot [/bib_ref] [bib_ref] Dietary habits as risk factors for inflammatory bowel disease, Tragnone [/bib_ref] , and some reports from Japan showed a causal relationship between CD and ''fast foods'' with high contents of fats and sugar [bib_ref] Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in..., Sakamoto [/bib_ref]. However, no food has been concluded to be a risk factor for CD. Smoking is considered to be a risk factor for CD. Reports have shown that smoking is not only related to the onset, relapse, and exacerbation of CD, but also that smoking cessation lowered the postoperative recurrence rate [bib_ref] Crohn's disease patients who quit smoking have a reduced risk of reoperation..., Ryan [/bib_ref]. Smoking also affects the efficacy of infliximab treatment [bib_ref] Predictors of response to infliximab in patients with Crohn's disease, Parsi [/bib_ref]. Among many drugs evaluated, NSAIDs and oral contraceptives have been shown to be associated with the onset and exacerbation of CD [bib_ref] Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study, Felder [/bib_ref] [bib_ref] Increased risk of inflammatory bowel disease associated with oral contraceptive use, Boyko [/bib_ref]. I-4. Pathophysiology, classification, and disease activity CQ4: What kind of pathophysiological conditions are present in CD, and how are they recognized? [bib_ref] A simple classification of Crohn's disease: report of the Working Party for..., Gasche [/bib_ref] - To provide appropriate treatment, it is necessary to exactly recognize the disease extent, disease pattern, and degree of disease activity. B* (Japan VI, overseas: VI 9). ## Comments The pathophysiological conditions of CD are complex, but correct recognition is the first step for appropriate management. It is important to identify the distribution of the lesions, to recognize the disease pattern, and to assess disease activity/severity. The lesions are often found in the small intestine, the colon (particularly in the ileocecal region), and the perianal region, and are classified as the ileal, colonic, and ileocolonic types. Note, however, that lesions can occur at any site in the gastrointestinal tract; moreover, CD may have extra-intestinal complications causing systemic involvement. Treatment plans differ according to the sites of involvement. According to an international proposal, the disease patterns can be classified as ''Inflammatory'', ''Penetrating'', and ''Stricturing'' [bib_ref] A simple classification of Crohn's disease: report of the Working Party for..., Gasche [/bib_ref]. Recognition of the disease pattern is also important for appropriate treatment. Furthermore, it is necessary to assess the disease activity. Treatment during the remission phase when the symptoms have abated or are absent is different from treatment during the active phase when various symptoms interfere with daily life. For the objective evaluation of the disease activity and severity, the Crohn's Disease Activity Index (CDAI) is available, but it is not suitable for daily clinical practice. The Index of Inflammatory Bowel Disease (IO-IBD) is simple, but it does not assist in the selection of appropriate treatment options. At present, there is no universal classification of CD severity available for use in Japan. In general clinical practice, the disease activity can be assessed by the comprehensive evaluation of subjective symptoms, clinical findings, and laboratory investigations. ## I-5. cd progression CQ5: How does CD progress in the long term? Is there an increased risk of cancer? Is life expectancy shortened? [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Carter [/bib_ref] [bib_ref] The risk of cancer in patients with Crohn's disease, Von Roon [/bib_ref] [bib_ref] Crohn's disease and intestinal cancer, Matsui [/bib_ref] [bib_ref] Risks and clinical features of colorectal cancer complicating Crohn's disease in Japanese..., Yano [/bib_ref] [bib_ref] Systematic review: has disease outcome in Crohn's disease changed during the last..., Wolters [/bib_ref] [bib_ref] Clinical course and longterm prognosis of Japanese patients with Crohn's disease: predictive..., Oriuchi [/bib_ref] [bib_ref] Mortality and cause of death in Japanese patients with Crohn's disease, Uno [/bib_ref] - CD persists, with remissions and relapses, for a long period of time. C1 (Japan VI, overseas VI; 9). - During disease progression, the daily life of CD patients is often disturbed. C1 (Japan V, overseas V; 8). - The incidence of cancer among CD patients is slightly elevated. B (Japan V, overseas IVb; 8). - The life expectancy of CD patients is slightly shorter than that of healthy individuals. C1 (Japan V, overseas IVb; 7). overseas, 15 % of CD patients become unable to work 5-10 years after the diagnosis [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Carter [/bib_ref]. According to a crosssectional study in Japan, fewer than 30 % of CD patients are able to work in full-time employment throughout the year. Intra-and extra-intestinal complications are considered to have the most negative impact on the activities of daily living (ADL) among CD patients. An overseas meta-analysis report indicates that the relative risks of cancer in the colon and the small intestine in CD patients are 2.4 and 28.4, respectively [bib_ref] The risk of cancer in patients with Crohn's disease, Von Roon [/bib_ref]. Although the relative risk of small-intestinal cancer is conspicuously higher than that of the colon, its significance is not clear because the absolute number of these cancer cases is very small. According to a Japanese report on the association of CD and cancer in the colon, the small intestine, and the anal canal, most cases of such cancers are discovered at an advanced stage. Most reports on the incidence of cancer in CD patients in Japan are based on case-series studies, but some controlled studies suggest that the incidence in Japan is similar to that in Europe and North America [bib_ref] Crohn's disease and intestinal cancer, Matsui [/bib_ref] [bib_ref] Risks and clinical features of colorectal cancer complicating Crohn's disease in Japanese..., Yano [/bib_ref]. Six of seven overseas area cohort studies estimate that the mortality in CD patients has been greater than 1.0, and has been stable in the past 40 years [bib_ref] Systematic review: has disease outcome in Crohn's disease changed during the last..., Wolters [/bib_ref]. Two reports from Japan showed different conclusions: one reported that mortality among CD patients was higher, while the other reported that mortality was similar to that of the healthy population [bib_ref] Clinical course and longterm prognosis of Japanese patients with Crohn's disease: predictive..., Oriuchi [/bib_ref] [bib_ref] Mortality and cause of death in Japanese patients with Crohn's disease, Uno [/bib_ref]. In general, CD does not seem to significantly reduce the life expectancy of the patients. II. Diagnosis [fig_ref] Figure 1: Diagnostic [/fig_ref] II-1. Clinical symptoms CQ1: What are the clinical symptoms of CD? [bib_ref] Clinical presentation and diagnosis of Crohn's disease, Forbes [/bib_ref] - Abdominal pain and diarrhea are the most common symptoms. Symptoms due to perianal lesions and hematochezia are also commonly encountered. C1 (Japan VI, overseas V; 8). - Although systemic symptoms and signs such as weight loss, fever, general malaise and anorexia, and oral aphthous ulcerations are often observed, they are not highly specific for CD. C1 (Japan VI, overseas V; 8). ## Comments Abdominal pain (70 %) and diarrhea are commonly encountered at the time of diagnosis. Hematochezia is observed in 30 % of patients, but is usually not massive. Generally, abdominal pain is more common in the smallintestinal type, whereas hematochezia and diarrhea are more common in the colonic type. In the course of the disease progress, perianal lesions are observed in more than 50 % of patients, and fistulas and abscesses manifest in approximately 15 % of patients [bib_ref] Clinical presentation and diagnosis of Crohn's disease, Forbes [/bib_ref]. Systemic symptoms and signs such as weight loss and fever are found in 40-70 % of patients at the time of diagnosis. Weight loss is more common in the small-intestinal type. Systemic symptoms such as general malaise and anorexia, aphthous stomatitis, and shallow ulcers in the oral cavity are often observed during the progress of the disease, but they are not highly specific for CD [bib_ref] Clinical presentation and diagnosis of Crohn's disease, Forbes [/bib_ref]. Extra-intestinal complications such as lesions in the joints, skin, and eyes are observed in approximately 2-10 % of patients [bib_ref] Clinical presentation and diagnosis of Crohn's disease, Forbes [/bib_ref]. CQ2: What are the complications associated with CD? [bib_ref] Clinical presentation and diagnosis of Crohn's disease, Forbes [/bib_ref] [bib_ref] Predictors of Crohn's disease, Beaugerie [/bib_ref] [bib_ref] Clinical phenotype is related to HLA genotype in the peripheral arthropathies of..., Orchard [/bib_ref] [bib_ref] Incidence and prevalence of Crohn's disease in the county of Copenhagen, 1962-87:..., Munkholm [/bib_ref] [bib_ref] The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study, Bernstein [/bib_ref] [bib_ref] Sweet's syndrome: an unusual cutaneous feature of Crohn's disease or ulcerative colitis...., Travis [/bib_ref] - Intestinal complications of CD include stenosis, fistulas (internal and external), abscess formation, massive hemorrhage, and colorectal cancer. B* (Japan V, overseas V; 9). - Extra-intestinal complications of CD include joint lesions (e.g., joint pain, acute peripheral arthritis, and reactive arthritis), skin lesions (e.g., erythema nodosum, Sweet's disease, and pyoderma gangrenosum), eye lesions (e.g., iritis and episcleritis), and primary sclerosing cholangitis (PSC). C1 (Japan V, overseas V; 8). - Complications to which children are susceptible include growth retardation, osteoporosis, and angitis. C1 (Japan V, overseas V; 7). ## Comments Intestinal complications of CD include stenosis, internal and/or external fistulas, and abscess formation, any of which are not infrequently candidates for surgical interventions. Complications increase with the disease progress [bib_ref] Predictors of Crohn's disease, Beaugerie [/bib_ref]. CD with intestinal complications is known as the disabling type [bib_ref] Predictors of Crohn's disease, Beaugerie [/bib_ref] , and thus it is important to prevent these complications or treat them appropriately in order to maintain the patients' QOL. Massive hemorrhage occurs in 0.6-5 % of patients, and it usually arises from anastomotic sites and the small intestine [bib_ref] Clinical presentation and diagnosis of Crohn's disease, Forbes [/bib_ref]. Signs of joint lesions include joint pain or acute peripheral arthritis (type 1: fewer than five joints, mainly in the large joints, associated with the CD activity) and reactive arthritis (type 2: polyarthritis in the small joints, not associated with the CD activity) [bib_ref] Clinical phenotype is related to HLA genotype in the peripheral arthropathies of..., Orchard [/bib_ref]. Joint symptoms are found in 30 % or more (arthralgia, 14.3 %; type 1 arthritis, 6 %; type 2 arthritis, 4 %; and axial arthropathy, 9.9 %) [bib_ref] Clinical phenotype is related to HLA genotype in the peripheral arthropathies of..., Orchard [/bib_ref]. The reported association of CD with skin lesions, including erythema nodosum, Sweet's disease, and pyoderma gangrenosum, has been increasing. According to an overseas report, approximately 2.2 % of IBD patients have skin symptoms [bib_ref] Incidence and prevalence of Crohn's disease in the county of Copenhagen, 1962-87:..., Munkholm [/bib_ref] [bib_ref] The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study, Bernstein [/bib_ref]. The frequency of erythema nodosum is about three times as high as that of pyoderma in IBD patients. Both skin conditions are more likely to manifest as a complication of CD rather than UC. Sweet's disease is rarely found in CD patients (30 reported cases in Europe and North America) [bib_ref] Sweet's syndrome: an unusual cutaneous feature of Crohn's disease or ulcerative colitis...., Travis [/bib_ref]. Nonspecific skin eruptions are more often seen among CD patients than in healthy people, but they are not correlated with the disease activity. Iritis and episcleritis are found in 1-2 % of IBD patients [bib_ref] The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study, Bernstein [/bib_ref]. PSC as a complication of CD is found at a rate of 1-3 %, which is lower than that in UC. Psoriasis is more common in CD patients and their siblings than in the general population. Complications more often found in children include growth retardation, osteoporosis, and angitis [bib_ref] Clinical presentation and diagnosis of Crohn's disease, Forbes [/bib_ref]. The frequency of extra-intestinal complications is higher among children with IBD than in adults with IBD, and some reports indicate that the rate of such complications in children is as high as 35 % [bib_ref] Clinical presentation and diagnosis of Crohn's disease, Forbes [/bib_ref] [bib_ref] Clinical phenotype is related to HLA genotype in the peripheral arthropathies of..., Orchard [/bib_ref] [bib_ref] The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study, Bernstein [/bib_ref]. CQ3: What kind of perianal lesions are caused by CD? [bib_ref] AGA technical review on perianal Crohn's disease, Sandborn [/bib_ref] [bib_ref] Surgical pathology and management of anorectal Crohn's disease, Hughes [/bib_ref] - Perianal lesions include anal fissures, anal ulcers, skin tags, anal fistulas, perianal abscesses, anovaginal fistulas, cavitating ulcers, piles, and anal canal cancer. C1 (Japan V, overseas V; 8). Intestinal and extra-intestinal complications ## Comments Perianal lesions are found in more than 50 % of patients with CD, and often precede other symptoms . The frequency of perianal lesions as complications is significantly higher in cases of CD with rectal stenosis than in those without such stenosis [bib_ref] AGA technical review on perianal Crohn's disease, Sandborn [/bib_ref] [bib_ref] Surgical pathology and management of anorectal Crohn's disease, Hughes [/bib_ref]. Hughes [bib_ref] Surgical pathology and management of anorectal Crohn's disease, Hughes [/bib_ref] classified perianal lesions according to the pathological conditions, as follows: primary lesions, i.e., deep ulcers (deep anal fissures and anal ulcers) caused by CD itself; secondary lesions, i.e., secondary lesions originating from the primary lesions via infection or other causes; and incidental lesions, i.e., lesions not related to CD. Recently, cases of anal canal cancer as a complication have also been reported in Japan. It is necessary to survey these lesions carefully in patients with long-term progression of the disease. ## Ii-2. medical interview and physical examination CQ4: What kind of symptoms and physical findings make CD suspected?- Chronic abdominal pain and/or diarrhea in young individuals suggest the possibility of CD, especially when accompanied by weight loss and fever. C1 (Japan VI, overseas VI; 8). - On physical examination, characteristic perianal lesions (preferably checked by colorectal surgeons familiar with CD), findings similar to appendicitis, bowel obstruction, and rectal bleeding indicate CD. C1 (Japan VI, overseas VI; 7). - Although the onset of CD is usually at young ages, it is not rare in the elderly. C1 (Japan VI, overseas VI; 7). ## Comments According to the Proposed Diagnostic Criteria for Crohn's Disease, this disease presents with initial symptoms of ''abdominal pain, diarrhea, weight loss, fever, perianal lesions, symptoms particularly similar to appendicitis, bowel obstruction, intestinal perforation, and/or massive hemorrhage. Furthermore, it may occur with perianal lesions and/or fever (of unknown causes), without abdominal symptoms''. ## Ii-3. diagnostic strategies CQ5: If CD is suspected, how do physicians proceed to the diagnosis? What kind of investigations are required? [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] [bib_ref] Crohn's disease of the upper gastrointestinal tract: the value of endoscopic examination, Witte [/bib_ref] - Obtain blood tests to check for inflammatory activity, malnutrition, and iron-deficiency anemia. C1 (Japan VI, overseas VI; 8). ## Comments Apply blood tests to examine for abnormal inflammatory responses (in terms of white blood cell count, C-reactive protein [CRP], platelet count, and erythrocyte sedimentation rate [ESR]), malnutrition (low serum total protein and albumin, and/or low total cholesterol), and anemia. Employ lower gastrointestinal endoscopy (including histological evaluation), barium enema, and/or smallintestinal contrast radiography as imaging examinations. Check for longitudinal ulcers, a cobblestone-like appearance, stenosis, and fistulas, which are characteristic of CD in such examinations. Use upper gastrointestinal endoscopy with biopsy as much as possible to detect multiple aphthous ulcerations, ulcers, stenosis, and a cobblestonelike appearance as lesions of CD in the upper gastrointestinal tract [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] [bib_ref] Crohn's disease of the upper gastrointestinal tract: the value of endoscopic examination, Witte [/bib_ref]. Imaging procedures are usually used to exclude similar disorders. Stool cultures and serum antibodies are utilized to check for infectious enterocolitis. Regarding intestinal complications, use computed tomography (CT) and/or magnetic resonance imaging (MRI) to check for the presence and the severity of perianal abscesses, anal fistulas, and intra-abdominal abscesses. CQ6: What morphological examinations are necessary to make a diagnosis of CD? [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] [bib_ref] Crohn's disease of the upper gastrointestinal tract: the value of endoscopic examination, Witte [/bib_ref] - Lower-gastrointestinal endoscopy, barium enema radiography, small-intestinal radiography, upper-gastrointestinal endoscopy, upper-gastrointestinal contrast radiography, and histopathological examination are necessary. B* (Japan VI, overseas VI; 9). ## Comments The common sites of involvement by CD are the colon and the distal ileum; therefore, barium enema radiography, lower-gastrointestinal endoscopy (including examination of the terminal ileum and histological evaluation of biopsy specimens), and small-intestinal radiography are usually conducted prior to other examinations. Although upper-gastrointestinal endoscopy is not indispensable, it should be used in cases where a definitive diagnosis could not be made by barium enema radiography or lower-gastrointestinal endoscopy. Small-intestinal endoscopy is helpful in cases where CD lesions are not found on the lower and upper gastrointestinal endoscopic examinations or on contrast radiography despite the clinical suspicion of CD. Although capsule endoscopy is used overseas to detect lesions in the small intestine, it has not been approved for clinical use in Japan because of potential complications at the site of a stenosis. CQ7: What kind of laboratory markers are useful to evaluate the activity of CD? [bib_ref] Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study, Best [/bib_ref] [bib_ref] Development and validation of an endoscopic index of the severity for Crohn's..., Mary [/bib_ref] [bib_ref] Assessment of endoscopic activity index and biological inflammatory markers in clinically active..., Denis [/bib_ref] - Markers of inflammatory response (CRP and ESR) are considered to correlate with the disease activity. C1 (Japan VI, overseas VI; 8). - Nutritional indices (serum total protein and serum albumin) also reflect the disease activity in many cases. C1 (Japan VI, overseas VI; 7). - There is no single index with which to quantitate disease activity to enable an objective assessment; therefore, it is necessary to assess CD disease activity in a comprehensive manner. C1 (Japan VI, overseas VI; 9). ## Comments The disease activity of CD is generally assessed by the CDAI or IOIBD. The CDAI is the most commonly used assessment tool worldwide [bib_ref] Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study, Best [/bib_ref]. CD causes lesions at any site along the entire gastrointestinal tract, and the sites and extent of lesions are related to the disease activity. Generally, the markers of inflammatory response (CRP and ESR) are comparatively well correlated with the CDAI scores indicating the disease activity, but with occasional discrepancies. In patients with severe and extensive disease, especially those with extensive small-intestinal lesions, hypoproteinemia is often present. However, values for nutritional indices may be affected by treatments such as nutritional therapy. Accordingly, no single laboratory test can contribute to the assessment of the disease activity. The Endoscopic Index of Severity of Crohn's Disease (CDEIS) has been proposed as an endoscopic index of disease activity [bib_ref] Development and validation of an endoscopic index of the severity for Crohn's..., Mary [/bib_ref] [bib_ref] Assessment of endoscopic activity index and biological inflammatory markers in clinically active..., Denis [/bib_ref]. This index is obtained by dividing the intestinal tract into five segments (the rectum, the sigmoid/descending colon, the transverse colon, the ascending colon/cecum, and the ileum), determining scores and obtaining subtotals according to the depth and length of ulceration and the area of lesions in each segment, and then calculating an average based on the number of segments with lesions, and adding points for stenosis to the average. Calculation of values in this index is complicated and timeconsuming. The index is not commonly used to evaluate disease activity in clinical practice. ## Ii-4. endoscopy CQ8: When is endoscopic examination necessary to make a diagnosis of CD? [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] [bib_ref] Development and validation of an endoscopic index of the severity for Crohn's..., Mary [/bib_ref] [bib_ref] Assessment of endoscopic activity index and biological inflammatory markers in clinically active..., Denis [/bib_ref] [bib_ref] Colonoscopy in inflammatory bowel disease. Diagnostic accuracy and proposal of an endoscopic..., Pera [/bib_ref] - When clinical symptoms and the laboratory test results suggest CD, promptly examine the patient using lowergastrointestinal endoscopy (including an observation of the terminal ileum) and histological evaluation of biopsy specimens. C1 (Japan VI, overseas VI; 8). - Examine the patient using upper-gastrointestinal endoscopy when a definitive diagnosis has not been made with lower-gastrointestinal endoscopy or when the patient complains of symptoms in the upper gastrointestinal tract. C1 (Japan VI, overseas VI; 8). Comments CD can affect the entire gastrointestinal tract, but the common sites are the colon and the distal ileum. When clinical symptoms and the laboratory test results suggest CD, promptly examine the patient using lower-gastrointestinal endoscopy, including an observation of the terminal ileum, to make a definitive diagnosis, to determine the extent and severity of inflammation, and also to take a biopsy sample for histological examination [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] [bib_ref] Development and validation of an endoscopic index of the severity for Crohn's..., Mary [/bib_ref] [bib_ref] Assessment of endoscopic activity index and biological inflammatory markers in clinically active..., Denis [/bib_ref] [bib_ref] Colonoscopy in inflammatory bowel disease. Diagnostic accuracy and proposal of an endoscopic..., Pera [/bib_ref]. Endoscopy has recently been employed for the treatment of stenosis. Small-intestinal balloon endoscopy may be useful. Upper-gastrointestinal lesions are not rare and may occur at a high rate in patients with CD, with or without related symptoms. The Japanese proposed diagnostic criteria for Crohn's diseaserefer to irregularshaped ulcers and aphthous ulcerations found in both the upper and lower gastrointestinal tract as minor findings39. Accordingly, to make a definitive or differential diagnosis of CD, it is useful to explore lesions by using upper-gastrointestinal endoscopy and by examining biopsy samples for histological evaluation (to check for the presence of noncaseating epithelioid cell granuloma). CQ9: What endoscopic findings are characteristic of CD? [bib_ref] Colonoscopy in inflammatory bowel disease. Diagnostic accuracy and proposal of an endoscopic..., Pera [/bib_ref] [bib_ref] Imaging of the small bowel in Crohn's disease: a review of old..., Saibeni [/bib_ref] - Lower-gastrointestinal endoscopic findings characteristic of CD include discrete or segmental lesions (socalled skip lesions), a cobblestone-like appearance, longitudinal ulcers, irregular-shaped ulcers, multiple aphthous ulcerations, abnormal narrowing and/or stenosis, and fistulas (internal and/or external fistulas). B* (Japan V, overseas VI; 9). - Upper-gastrointestinal endoscopic findings characteristic of CD include a bamboo joint-like appearance, a notch-shaped appearance, cobblestone-like appearance, multiple aphthous ulcerations, erosion, irregular-shaped ulcers, bead-like protrusions, nodular folds, granular mucous membrane, and stenosis. C1 (Japan V, overseas VI; 8). ## Comments It was reported that lower-gastrointestinal endoscopic findings make it possible to differentiate 89 % of CD cases from UC among suspected cases of IBD [bib_ref] Colonoscopy in inflammatory bowel disease. Diagnostic accuracy and proposal of an endoscopic..., Pera [/bib_ref]. Findings helpful in differentiating CD from UC are discrete lesions, cobblestone-like appearance, aphthous ulcerations and longitudinal ulcers, and perianal lesions [bib_ref] Imaging of the small bowel in Crohn's disease: a review of old..., Saibeni [/bib_ref]. Frequently encountered upper-gastrointestinal lesions of CD are a bamboo joint-like appearance in the stomach, gastric and duodenal erosions and/or ulcers, and duodenal notch-like protrusions and/or longitudinal erosions. CQ10: Is examination of the entire gastrointestinal tract necessary in the diagnosis of CD? [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] [bib_ref] Crohn's disease of the upper gastrointestinal tract: the value of endoscopic examination, Witte [/bib_ref] [bib_ref] Imaging of the small bowel in Crohn's disease: a review of old..., Saibeni [/bib_ref] - Examinations of the lower gastrointestinal tract (using endoscopy or barium enema radiography) are almost indispensable for making a diagnosis of CD. B* (Japan VI, overseas VI; 9). - Even after a definitive diagnosis has been made, it is preferable to examine the patient using small-intestinal contrast radiography and upper-gastrointestinal endoscopy. C1 (Japan VI, overseas VI; 8). ## Comments For the definitive diagnosis of CD, use lower-gastrointestinal endoscopy with biopsy for histopathological evaluation before undertaking other investigations. Even after the diagnosis is made, it is preferable to investigate the entire gastrointestinal tract, using small-intestinal contrast radiography and upper-gastrointestinal endoscopy, in order to determine the disease type, as determination of the type will contribute to the selection of the appropriate treatment and scheduling of the follow up. In cases where the results of a lower-gastrointestinal endoscopic examination do not produce a definitive diagnosis, it is absolutely necessary to explore lesions in the small intestine and the upper gastrointestinal tract [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] [bib_ref] Crohn's disease of the upper gastrointestinal tract: the value of endoscopic examination, Witte [/bib_ref] [bib_ref] Imaging of the small bowel in Crohn's disease: a review of old..., Saibeni [/bib_ref]. If lesions are not found using small-intestinal contrast radiography or upper-and lower-gastrointestinal endoscopy despite clinical suspicions of CD, exploration of the small-intestinal lesions using capsule endoscopy may be useful in some cases; however, this procedure is not yet approved for clinical use in Japan for suspected cases of CD. The usefulness of small-intestinal endoscopy in the diagnosis of CD has not been established clearly, although it is useful in some cases of diagnostic difficulty. ## Ii-5. contrast radiography CQ11: When is contrast radiography necessary to make a diagnosis of CD? [bib_ref] Imaging of the small bowel in Crohn's disease: a review of old..., Saibeni [/bib_ref] [bib_ref] Balloon-occluded endoscopic retrograde ileography, Taruishi [/bib_ref] [bib_ref] Crohn's disease-X-ray examination of the small intestine, Iida [/bib_ref] - As CD may be complicated with intestinal stenosis, fistulas, abscess, and/or adhesions, the addition of barium enema radiography to colonoscopy would be advisable. C1 (Japan VI, overseas VI; 8). - Even if a diagnosis of CD is made by barium enema radiography, small-intestinal contrast radiography is valuable to determine the extent of the lesions and to establish treatment strategies. C1 (Japan VI, overseas VI; 8). ## Comments Barium enema radiography is helpful to overview the entire colon and rectum, and small-intestinal contrast radiography can be performed safely if there is no severe stenosis in the colon. To explore small-intestinal lesions, contrast radiography is still useful, with a sensitivity of 85-95 % and specificity of 89-94 % to detect typical lesions of CD [bib_ref] Imaging of the small bowel in Crohn's disease: a review of old..., Saibeni [/bib_ref] [bib_ref] Balloon-occluded endoscopic retrograde ileography, Taruishi [/bib_ref] [bib_ref] Crohn's disease-X-ray examination of the small intestine, Iida [/bib_ref]. CQ12: Which findings of contrast radiography are characteristic of CD? [bib_ref] Crohn's disease-X-ray examination of the small intestine, Iida [/bib_ref] [bib_ref] Clinical features of Crohn's disease: relationship of disease type and severity to..., Tominaga [/bib_ref] [bib_ref] Detection of inflammatory bowel disease: diagnostic performance of cross-sectional imaging modalities, Horsthuis [/bib_ref] [bib_ref] Diagnostics of inflammatory bowel disease, Nikolaus [/bib_ref] - Longitudinal ulcers (asymmetric sclerotic appearance), cobblestone-like appearance, stenosis, aphthous ulcerations, irregular-shaped ulcers, fissures, and fistulas are typically found. B* (Japan V, overseas VI; 9). ## Comments A longitudinal ulcer is an ulcer 5 cm or longer that runs along the longitudinal direction of the gastrointestinal tract on the mesentery side in the small intestine and along the teniae coli in the colon, varying in width from a wide band to a thin line. Shortening of the mesentery side of the small intestine due to longitudinal ulcers produces an asymmetric sclerotic appearance, which is found in approximately 84 % of CD cases [bib_ref] Crohn's disease-X-ray examination of the small intestine, Iida [/bib_ref] [bib_ref] Clinical features of Crohn's disease: relationship of disease type and severity to..., Tominaga [/bib_ref] [bib_ref] Detection of inflammatory bowel disease: diagnostic performance of cross-sectional imaging modalities, Horsthuis [/bib_ref] [bib_ref] Diagnostics of inflammatory bowel disease, Nikolaus [/bib_ref]. A cobblestone-like appearance is where scattered polyplike protrusions are formed in an area of mucous membrane surrounded by a longitudinal ulcer and with smaller ulcers running transversely. It is assumed that mucosal edema, shortening of mucosal muscle, inflammatory cell infiltration, and fibrosis produce such a distinctive feature [bib_ref] Diagnostics of inflammatory bowel disease, Nikolaus [/bib_ref]. II-6. Other imaging procedures CQ13: How can imaging procedures such as CT and abdominal ultrasonography (US) contribute to making a diagnosis of CD? [bib_ref] Value of virtual computed tomographic colonography for Crohn's colitis: comparison with endoscopy..., Ota [/bib_ref] - CT and US are useful for evaluating the extent and severity of gastrointestinal inflammation, and for the detection of abscess formation. C1 (Japan VI, overseas VI; 8). ## Comments CT and US can be used to assess intestinal inflammation, based on thickening of the intestinal walls and the increased density of surrounding fatty tissues. Contrast CT and MRI are helpful in detecting abscess formation. CT colonography, although useful in assessing lesions proximal to a stenosis, is not universally available [bib_ref] Value of virtual computed tomographic colonography for Crohn's colitis: comparison with endoscopy..., Ota [/bib_ref]. ## Ii-7. histopathological examination CQ14: What pathological findings are characteristic of CD? [bib_ref] Diagnostics of inflammatory bowel disease, Nikolaus [/bib_ref] [bib_ref] Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in..., Meucci [/bib_ref] - Findings for a definitive diagnosis of CD include: (1) noncaseating epithelioid cell granuloma, (2) transmural inflammation, (3) fissure, and (4) ulcers. C1 (Japan VI, overseas VI; 8). ## Comments Abnormal alignment of crypts and basal cell plasmacytosis are found in the biopsy specimen, and these are findings in common with those of IBD. A key to differentiating CD from UC is focal inflammation. Granuloma is composed of such cells as epithelioid cells, macrophages, lymphocytes, and multinucleate giant cells. Although noncaseating epithelioid cell granuloma is a principal basis for a diagnosis of CD, it is detected in 40-60 % of surgical specimens, and in only 15-36 % of biopsy specimens [bib_ref] Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in..., Meucci [/bib_ref]. Multiple biopsy specimens for serial sections may improve the rate of detection of granuloma. Note, however, that multinucleate giant cells may be found in foreign-body granulomas, and that noncaseating epithelioid cell granulomas may be found in tuberculosis [bib_ref] Diagnostics of inflammatory bowel disease, Nikolaus [/bib_ref]. In transmural inflammation, focal aggregations, mainly of lymphocytes, are found to be transmurally distributed unevenly. Lymphangiectasis, edema, and fibrosis are also found. Disproportionate inflammation, manifested more strongly in the submucosa than in the lamina propria, is a convincing key to the biopsy diagnosis of CD. Fissure formation is a vertical tissue defect along a lymphatic duct. ## Ii-8. definitive diagnosis CQ15: How can a definitive diagnosis be made? What diagnostic criteria are used?- If CD is suspected based on medical interview, physical examination, and laboratory test results, gastrointestinal investigations should be conducted. C1 (Japan VI, overseas VI; 9). - The Japanese proposed diagnostic criteria for Crohn's disease [fig_ref] Table 5: Proposed diagnostic criteria for Crohn's disease in Japan [/fig_ref] consist mainly of morphological findings of the gastrointestinal tract. C1 (Japan VI; 8). ## Comments Among major findings, longitudinal ulcers in CD can be differentiated from those in UC or ischemic colitis by the presence of protrusions due to inflammatory edema. The cobblestonelike appearance in CD involves dense protrusions of mucous membrane of uneven sizes, large or small, surrounded by a longitudinal ulcer and smaller ulcers. This appearance may be seen in ischemic colitis, but in ischemic colitis the protrusions are less dense and hyperemia is more intense. CQ16: If a diagnosis of CD is not definitive, what should be done? [bib_ref] Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in..., Meucci [/bib_ref] [bib_ref] Clinical features and pattern of indeterminate colitis: Crohn's disease with ulcerative colitis-like..., Matsui [/bib_ref] - In indeterminate colitis where it is difficult to differentiate CD from UC, choose treatment strategies for the more suspected disease, observe progress with regular check-ups, and make a definitive diagnosis as soon as the features of one or the other disorder become dominant. C1 (Japan VI, overseas VI; 8). - If the diagnosis of CD is not definitive, as in patients with only aphthous ulcerations, observe progress with regular check-ups, and a definitive diagnosis of CD can be made when morphological examinations fulfill the criteria for the diagnosis. C1 (Japan VI, overseas VI; 8). ## Comments The number of reports of indeterminate colitis (IC), which has clinical and histopathological features of both UC and CD and is thus difficult to differentiate from either of these conditions, is increasing [bib_ref] Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in..., Meucci [/bib_ref] [bib_ref] Clinical features and pattern of indeterminate colitis: Crohn's disease with ulcerative colitis-like..., Matsui [/bib_ref]. IC accounts for approximately 4 % of IBD cases in Japan [bib_ref] Clinical features and pattern of indeterminate colitis: Crohn's disease with ulcerative colitis-like..., Matsui [/bib_ref]. Even after intestinal resection, in approximately 5 % (range 1-20 %) of cases, a definitive diagnosis cannot be made, because of overlapping histopathological features [bib_ref] Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in..., Meucci [/bib_ref] [bib_ref] Clinical features and pattern of indeterminate colitis: Crohn's disease with ulcerative colitis-like..., Matsui [/bib_ref]. Although the usefulness of serum anti-Saccharomyces cerevisiae (ASCA) and anti-neutrophil cytoplasmic antibody (ANCA) measurements has been reported, their diagnostic accuracy for IC has not been established. At present, serial observations with endoscopy and other procedures are important, and a definitive diagnosis is made when characteristic features of either UC or CD are obtained (i.e., when the criteria for diagnosis of either one are satisfied). After observing the progress of IC for 8 years, a definitive diagnosis of CD or UC was made in 80 % of cases [bib_ref] Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in..., Meucci [/bib_ref]. Treatment strategies are decided with a tentative diagnosis based on the clinical and imaging features. When CD is suspected but without a definitive diagnosis, as in patients with aphthous ulcers that show no longitudinal arrangement and patients who do not have noncaseating epithelioid cell granuloma, regular follow up, using laboratory test results and morphological examinations is necessary to be able to make a definitive diagnosis of CD when the criteria for the diagnosis are met. Use mainly symptomatic treatments until a definitive diagnosis is made. If morphological examinations cannot confirm the diagnosis, but CD is suspected comprehensively by symptoms and laboratory test results, treatments for CD may be initiated, while observing the patient's progress and conducting follow-up examinations. The rate of detection of this granuloma is improved by creating serial sections. It is advisable that a pathologist familiar with the gastrointestinal tract examine a specimen of it c In typical cases, the ulcers are arranged longitudinally, but this does not occur in some cases. It is necessary that they persist for at least 3 months. With regard to this condition, it is necessary to exclude enteric tuberculosis, intestinal Behçet's disease, simple ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers, and infectious enterocolitis d These lesions consist of anal fissures, cavitating ulcers, anal fistulas, perianal abscesses, and edema-like anal skin tags. Preferably, colorectal surgeons familiar with Crohn's disease are consulted to examine such lesions, referring to the Atlas of findings by visual observation of lesions in the anus of Crohn's diseasee These lesions have a bamboo joint-like appearance, with notch-like depressions. Preferably, specialists familiar with Crohn's disease are consulted to examine such lesions f In cases with only longitudinal ulcers, it is necessary to exclude ischemic intestinal lesions and ulcerative colitis. In cases with only a cobblestone-like appearance, it is necessary to exclude ischemic intestinal lesions g It is necessary to exclude inflammatory diseases with granulomas such as intestinal tuberculosis II-9. Determination of severity CQ17: How are the severity and activity of the disease determined? [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref] [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref] - The severity and activity are usually determined on the basis of clinical symptoms. C1 (Japan VI, overseas VI; 7). - The IOIBD and CDAI can be used to quantify the disease activity, but these indices are not easy to use in daily clinical practice. C1 (Japan VI, overseas VI; 8). ## Comments The IOIBD score consists of nine clinical parameters and hemoglobin, and it is a convenient index that is used in the disease datasheet of the Japanese national CD registration. Though the IOIBD data have a certain level of correlation with the CDAI scores [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] , the number of items showing correlation is limited, and the IOIBD is not suitable for detailed evaluation of the long-term progress of the disease. In Europe and North America, the CDAI [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] , in which eight indices are calculated, is used as a standard index for the assessment of disease activity; it is also used to assess treatment efficacy in clinical studies in Japan. However, calculation of the CDAI requires that clinical symptoms and laboratory test data are available over the 7 days immediately before the day of calculation. Thus, it is not suitable for use in daily clinical practice. Although assessment of severity is important for treatment, severity does not always correlate with disease activity [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref]. In some patients, particularly those with smallintestinal lesions, the clinical symptoms are mild, and disease activity is not reflected in the CDAI scores. In selecting treatment options, comprehensive evaluation should be made. The initial treatment might be modified during the follow-up period. A recent opinion suggests that the disease pattern (whether the case is susceptible to fistulation or stenosis) and the mucosal healing of gastrointestinal lesions should be evaluated. The European Crohn's and Colitis Organisation (ECCO) has classified disease activity in the categories of mild, moderate, and severe according to the criteria shown in [fig_ref] Table 6: Classification of disease severity [/fig_ref] [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref]. III. General principles of treatment III-1. Outline of treatment CQ1: If a patient has a diagnosis of CD, what will the treatments be, and how will this affect the patient's lifestyle? [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref] [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref] - In the active stage, the treatments are directed to induce remission; once remission is induced, the treatments are given to maintain remission for a prolonged period. B* (Japan VI, overseas VI; 9). - Therapeutic modalities include medical treatments, such as drug therapies and nutritional therapies, and surgical treatments. They are selected as monotherapy or combination therapy. B* (Japan VI, overseas: VI 9). - The majority of patients can live a normal daily life, with regular school life or working hours. In patients with severe or fulminant symptoms, or frequent relapses, the patient needs to be hospitalized, or requires surgical treatment, and faces dietary and lifestyle restrictions. C1 (Japan VI; 8). ## Comments Repeated remissions and relapses are characteristic during the course of CD. Because CD is not curable at present, the goal of the treatment is to control disease activity and to improve the QOL of the patient. For this purpose, it is important to control the symptoms, to maintain nourishment, and to prevent relapse or postoperative recurrence by combining drug therapies, nutritional therapies, and surgical treatments. Treatments are selected according to the sites of lesions, the levels of inflammation, the disease pattern, the responses to treatments in the past, and the presence or absence of complications. Although there is abundant evidence in regard to the efficacy of different treatments in relation to disease severity or location, the patients should be fully instructed about the disorder, and the treatment should be chosen according to the social background and environment of the patients, as well as the individual pathological conditions [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref] [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref]. In mild to moderate cases, remission is sufficiently attained with drug and/or nutritional therapies, and the patient can live a normal daily life with maintenance treatment and some attention to daily life. For moderate cases, the patient needs to be hospitalized during periods of relapse, but can otherwise live an almost normal life. ## Iii-2. consultation CQ2: Should a CD patient be referred to a specialist for the treatment? [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Carter [/bib_ref] - On many occasions in the management of CD, consultation with a specialist is necessary. B* (Japan VI, overseas VI; 9). - Consultation is required for nutritional therapy, antitumor necrosis factor (TNF) therapy, failure to maintain remission, and surgical treatment. B* (Japan VI, overseas VI; 9). ## Comments Except for very typical cases, consultation with a specialist should be considered for any diagnostic difficulty. If the institution is not sufficient for diagnostic investigations, the patient should be referred to a specialist to establish the diagnosis and to determine the extent and severity of the disease [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Carter [/bib_ref]. At the initial diagnosis of CD, consultation with a specialist is preferable for education and general guidance. Quiescent cases can be managed by a general practitioner for remission maintenance and follow up. Steroid-dependency and the administration of immunomodulators or biologic agents are indications for consultation. In cases of intestinal/extra-intestinal complications, the patient should be referred to specialists in the relevant areas. ## Iii-3. hospitalization CQ3: Under what circumstances should a CD patient be hospitalized? [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref] [bib_ref] An analysis of an inflammatory bowel disease practice in an urban community..., Adam [/bib_ref] - Consider hospitalization when the patient does not improve on outpatient treatment. B* (Japan VI, overseas VI; 9). ## Comments If a patient does not improve with outpatient drug or nutritional therapies, and has persistent symptoms such as frequent diarrhea, abdominal pain, fever, and weight loss, and/or elevated inflammatory markers, hospitalization should be considered [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref]. In patients with stenosis causing bowel obstruction and those with intra-abdominal abscess formation, hospitalization and surgical treatment should be considered [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref]. According to a case series study, a high proportion (50-80 %) of CD patients with small-intestinal lesions require hospitalization/surgery as the disease progresses [bib_ref] An analysis of an inflammatory bowel disease practice in an urban community..., Adam [/bib_ref]. ## Iii-4. exercise and social activities CQ4: Does a CD patient require rest and restriction of social activities? [bib_ref] Predictors of Crohn's disease, Beaugerie [/bib_ref] [bib_ref] Exercise and Crohn's disease: speculations on potential benefits, Ng [/bib_ref] - Generally, patients do not require rest or restriction of activities. C1 (Japan VI, overseas VI; 8). ## Comments In the long-term progression of CD, the QOL of the patients is generally well maintained. The number of patients with poor QOL for whom social activities are significantly restricted due to symptoms and/or treatment is limited [bib_ref] Predictors of Crohn's disease, Beaugerie [/bib_ref]. If remission is maintained, normal exercise, work, and school attendance are expected. However, in the active phase, too much exercise causing a heavy physical or mental burden is to be avoided [bib_ref] Predictors of Crohn's disease, Beaugerie [/bib_ref]. There is no evidence that bed rest or lifestyle restrictions contribute to the maintenance of remission. Rather, some reports have indicated that moderate exercise reduces CD disease activity and mental stress [bib_ref] Exercise and Crohn's disease: speculations on potential benefits, Ng [/bib_ref]. ## Iii-5. diet CQ5: Is dietary therapy necessary for the treatment of CD? [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Carter [/bib_ref] - There are no specific dietary therapies to cure or improve CD. C1 (Japan VI, overseas: VI; 9). - For patients in the active phase, considerinflammation in the gastrointestinal tract when selecting foods, . C1 (Japan VI, overseas VI; 8). - Do not allow the patient to take food orally in the presence of severe inflammation or obstruction. C1 (Japan VI, overseas VI; 8). ## Comments Dietary therapy denotes management in which the amounts of meals or food ingredients are adjusted, with the aim being to overcome or alleviate a disease. Unlike findings with hypertension, hyperlipidemia, and diabetes, no primary therapeutic effect of any dietary therapy in CD has been scientifically proven. Dietary guidance or advice is preferably minimal, such as cautions to avoid excessive drinking and eating or stimulants. Although the causes of CD are unknown, it is assumed that some dietary factors are involved in the onset and the persistence of inflammation. In many cases, the oral intake of foods exacerbates the symptoms, and these patients have usually had an unbalanced diet before the onset of the disease; thus, it can be presumed that diet may have some relationship to CD. In general, patients with inflammation in the gastrointestinal tract are recommended to avoid fats, stimulants, and dietary fiber. In CD patients, this recommendation also means that the antigens in the diet are reduced to keep the intestinal tract at rest. Nutritional deficiency is often found in CD patients due to various causes. When CD is diagnosed, the nutritional condition of the patient should therefore be assessed, and assessment should be carried out regularly during the progress of the disease, with nutritional support being provided according to the patient's pathophysiological condition [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Carter [/bib_ref]. CQ6: What kind of general dietary recommendations should be made? [bib_ref] Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in..., Sakamoto [/bib_ref] - Basic recommendations during the active phase include having a low-fat, low-residue diet with low levels of stimulants, and food high in protein and calories, to improve the nutritional state while keeping the intestinal tract at rest. C1 (Japan VI, overseas VI; 7). - In the remission phase, no strict dietary restrictions are necessary, but a low-fat diet is preferred. C1 (Japan IVb; 7). - The response of the gastrointestinal tract to foods varies considerably from person to person. Accordingly, individual patients should avoid specific foods that make their symptoms worse. C1 (Japan VI, overseas VI; 8). ## Comments Dietary guidance differs according to the individual and their symptoms. Basically, no foods are absolutely restricted; however, it is advisable that CD patients maintain an orderly and regular diet, and learn which foods exacerbate their condition, and avoid such foods. Although there is little evidence to show any relationship between the diet and food ingredients and the disease activity of CD, a Japanese case-control study has indicated that fats are a risk factor for CD [bib_ref] Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in..., Sakamoto [/bib_ref]. Low-fat, low-residue, high-protein, and high-calorie foods are basic dietary suggestions for CD. When a patient undergoes a resection of the small or large intestine, the diet should be considered according to the region that has been resected. As evidence is lacking for the effects of health food products and popular supplements, and because their safety has not been confirmed, they are not recommended. ## Iii-6. smoking CQ7: Should a CD patient refrain from smoking? [bib_ref] Active and passive smoking in childhood is related to the development of..., Mahid [/bib_ref] [bib_ref] Risk factors regarding the need for a second operation in patients with..., Avidan [/bib_ref] [bib_ref] Effects of current and former cigarette smoking on the clinical course of..., Cosnes [/bib_ref] [bib_ref] Inflammatory bowel disease: is there any relation between smoking status and disease..., Russel [/bib_ref] [bib_ref] Smoking cessation and the course of Crohn's disease: an intervention study, Cosnes [/bib_ref] [bib_ref] Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor..., Vermeire [/bib_ref] - Upon diagnosis, the patient with CD should quit smoking. B (overseas III; 8). ## Comments An analytical epidemiological study showed that smoking was associated with the onset of CD. It has also been reported that in infants exposed to passive smoking this has an adverse effect [bib_ref] Active and passive smoking in childhood is related to the development of..., Mahid [/bib_ref]. Case-control studies have indicated that, after remission is induced by medical or surgical treatments, the relapse rates and requirements for surgery are higher among smokers [bib_ref] Risk factors regarding the need for a second operation in patients with..., Avidan [/bib_ref] [bib_ref] Effects of current and former cigarette smoking on the clinical course of..., Cosnes [/bib_ref] [bib_ref] Inflammatory bowel disease: is there any relation between smoking status and disease..., Russel [/bib_ref]. An interventional trial showed that a group that continued to refrain from smoking for more than 1 year had a better prognosis than continuos smoker [bib_ref] Smoking cessation and the course of Crohn's disease: an intervention study, Cosnes [/bib_ref]. With these lines of evidence, smoking cessation is recommended for those who have a diagnosis of CD. A multivariate analysis of the factors influencing the therapeutic effect of infliximab concluded that smoking was not an independent factor influencing the therapeutic effect; however, for the above-mentioned reasons, patients with CD are recommended to quit smoking [bib_ref] Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor..., Vermeire [/bib_ref]. ## Iii-7. alcohol drinking CQ8: Should a CD patient refrain from drinking alcohol?- It is not necessary to recommend to every patient with CD that they refrain from drinking alcohol. However, it is preferable to avoid excessive drinking and to stop drinking when the disease is in the active phase. C1 (Japan VI, overseas VI; 7). ## Comments There is little evidence that drinking alcohol affects the disease activity or progression of CD. However, alcohol may injure the mucosa of the intestinal tract and exacerbate the symptoms of CD. In the remission phase, drinking modest amounts of alcohol is acceptable, but it would be a good practice to advise patients to restrain themselves when drinking, as some people tend to drink excessively. IV. Therapeutic intervention [fig_ref] Figure 2: Treatment of Crohn's disease [/fig_ref] IV-1. is to maintain remission for as long as possible. For these purposes, select drug, nutritional, and surgical therapies as indicated to attenuate symptoms, to maintain nourishment, and to prevent relapse. Patients should be fully instructed about the disorder, and the treatment should be chosen according to the social background and environment of the patients, as well as the individual pathological conditions [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref] [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref]. Both drug and nutritional therapies for CD inevitably have adverse effects. However, the benefit of each therapeutic modality outweighs the risk. Some therapies are safe in the short term, but may produce adverse effects in the long term. It is desirable that nutritional therapies and drug therapies be used to supplement each other. ## Iv-2. steroids CQ2: When are steroids indicated? What kinds of benefits and harms are expected? [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Carter [/bib_ref] [bib_ref] Traditional corticosteroids for induction of remission in Crohn's disease, Benchimol [/bib_ref] [bib_ref] Corticosteroids for maintenance of remission in Crohn's disease, Steinhart [/bib_ref] [bib_ref] Budesonide for induction of remission in Crohn's disease, Seow [/bib_ref] - Steroids possess potent anti-inflammatory effects. They are effective in inducing remission, but ineffective for maintaining remission. A (Japan V; overseas I; 8). - Steroids may cause adverse effects, particularly with longterm administration. Thus, steroids should be administered mainly to induce remission, and the dosage should be tapered until they are discontinued. C1 (Japan VI, overseas VI; 8). - Steroids are indicated for patients with moderate to severe disease activity, as well as for mildly active disease that is refractory to 5-ASA preparations. A (Japan VI, overseas II; 8). ## Comments Randomized controlled trials were conducted in Europe and North America in the 1970s and 1980s to evaluate the effect of steroids, and a meta-analysis showed their efficacy in inducing remission [bib_ref] Traditional corticosteroids for induction of remission in Crohn's disease, Benchimol [/bib_ref]. However, efficacy in maintaining remission was not shown [bib_ref] Corticosteroids for maintenance of remission in Crohn's disease, Steinhart [/bib_ref]. In the randomized controlled trials adopted in the meta-analysis, steroids were shown to be more efficacious than placebo or 5-ASA preparations in cases of disease of varying severity, with CDAI scores ranging from 150 to 450 [bib_ref] Traditional corticosteroids for induction of remission in Crohn's disease, Benchimol [/bib_ref]. However, the indication for steroids has changed with the emergence of anti-TNF agents. While steroids have potent anti-inflammatory effects, they may cause adverse effects such as compromised immune functions, impaired glucose tolerance, delayed wound healing, and osteoporosis. Furthermore, they are not effective in maintaining remission. Accordingly, steroids should not be administered for prolonged periods [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Carter [/bib_ref]. In cases where 5-ASA preparations cannot induce remission, oral administration of steroids is recommended. When administering steroids, the dosage should be tapered down to eventual termination irrespective of the response [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Carter [/bib_ref] [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref]. Daily administration of 9 mg budesonide (not yet approved in Japan), which is a steroid with reduced systemic side effects, is effective in inducing remission in mild to moderate cases [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref] [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref] [bib_ref] Budesonide for induction of remission in Crohn's disease, Seow [/bib_ref]. ## Iv ## Comments According to a meta-analysis of randomized controlled trials, in cases with mild to moderate activity, mesalazine 4 g/day significantly reduced CDAI scores compared with placebo [bib_ref] Oral Pentasa in the treatment of active Crohn's disease: a meta-analysis of..., Hanauer [/bib_ref]. Another meta-analysis performed to evaluate the efficacy of 5-ASA preparations in remission maintenance did not show any difference between the 5-ASA preparations and placebo [bib_ref] Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's disease, Akobeng [/bib_ref]. Another meta-analysis suggested that 5-ASA preparations were significantly efficacious in maintaining remission in CD. Because the safety profiles of 5-ASA preparations are good, these preparations are frequently used in actual practice. They are also administered in the long term in many patients for the purpose of maintaining remission. ## Iv-4. immunomodulators CQ4: When are immunomodulators indicated? What kinds of benefits and harms are expected? [bib_ref] Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease, Sandborn [/bib_ref] [bib_ref] Azathioprine for maintaining remission of Crohn's disease, Pearson [/bib_ref] - Azathioprine (AZA) and 6-mercaptopurine (6-MP)* are effective in inducing remission in CD, but their adverse effects should be noted. A (overseas I; 8) Not covered by Japanese public health insurance. - AZA is effective in maintaining remission in CD, and has a steroid-sparing effect. A (overseas I; 9). ## Comments Daily administration of 2.0-3.0 mg/kg AZA, and daily administration of 50 mg (or of 1.5 mg/kg) 6-MP, are both useful in inducing remission in CD in the active phase [bib_ref] Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease, Sandborn [/bib_ref]. Daily administration of 1.0-2.5 mg/kg AZA in patients with quiescent CD is effective to prevent relapse for 6 months to 2 years. The steroid-sparing effect of immunomodulators is useful for withdrawing steroids. However, it is not clear whether AZA has a long-term effect on remission maintenance [bib_ref] Azathioprine for maintaining remission of Crohn's disease, Pearson [/bib_ref]. A higher dose (2.5 mg/kg daily) of AZA has a more potent effect on remission maintenance than a lower dose (1.0 or 2.0 mg/kg daily). Immunomodulators are slow-acting drugs, and may cause serious side effects (e.g., myelosuppression and pancreatitis.); therefore, the benefits and harms of these drugs should be carefully considered. Because Japanese have a lower ability to metabolize these drugs than Caucasian, Japanese patients are particularly susceptible to the dose-dependent adverse effects of immunomodulators. Smaller doses (AZA 50-100 mg daily) than those used overseas are usually administered in Japan. ## Iv-5. anti-tnf agents CQ5: When are anti-TNF agents indicated? What kinds of benefits are expected? [bib_ref] Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn's disease, Behm [/bib_ref] [bib_ref] Infliximab maintenance therapy for fistulizing Crohn's disease, Sands [/bib_ref] [bib_ref] Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLAS-SIC-I..., Hanauer [/bib_ref] [bib_ref] Adalimumab for maintenance of clinical response and remission in patients with Crohn's..., Colombel [/bib_ref] [bib_ref] Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized..., Sandborn [/bib_ref] - Anti-TNF agents are effective to induce remission. A (overseas I; 9). - In CD patients brought into remission by anti-TNF agents, these agents are also effective for fistula-closure and remission maintenance. A (overseas I; 8). - When infliximab has not been successful, adalimumab may be effective in inducing remission and attenuating symptoms. A (overseas I; 8). ## Comments Adalimumab, a humanized anti-TNF-a monoclonal antibody agent, was approved in Japan for the treatment of CD in 2010, in addition to infliximab. A randomized controlled trial on the remission induction effect of infliximab in patients with active CD indicated that a single administration of 5 mg/kg was efficacious in inducing remission in CD. Moreover, 5 mg/kg or 10 mg/kg of infliximab given every 8 weeks to patients with CD in remission brought about by infliximab was efficacious in maintaining remission and fistula closure [bib_ref] Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn's disease, Behm [/bib_ref] [bib_ref] Infliximab maintenance therapy for fistulizing Crohn's disease, Sands [/bib_ref]. In clinical practice, 5 mg/kg of infliximab is administer at week 0, week 2, and week 6, and then at intervals of 8 weeks. If the required effect is not obtained, consider other treatments instead of simply continuing this agent. A randomized controlled trial on the remission induction effect of adalimumab indicated that two subcutaneous administrations of 80/40 or 160/80 mg of this drug in CD patients with moderate disease activity showed a significant remission induction effect at week 4 [bib_ref] Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLAS-SIC-I..., Hanauer [/bib_ref]. A trial on its remission maintenance effect indicated that administration of 40 mg subcutaneously at intervals of 2 weeks or 1 week showed a significant remission maintenance effect at week 56 [bib_ref] Adalimumab for maintenance of clinical response and remission in patients with Crohn's..., Colombel [/bib_ref]. In clinical practice, 160 mg of adalimumab is initially administered subcutaneously, followed by 80 mg 2 weeks later, and then 40 mg at intervals of 2 weeks, in order to maintain remission. In patients with active CD in whom infliximab was unsuccessful (due to intolerance or symptoms persisting after its administration), adalimumab had a significant effect on remission induction and had attenuated symptoms at 4 weeks after administration [bib_ref] Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized..., Sandborn [/bib_ref]. That trial, however, did not directly compare adalimumab with infliximab, nor did it deal with remission maintenance. CQ6: What harms are anticipated with the use of anti-TNF agents? [bib_ref] Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn's disease, Behm [/bib_ref] [bib_ref] Serious infections and mortality in association with therapies for Crohn's disease: TREAT..., Lichtenstein [/bib_ref] [bib_ref] Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent, Keane [/bib_ref] [bib_ref] Factors associated with the development of intestinal strictures or obstructions in patients..., Lichtenstein [/bib_ref] [bib_ref] Safety of infliximab and other Crohn's disease therapies-updated TREAT Registry data with..., Lichtenstein [/bib_ref] [bib_ref] Infliximab and newly diagnosed neoplasia in Crohn's disease: a multicentre matched pair..., Biancone [/bib_ref] [bib_ref] Adalimumab safety and mortality rates from global clinical trials of six immune-mediated..., Burmester [/bib_ref] - Cases of serious infections and cases of opportunistic infections have been reported among patients who received infliximab or adalimumab. B (overseas IVa; 8). - Infliximab increases the chance of tuberculosis infection (including reactivation). B (overseas IVa; 8). - The occurrence of malignant tumors, including lymphoma, was reported among patients who received infliximab. B (overseas IVa; 8). - The incidence of cancer in general among patients who received adalimumab does not seem to be different from that in the general population. C1 (overseas V; 8). ## Comments A meta-analysis of studies of infliximab indicated no significant difference in the incidence of serious infections between the infliximab and placebo groups [bib_ref] Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn's disease, Behm [/bib_ref]. A multivariate analysis of a prospective study of more than 6,000 people in the TREAT Registry suggests that the causes of increases in serious infections in CD patients are not related to the use of infliximab, but to steroids, narcotic analgesics, and the severity of the disease [bib_ref] Serious infections and mortality in association with therapies for Crohn's disease: TREAT..., Lichtenstein [/bib_ref]. In addition, the risk of opportunistic infection in patients with IBD was shown to increase due to the combined use of multiple immunomodulators with infliximab and old age. However, infliximab is known to increase the reactivation and incidence of tuberculosis infection. In addition, it is known that it increases extra-pulmonary lesions and disseminated tuberculosis [bib_ref] Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent, Keane [/bib_ref]. Screen patients with CD for tuberculosis infection before administering infliximab, and consider the prophylactic administration of anti-tuberculosis drugs, as necessary. Analysis of the TREAT Registry indicated a worsening of intestinal stenosis in those who received infliximab, but a multivariate analysis concluded that the only risk factors were the duration and severity of the disease, small-intestinal lesions, and the initiation of steroid therapy [bib_ref] Factors associated with the development of intestinal strictures or obstructions in patients..., Lichtenstein [/bib_ref]. Although few studies have indicated a relationship between infliximab and the occurrence of stenosis, patients should be informed of the risk of stenosis after taking infliximab, and surgeons should be notified if a CD patient is receiving this drug. A further study with the TREAT Registry indicated a significant difference in the incidence of malignant tumors, including lymphoma, between groups with and without the use of infliximab [bib_ref] Safety of infliximab and other Crohn's disease therapies-updated TREAT Registry data with..., Lichtenstein [/bib_ref]. A multicenter matched-pair study in Italy showed similar results [bib_ref] Infliximab and newly diagnosed neoplasia in Crohn's disease: a multicentre matched pair..., Biancone [/bib_ref]. However, the observation periods in these two studies were not long enough to reach definitive conclusions. Nevertheless, patients should be notified of the risk before infliximab treatment is initiated. Adverse effects over a period of 10 years were reported in 20,000 patients from 36 clinical studies on six immunemediated diseases [bib_ref] Adalimumab safety and mortality rates from global clinical trials of six immune-mediated..., Burmester [/bib_ref]. In patients with CD, abscesses in the abdominal cavity or the gastrointestinal tract and opportunistic infections were found, but in general, no risk of major infections was found. The incidence of cancer in these CD patients was equivalent to that in the general population. The harmful effects noted above are considered to be common to all anti-TNF agents. IV-6. Antimicrobial drugs CQ7: When are antimicrobial drugs indicated, and what kinds of benefits and harms are anticipated? [bib_ref] A meta-analysis of broad-spectrum antibiotic therapy in patients with active Crohn's disease, Rahimi [/bib_ref] [bib_ref] Antimycobacterial therapy in Crohn's disease: results of a controlled, double-blind trial with..., Prantera [/bib_ref] [bib_ref] An antibiotic regimen for the treatment of active Crohn's disease: a randomized,..., Prantera [/bib_ref] [bib_ref] Combined budesonide and antibiotic therapy for active Crohn's disease: a randomized controlled..., Steinhart [/bib_ref] [bib_ref] Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, placebo-controlled..., Rutgeerts [/bib_ref] - Antimicrobial drugs are sometimes effective in attenuating the clinical symptoms of CD. A (overseas I; 8). Antimicrobial drugs are not covered by the Japanese public health insurance system when used for the treatment of CD. - These drugs are more effective for colonic lesions than for small-intestinal lesions. A (overseas II; 8). ## Comments In some cases, antimicrobial drugs such as metronidazole and ciprofloxacin are used for the treatment of CD. Multiple randomized controlled studies have been conducted to evaluate the efficacy of antimicrobial drugs for treating active CD, and the drugs showed efficacy in attenuating the clinical symptoms [bib_ref] A meta-analysis of broad-spectrum antibiotic therapy in patients with active Crohn's disease, Rahimi [/bib_ref] [bib_ref] Antimycobacterial therapy in Crohn's disease: results of a controlled, double-blind trial with..., Prantera [/bib_ref] [bib_ref] An antibiotic regimen for the treatment of active Crohn's disease: a randomized,..., Prantera [/bib_ref] [bib_ref] Combined budesonide and antibiotic therapy for active Crohn's disease: a randomized controlled..., Steinhart [/bib_ref]. They were more efficacious for colonic lesions than for small-intestinal lesions [bib_ref] Combined budesonide and antibiotic therapy for active Crohn's disease: a randomized controlled..., Steinhart [/bib_ref]. Another report indicated that the administration of antimicrobial drugs was efficacious in preventing the postoperative recurrence of CD [bib_ref] Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, placebo-controlled..., Rutgeerts [/bib_ref]. However, the indications and the specific treatment strategies for antimicrobial therapies for CD have not yet been established. When antimicrobial drugs are used for a long period of time, caution should be exercised regarding potential adverse effects. Metronidazole, in particular, may cause peripheral neuropathy. ## Iv-7. enteral nutriton CQ8: When is enteral nutrition indicated, and what kinds of benefits and harms are expected? [bib_ref] How effective is enteral nutrition in inducing clinical remission in active Crohn's..., Fernandez-Banares [/bib_ref] [bib_ref] Metaanalysis of enteral nutrition as a primary treatment of active Crohn's disease, Griffiths [/bib_ref] [bib_ref] Polymeric diet alone versus corticosteroids in the treatment of active pediatric Crohn's..., Borrelli [/bib_ref] [bib_ref] Enteral nutrition and corticosteroids in the treatment of acute Crohn's disease in..., Heuschkel [/bib_ref] [bib_ref] Controlled trial comparing an elemental diet with prednisolone in the treatment of..., Okada [/bib_ref] [bib_ref] Effectiveness of an 'half elemental diet' as maintenance therapy for Crohn's disease:..., Takagi [/bib_ref] [bib_ref] Home elemental enteral hyperalimentation (HEEH) for the maintenance of remission in patients..., Hirakawa [/bib_ref] [bib_ref] Preventive effect of nutritional therapy against postoperative recurrence of Crohn disease, with..., Esaki [/bib_ref] - The efficacy of enteral nutrition for inducing remission in active CD is equivalent or slightly inferior to that of corticosteroids. A (Japan III, overseas I; 8). - Elemental diet therapy is effective in maintaining remission in CD. A (Japan II; 8). - Although enteral nutrition is safe, maintenance of the patient's acceptance is often difficult. C1 (Japan VI; 8). ## Comments The results of several randomized controlled studies have indicated that the efficacy of enteral nutrition for remission induction in active CD is equivalent or slightly inferior to that of corticosteroids [bib_ref] How effective is enteral nutrition in inducing clinical remission in active Crohn's..., Fernandez-Banares [/bib_ref] [bib_ref] Metaanalysis of enteral nutrition as a primary treatment of active Crohn's disease, Griffiths [/bib_ref] [bib_ref] Polymeric diet alone versus corticosteroids in the treatment of active pediatric Crohn's..., Borrelli [/bib_ref] [bib_ref] Enteral nutrition and corticosteroids in the treatment of acute Crohn's disease in..., Heuschkel [/bib_ref] [bib_ref] Controlled trial comparing an elemental diet with prednisolone in the treatment of..., Okada [/bib_ref]. A Japanese report indicated that enteral nutrition with an elemental diet had a higher rate of remission induction than prednisolone and was particularly effective for attenuating intestinal lesions [bib_ref] Controlled trial comparing an elemental diet with prednisolone in the treatment of..., Okada [/bib_ref]. This therapy is safer than corticosteroids. Enteral nutrition is effective for the maintenance of remission. It was reported that enteral nutrition with an elemental diet for half of the total intake of calories was efficacious in maintaining remission [bib_ref] Effectiveness of an 'half elemental diet' as maintenance therapy for Crohn's disease:..., Takagi [/bib_ref]. It was also reported that continuing an elemental diet of 30 kcal per kilogram per day was efficacious in preventing CD relapse [bib_ref] Home elemental enteral hyperalimentation (HEEH) for the maintenance of remission in patients..., Hirakawa [/bib_ref] [bib_ref] Preventive effect of nutritional therapy against postoperative recurrence of Crohn disease, with..., Esaki [/bib_ref]. However, it is frequently difficult to continue enteral nutrition for an extended period because its acceptability to the patient decreases. CQ9: Are there differences in the therapeutic effect between oligomeric and polymeric nutrients? [bib_ref] How effective is enteral nutrition in inducing clinical remission in active Crohn's..., Fernandez-Banares [/bib_ref] [bib_ref] Metaanalysis of enteral nutrition as a primary treatment of active Crohn's disease, Griffiths [/bib_ref] [bib_ref] Short-term efficacy of enteral nutrition in the treatment of active Crohn's disease:..., Sakurai [/bib_ref] [bib_ref] A randomized controlled study of total parenteral nutrition and enteral nutrition by..., Kobayashi [/bib_ref] - There are no significant differences between oligomeric and polymeric nutrients in terms of their efficacy in remission induction for active CD. A (Japan III, overseas I; 7). ## Comments Oligomeric nutrients are enteral formulas which have amino acids and oligopeptides as a nitrogen source, with a lowcontent of fats, and these formulas are therefore easily digested and assimilated. Among oligomeric nutrients, an elemental diet has amino acids as a nitrogen source, and contains little fat. Polymeric nutrients have proteins as a nitrogen source and contain some fats. Polymeric nutrients contain various nutrients in a good balance, and are easily taken orally. Many randomized controlled studies have been conducted to examine the differences among various enteral nutrients in terms of their therapeutic efficacy for active CD. The results have indicated no significant differences in the effect of remission induction between oligomeric and polymeric nutrients [bib_ref] How effective is enteral nutrition in inducing clinical remission in active Crohn's..., Fernandez-Banares [/bib_ref] [bib_ref] Metaanalysis of enteral nutrition as a primary treatment of active Crohn's disease, Griffiths [/bib_ref] [bib_ref] Short-term efficacy of enteral nutrition in the treatment of active Crohn's disease:..., Sakurai [/bib_ref] [bib_ref] A randomized controlled study of total parenteral nutrition and enteral nutrition by..., Kobayashi [/bib_ref]. In Japan, there are some opinions that oligomeric nutrients are clinically superior to polymeric nutrients. CQ10: When is it necessary to administer enteral nutrients through a nasogastric tube? - A nasogastric tube is necessary in cases where enteral nutrients should be given at a fixed rate, the oral intake of such nutrients is difficult, or such nutrients need to be given to patients at home during sleep at night. C1 (Japan VI, overseas VI; 8). ## Comments Enteral nutrients for patients with CD are taken orally, or through a nasogastric tube inserted into the stomach or duodenum. Unpalatable oligomeric nutrients are difficult to take orally, and in many cases are given through a nasogastric tube. Enteral nutrient feeding through a nasogastric tube at a fixed rate, using an enteral feeding pump, causes fewer side effects (such as diarrhea or abdominal pain) than orally taken enteral nutrients. For home enteral feeding, it is possible to give enteral nutrients to a patient through a nasogastric tube at night, while the patient is sleeping.. However, in practice, it is necessary to select a feeding method according to the individual's condition. ## Iv-8. parenteral nutrition The results of several randomized controlled studies have shown that TPN, among other parenteral feeding methods, has a remission induction effect for active CD equivalent to that of the enteral feeding of elemental nutrients [bib_ref] A randomized controlled study of total parenteral nutrition and enteral nutrition by..., Kobayashi [/bib_ref] [bib_ref] Comparison of total parenteral nutrition and elemental diet in induction of remission..., Jones [/bib_ref]. TPN can also attenuate intestinal lesions [bib_ref] Comparison of total parenteral nutrition and elemental diet in induction of remission..., Jones [/bib_ref] [bib_ref] Effects of total parenteral nutrition on colonic lesions in Crohn's disease: radiographic..., Fuchigami [/bib_ref]. When the CD patient's condition becomes stable on TPN, the TPN can be switched to enteral feeding. If TPN is provided through a central venous line, catheter-related complications such as sepsis and hepatic disorders could occur. Particularly in patients undergoing parenteral nutrition at home through a central venous line, an infected feeding port is likely to progress to sepsis [bib_ref] A century of home parenteral nutrition for Crohn's disease, Galandiuk [/bib_ref]. ## Iv-9. cytapheresis CQ12: When is cytapheresis indicated, and what kinds of benefits and harms are expected? [bib_ref] Adsorptive granulocyte and monocyte apheresis for refractory Crohn's disease: an open multicenter..., Fukuda [/bib_ref] - Cytapheresis is indicated in patients with active CD with colonic involvement in whom drug and/or nutritional therapies are ineffective or inapplicable; the addition of granulocyte-monocyte apheresis (GMA) may accelerate induction of remission. C1 (Japan V; 7). ## Comments Cytapheresis has become an established therapeutic modality for UC in Japan. For CD, the effects of GMA in combination with other therapies were studied in 21 cases refractory to existing drug and/or nutritional therapies. The results showed remission (i.e., CDAI less than 150) in 27.8 %, and improvement (i.e., reduction of CDAI by 50 or more) in 16.7 % [bib_ref] Adsorptive granulocyte and monocyte apheresis for refractory Crohn's disease: an open multicenter..., Fukuda [/bib_ref]. GMA was approved for clinical use in CD with colonic lesions in Japan in 2010. Although some adverse events, such as headache, dizziness, palpitation, and minor nonspecific abnormal laboratory test results have been reported, these therapies are generally considered to be safe. ## Iv-10. surgical treatment CQ13: What kind of benefits and harms are expected with surgical treatment? [bib_ref] Effect of surgery on health-related quality of life in patients with inflammatory..., Thirlby [/bib_ref] [bib_ref] Growth, course, and prognosis after surgery for Crohn's disease in children and..., Homer [/bib_ref] - Surgical treatment for the complications of CD is expected to attenuate the symptoms and improve the QOL. B (overseas IVa; 9). - Surgical treatment reduces the doses of therapeutic drugs and thus the possibility of adverse effects. C1 (Japan V, overseas IVa; 7). - Surgical treatment involves the risk of postoperative complications such as short-bowel syndrome and anastomotic leaks. C1 (Japan V, overseas V; 8). ## Comments There are no therapies that can cure CD completely. The purpose of surgical treatment is to attenuate the symptoms due to complications that are the causes of the patient's disability, and to improve the patient's QOL [bib_ref] Effect of surgery on health-related quality of life in patients with inflammatory..., Thirlby [/bib_ref]. If the symptoms are attenuated, the doses of therapeutic drugs such as steroids can be reduced, thus preventing possible adverse effects (such as growth retardation) [bib_ref] Growth, course, and prognosis after surgery for Crohn's disease in children and..., Homer [/bib_ref]. However, reoperation becomes necessary in some cases (the rate of reoperation in Japan was reported to be as high as 28-30 %). Short-bowel syndrome due to repeated bowel resections can compromise the patient's QOL; resection should therefore be kept to the minimum necessary. ## Iv-11. endoscopic treatment CQ14: When is endoscopic balloon dilation indicated, and what kinds of benefits and harms are expected? [bib_ref] Long-term outcome of endoscopic balloon dilation in obstructive gastrointestinal Crohn's disease, Matsui [/bib_ref] [bib_ref] Systematic review: endoscopic dilatation in Crohn's disease, Hassan [/bib_ref] - Endoscopic balloon dilation is indicated for benign stenosis with bowel obstruction in the gastrointestinal tract without accompanying deep ulcers or fistulas. C1 (Japan VI, overseas VI; 7). - This therapy may alleviate bowel obstruction and may avoid a surgical operation. C1 (Japan V, overseas V; 8). - Care must be taken with regard to complications such as perforation or restenosis. C1 (Japan V, overseas V; 9). ## Comments The major endoscopic treatment for CD is endoscopic balloon dilation (EBD). In CD, EBD is indicated for benign stenosis of comparatively short length with few flexures producing clinical features of bowel obstruction, without deep ulcers or fistulas. Accordingly, it is necessary to employ endoscopy or contrast imaging to observe the stenosis well before EBD is performed. The effectiveness of EBD for CD has been reported from many medical institutions in Japan and overseas [bib_ref] Long-term outcome of endoscopic balloon dilation in obstructive gastrointestinal Crohn's disease, Matsui [/bib_ref] [bib_ref] Systematic review: endoscopic dilatation in Crohn's disease, Hassan [/bib_ref]. It is particularly effective for stenosis of a comparatively short length, such as 4 cm or less [bib_ref] Long-term outcome of endoscopic balloon dilation in obstructive gastrointestinal Crohn's disease, Matsui [/bib_ref]. The incidence of complications involved in EBD was 2 %, and perforation accounted for most of the cases [bib_ref] Systematic review: endoscopic dilatation in Crohn's disease, Hassan [/bib_ref]. Other than perforation, care must be taken with regard to hemorrhage, fistulas, abscess formation, and further restenosis. V. Active phase treatment V-1. Mild to moderate CQ1: How is treatment initiated for mildly to moderately active CD? [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref] [bib_ref] Oral Pentasa in the treatment of active Crohn's disease: a meta-analysis of..., Hanauer [/bib_ref] [bib_ref] How effective is enteral nutrition in inducing clinical remission in active Crohn's..., Fernandez-Banares [/bib_ref] [bib_ref] Metaanalysis of enteral nutrition as a primary treatment of active Crohn's disease, Griffiths [/bib_ref] [bib_ref] Controlled trial comparing an elemental diet with prednisolone in the treatment of..., Okada [/bib_ref] [bib_ref] The clinical effect of salazosulphapyridine (Salazopyrin) in Crohn's disease. A controlled double-blind..., Anthonisen [/bib_ref] [bib_ref] Sulphasalazine and prednisone compared with sulphasalazine for treating active Crohn disease. A..., Rijk [/bib_ref] [bib_ref] National Cooperative Crohn's Disease Study: results of drug treatment, Summers [/bib_ref] [bib_ref] Clinical effects of N-5ASA (oral controlled -release mesalazine) on Crohn's disease: a..., Munakata [/bib_ref] [bib_ref] Mesalamine capsules for the treatment of active Crohn's disease: results of a..., Singleton [/bib_ref] [bib_ref] A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active..., Colombel [/bib_ref] [bib_ref] A randomized controlled study comparing elemental diet and steroid treatment in Crohn's..., Zoli [/bib_ref] - Administer salazosulfapyridine (SASP) in patients with mildly to moderately active CD with colonic lesions. A (overseas II; 8). - SASP is not effective for small-intestinal lesions. B (overseas III; 8). - The effect of 5-ASA preparations is limited, but they lack serious side effects and are easy to administer. In practice, they are often chosen as a first-line drug. A (overseas I; 8). - Daily administration of 1,000 mg ciprofloxacin is expected to have an effect similar to that of 5-ASA preparations for colonic lesions in CD. B (overseas III; 7) Not covered by Japanese public health insurance for treatment of CD. - The remission induction effect of enteral nutrition for active CD is equivalent or slightly inferior to that of corticosteroids. A (Japan III, overseas I; 8). ## Comments As described in section II-9, there are no practical criteria to determine the severity of CD, and thus it is determined on the basis of a comprehensive assessment of clinical findings [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref]. In these guidelines, mild to moderate cases are assumed to be those in which the patient is capable of visiting a hospital on an outpatient basis and of taking food orally, without findings including dehydration, fever, abdominal tenderness, bowel obstruction, or weight loss of 10 % or more [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref]. A meta-analysis and several randomized controlled trials have shown that SASP is effective for colonic lesions in mildly to moderately active CD [bib_ref] The clinical effect of salazosulphapyridine (Salazopyrin) in Crohn's disease. A controlled double-blind..., Anthonisen [/bib_ref] [bib_ref] Sulphasalazine and prednisone compared with sulphasalazine for treating active Crohn disease. A..., Rijk [/bib_ref] , but that it is not effective for small-intestinal lesions [bib_ref] National Cooperative Crohn's Disease Study: results of drug treatment, Summers [/bib_ref]. Some studies have also shown that mesalazine is effective for CD [bib_ref] Oral Pentasa in the treatment of active Crohn's disease: a meta-analysis of..., Hanauer [/bib_ref] [bib_ref] Clinical effects of N-5ASA (oral controlled -release mesalazine) on Crohn's disease: a..., Munakata [/bib_ref] [bib_ref] Mesalamine capsules for the treatment of active Crohn's disease: results of a..., Singleton [/bib_ref]. A recent meta-analysis indicated that the CDAI score in the mesalazine group was significantly reduced in comparison with that in the placebo group [bib_ref] National Cooperative Crohn's Disease Study: results of drug treatment, Summers [/bib_ref]. In Japan, where treatment options are limited, mesalazine is widely used for ileal and colonic lesions because of its safety profile and ease of administration. A randomized controlled trial has indicated that for mildly to moderately active CD, 1 g ciprofloxacin administered daily has an effect similar to that of 4 g mesalazine administered daily [bib_ref] A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active..., Colombel [/bib_ref]. Meta-analyses that compared enteral nutrition with steroid therapy concluded that steroids were more efficacious [bib_ref] How effective is enteral nutrition in inducing clinical remission in active Crohn's..., Fernandez-Banares [/bib_ref] [bib_ref] Metaanalysis of enteral nutrition as a primary treatment of active Crohn's disease, Griffiths [/bib_ref]. However, a randomized controlled small-size study has indicated that nutritional therapy using elemental nutrients has an effect of remission induction similar to that of steroids (prednisolone 0.5 mg/kg daily), and provides better nutritional status than steroids [bib_ref] A randomized controlled study comparing elemental diet and steroid treatment in Crohn's..., Zoli [/bib_ref]. Furthermore, a Japanese report indicated that enteral feeding of elemental nutrients exhibited a higher rate of remission induction than prednisolone treatment, particularly for intestinal lesions [bib_ref] Controlled trial comparing an elemental diet with prednisolone in the treatment of..., Okada [/bib_ref]. In Europe and North America, budesonide, a steroid with reduced systemic adverse effects, is used for lesions in the ileum to the right side of the colon. Budesonide exhibited a higher rate of remission induction than mesalazine. ## V-2. moderate to severe CQ2: How is treatment initiated for moderately to severely active CD? [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref] [bib_ref] Corticosteroids for maintenance of remission in Crohn's disease, Steinhart [/bib_ref] [bib_ref] Adsorptive granulocyte and monocyte apheresis for refractory Crohn's disease: an open multicenter..., Fukuda [/bib_ref] [bib_ref] National Cooperative Crohn's Disease Study: results of drug treatment, Summers [/bib_ref] [bib_ref] Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study..., Feagan [/bib_ref] [bib_ref] Methotrexate for induction of remission in refractory Crohn's disease, Alfadhli [/bib_ref] [bib_ref] A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor..., Targan [/bib_ref] [bib_ref] 69 disease: the ACCENT I randomised trial, Hanauer [/bib_ref] - Administer oral steroids (prednisolone, approximately 40 mg daily). B (overseas III; 8). - In cases where steroids are not effective, consider administering an anti-TNF agent. A (overseas II; 8). - The remission induction effect of enteral nutrition for active CD is equivalent or somewhat inferior to that of corticosteroids. A (Japan III, overseas I; 8). - In active CD with colonic lesions for which drug and/or nutrition therapies are ineffective or inapplicable, the addition of GMA may be helpful. C1 (Japan V; 7). ## Comments In these guidelines, moderate to severe cases are assumed to be those in which therapies for mild to moderate cases are not effective, or those in which the patient exhibits symptoms that include weight loss of 10 % or more, anemia, abdominal pain, and/or nausea/vomiting without bowel obstruction [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref]. Randomized controlled trials have shown that steroids are efficacious in inducing remission in CD [bib_ref] Corticosteroids for maintenance of remission in Crohn's disease, Steinhart [/bib_ref] [bib_ref] National Cooperative Crohn's Disease Study: results of drug treatment, Summers [/bib_ref]. However, steroids are not effective in maintaining remission [bib_ref] Corticosteroids for maintenance of remission in Crohn's disease, Steinhart [/bib_ref]. In patients in whom symptoms have worsened during the tapering of steroids, or those in whom there was a relapse shortly after withdrawal from steroids, or in those with repeated relapses, consider using an immunomodulator such as AZA or 6-MP in combination with steroids. In patients in whom AZA or 6-MP cannot be used because of adverse effects, methotrexate (MTX) is considered to be effective and is used overseas [bib_ref] Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study..., Feagan [/bib_ref] [bib_ref] Methotrexate for induction of remission in refractory Crohn's disease, Alfadhli [/bib_ref]. Anti-TNF agents, both with single administration and with scheduled successive administrations, were shown to be efficacious in cases refractory to steroids and/or immunomodulators [bib_ref] A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor..., Targan [/bib_ref] [bib_ref] 69 disease: the ACCENT I randomised trial, Hanauer [/bib_ref]. The addition of GMA was approved for clinical use in Japan in 2010 for active CD with colonic lesions not responsive to existing drug and/or nutrition therapies [bib_ref] Adsorptive granulocyte and monocyte apheresis for refractory Crohn's disease: an open multicenter..., Fukuda [/bib_ref]. ## V-3. severe to fulminant CQ3: How is treatment initiated for severe to fulminant CD? [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref] [bib_ref] Absorption of prednisolone in patients with Crohn's disease, Shaffer [/bib_ref] - The patient is generally hospitalized; as necessary; consider complete fasting, infusion of fluid, and/or blood transfusion, and administer an antimicrobial drug if the patient shows signs of infection. C1 (Japan VI, overseas VI; 8). - Exclude infections, and intravenously administer steroids (prednisolone equivalent to 40-60 mg daily). C1 (Japan VI, overseas VI; 8). - In cases resistant to steroids, consider administering an anti-TNF agent. C1 (overseas V; 8). - In cases where the patient's general condition is poor, or unresponsive to medical therapies, consult with surgeons at an early opportunity. C1 (Japan VI, overseas VI; 8). ## Comments In these guidelines, severe to fulminant cases are assumed to be those in which the patient's symptoms persist after oral administration of steroids, or those in which the patient presents with high fever, persistent vomiting, bowel obstruction, rebound tenderness, cachexia, and/or abscess [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref]. In general, the patient should be hospitalized to receive intensive general supportive care. Orally administered steroids are not as well assimilated as intravenous steroids, and intravenous administration is advantageous in terms of pharmacokinetics [bib_ref] Absorption of prednisolone in patients with Crohn's disease, Shaffer [/bib_ref] and preferred for severe cases. For fulminant cases not responsive to other medical treatments, there is only limited evidence on the effects of anti-TNF agents; however, they can still be a treatment option. They should be used only when the presence and/or risk of infectious complications such as abscesses are ruled out. Severe cases in which the patient has unstable hemodynamics, or those with peritoneal irritation, may be indications for surgical treatment, and therefore it is desirable to consult with surgeons at an early opportunity. V-4. Therapies according to disease extent CQ4: Are different therapies used for lesions in the small intestine, the colon, and both? [bib_ref] The clinical effect of salazosulphapyridine (Salazopyrin) in Crohn's disease. A controlled double-blind..., Anthonisen [/bib_ref] [bib_ref] Sulphasalazine and prednisone compared with sulphasalazine for treating active Crohn disease. A..., Rijk [/bib_ref] - Treatment options vary according to the disease extent. C1 (Japan VI, overseas VI; 8). - SASP is effective only for colonic lesions. A (overseas II; 8). - Antimicrobial drugs are more effective for colonic lesions than for small-intestinal lesions. B (overseas III; 8). Not covered by Japanese public health insurance for treatment of CD. - Enteral nutrition is more effective for small-intestinal lesions than for colonic lesions. A (Japan III, overseas I; 8). ## Comments Consideration of the mechanisms and sites of action of therapeutic drugs for CD indicates the appropriate use of these drugs depending on the sites of the lesions, and it is actually confirmed in some cases. SASP is effective only for mild colonic lesions [bib_ref] The clinical effect of salazosulphapyridine (Salazopyrin) in Crohn's disease. A controlled double-blind..., Anthonisen [/bib_ref] [bib_ref] Sulphasalazine and prednisone compared with sulphasalazine for treating active Crohn disease. A..., Rijk [/bib_ref]. Antimicrobial drugs, particularly metronidazole, are known to be generally effective for colonic and perianal lesions. Enteral nutrients are significantly more effective for small-intestinal lesions than for colonic lesions. Mesalazine is effective for both small-intestinal and colonic lesions; and systemic steroids, immunomodulators, and anti-TNF agents are not selective with respect to lesion sites. CQ5: What is the treatment for CD lesions in the upper gastrointestinal tract? [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref] [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref] - In cases of CD with upper-gastrointestinal lesions, administer a proton pump inhibitor (PPI). C1 (overseas VI; 7) Not covered by Japanese public health insurance for treatment of CD. - Administer steroids and/or immunomodulators, such as AZA or 6-MP, as necessary. C1 (overseas VI; 7). - In cases refractory to steroids, consider administering anti-TNF agents. C1 (overseas: VI; 8). - In patients with upper-gastrointestinal lesions with bowel obstruction, consider endoscopic dilation or surgical treatment. C1 (overseas VI; 8). ## Comments Evidence is not sufficient with regard to the treatment for upper-gastrointestinal lesions in active CD. PPIs are often used for inflammatory lesions in the upper gastrointestinal tract, in combination with other therapies, as in the treatment for lesions at other sites [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref] [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref]. 5-ASA preparations in their original forms do not act on the mucosa of the upper gastrointestinal tract, and therefore attempts have been made to administer these agents orally by crushing and grinding the tablets. However, the effectiveness and safety of these preparations have not been sufficiently studied. ## V-5. perianal lesions CQ6: What is the treatment for the perianal lesions of CD? [bib_ref] AGA technical review on perianal Crohn's disease, Sandborn [/bib_ref] [bib_ref] Infliximab maintenance therapy for fistulizing Crohn's disease, Sands [/bib_ref] [bib_ref] Practice parameters for the treatment of perianal abscess and fistula-in-ano (revised), Whiteford [/bib_ref] [bib_ref] American Gastroenterological Association medical position statement: perianal Crohn's disease, Sandborn [/bib_ref] [bib_ref] Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis, Pearson [/bib_ref] - Treat the intestinal lesions first, and wait to see if the perianal lesions are attenuated. C1 (Japan VI, overseas VI; 8). - Anti-TNF agents are effective as medical therapy for anal fistulas. A (overseas II; 8). - Antimicrobial drugs and immunomodulators are effective therapies for anal fistulas. A (overseas I; 8). - The Seton procedure is an effective surgical treatment for anal fistulas. In severe cases, consider a stoma. B (Japan V, overseas V; 9). ## Comments Perianal lesions in CD include primary lesions (fissures and cavitating ulcers), ulcerated piles with longitudinal ulcers, and secondary refractory lesions (perianal abscesses, anal fistulas). In patients with perianal lesions specific to CD, first employ medical therapies and/or surgical treatment for the intestinal lesions, and wait to see if the perianal lesions are attenuated. Among the secondary perianal lesions in CD, the Seton procedure is effective for anal fistulas; for common lesions, use ordinary treatments [bib_ref] Practice parameters for the treatment of perianal abscess and fistula-in-ano (revised), Whiteford [/bib_ref] [bib_ref] American Gastroenterological Association medical position statement: perianal Crohn's disease, Sandborn [/bib_ref]. An overseas randomized controlled trial indicated that an anti-TNF agent was effective for anal fistulas [bib_ref] Infliximab maintenance therapy for fistulizing Crohn's disease, Sands [/bib_ref]. Anti-TNF agents should be used after confirmation that any infection is under control. There are no randomized controlled studies on antimicrobial drugs (such as metronidazole) for perianal lesions; however, limited evidence and clinical experience indicate that these drugs have some efficacy. For immunomodulators (such as AZA), several randomized controlled trials and meta-analyses have shown effectiveness for anal fistulas [bib_ref] AGA technical review on perianal Crohn's disease, Sandborn [/bib_ref] [bib_ref] Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis, Pearson [/bib_ref]. ## V-6. refractory cases CQ7: What is the treatment for cases refractory to various medical treatment? [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref] [bib_ref] Practice parameters for the surgical management of Crohn's disease, Strong [/bib_ref] - Consider surgical treatment in cases refractory to medical treatment without attenuation of complications. B (Japan VI, overseas VI; 9). - The indication for surgical treatment should be determined with mutual communications among the gastroenterologist, the surgeon, and the patient. B* (Japan VI; 9). ## Comments Medical treatment is the primary therapy for CD, and surgical treatment remains as secondary. However, in cases refractory to medical treatment, in which the patient has extremely impaired QOL, with serious adverse reaction to drugs, or with a fibrous stenosis not expected to be improved by medical treatment, surgical treatment should be considered [bib_ref] European evidence based consensus on the diagnosis and management of Crohn's disease:..., Travis [/bib_ref] [bib_ref] Practice parameters for the surgical management of Crohn's disease, Strong [/bib_ref]. The indication for the surgical treatment should not be determined only by the surgeon, but by thorough discussions involving the relevant healthcare providers together with the patient. ## V-7. fistulas CQ8: What is the treatment for fistulas? [bib_ref] Infliximab maintenance therapy for fistulizing Crohn's disease, Sands [/bib_ref] [bib_ref] Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis, Pearson [/bib_ref] [bib_ref] Fistulizing Crohn's disease, Judge [/bib_ref] - Immunomodulators are effective for treating fistulas, but their onset of the action is delayed. A (overseas I; 8). - Anti-TNF agents are effective for treating fistulas. A (overseas II; 9). - Surgical treatment is indicated in patients with internal fistulas causing severe malabsorption. B (Japan VI, overseas VI; 8). - Consider surgical treatment for fistulas with abscess formation. B(Japan VI, overseas IV:9). ## Comments Some cases of CD are complicated with internal fistulas such as intestinal fistulas and external fistulas such as intestinal-cutaneous fistulas. No consensus has been reached with regard to either treatments for fistulas without symptoms or treatments for internal fistulas [bib_ref] Fistulizing Crohn's disease, Judge [/bib_ref]. As a medical treatment for fistulas, a meta-analysis of overseas randomized controlled studies has indicated that immunomodulators are effective [bib_ref] Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis, Pearson [/bib_ref] , although the onset of action of these drugs is delayed. An overseas large randomized controlled study (ACCENT II) demonstrated that infliximab was useful [bib_ref] Infliximab maintenance therapy for fistulizing Crohn's disease, Sands [/bib_ref]. A study of the effect of adalimumab on remission maintenance showed a significant effect in closing external fistulas completely at week 26 and week 56. Consider surgical treatment in patients in whom medical therapies have been unsuccessful. The indications for surgery include patients with internal fistulas causing severe malabsorption, patients in whom fistulas are spread over a broad area in the healthy bowel, patients with repeated urinary tract infections, patients with external fistulas with excessive leakage of intestinal juices, and patients with painful perianal external fistulas complicated with abscess formation [bib_ref] Fistulizing Crohn's disease, Judge [/bib_ref]. ## V-8. stenosis CQ9: What is the treatment for an intestinal stenosis due to CD? [bib_ref] Long-term outcome of endoscopic balloon dilation in obstructive gastrointestinal Crohn's disease, Matsui [/bib_ref] [bib_ref] Appropriate treatment for Crohn's disease: methodology and summary results of a multidisciplinary..., Vader [/bib_ref] [bib_ref] Colonoscopic balloon dilation of Crohn's strictures: a review of long-term outcomes, Thomas-Gibson [/bib_ref] - Administer steroids in patients with severe inflammation. C1 (Japan VI, overseas VI; 7). - Consider endoscopic dilation in patients in whom there has been no improvement with drug therapies or decompression. C1 (Japan V, overseas V; 7). - Consider surgery in patients whose condition has not been improved with medical treatment. B (Japan V, overseas V; 9). ## Comments Intestinal stenosis occurs with mucosal edema due to acute inflammation or transmural fibrotic changes in the intestine. Patients with stenosis mainly due to inflammation may improve with medical treatment such as steroids [bib_ref] Appropriate treatment for Crohn's disease: methodology and summary results of a multidisciplinary..., Vader [/bib_ref]. In patients that do not show improvement with anti-inflammatory treatments, suspect stenosis due to fibrosis, and consider the possibility of endoscopic dilation on the basis of the length of the stenosis, the number of stenotic sites, and the presence of ulcers. It is advisable to use endoscopic dilation when the inflammation and ulcers have disappeared or become reduced with enteral nutrition or other therapies. In a report overseas, endoscopic dilation brought about favorable results in 40 % of the subjects [bib_ref] Colonoscopic balloon dilation of Crohn's strictures: a review of long-term outcomes, Thomas-Gibson [/bib_ref]. A report from Japan showed the 5-year operation-free rate after endoscopic dilation was 58 % [bib_ref] Long-term outcome of endoscopic balloon dilation in obstructive gastrointestinal Crohn's disease, Matsui [/bib_ref]. Whether or not anti-TNF agents are indicated for cases of CD with stenosis has not yet been determined. ## V-9. hemorrhage CQ10: What is the treatment for hemorrhage from the CD lesions? [bib_ref] Acute massive hemorrhage from intestinal Crohn disease, Homan [/bib_ref] [bib_ref] Infliximab as a possible treatment for the hemorrhagic type of Crohn's disease, Tsujikawa [/bib_ref] [bib_ref] Severe gastrointestinal hemorrhage in Crohn's disease, Robert [/bib_ref] [bib_ref] Acute lower gastrointestinal bleeding in Crohn's disease: characteristics of a unique series..., Belaiche [/bib_ref] - First apply conservative management such as supportive care and drug therapies. C1 (Japan V, overseas V; 9). - Infliximab was reported to be effective in arresting hemorrhage. C1 (Japan V, overseas V; 8). - If conservative management is not successful in arresting hemorrhage, surgery is indicated. B* (Japan V, overseas V; 9). ## Comments Massive hemorrhage may occur in CD, although it is rare. In such cases, first perform intensive conservative management, and allow nothing by mouth to keep the intestinal tract at rest. It was reported that steroids were efficacious in such cases. Try endoscopic hemostasis where it is applicable. With regard to angiography, it was reported that the intraarterial injection of vasopressin and arterial embolization were successful in arresting hemorrhage [bib_ref] Acute massive hemorrhage from intestinal Crohn disease, Homan [/bib_ref]. However, arterial embolization may cause intestinal ischemia leading to intestinal necrosis. It was reported that the administration of infliximab was effective for treating the hemorrhagic type of CD [bib_ref] Infliximab as a possible treatment for the hemorrhagic type of Crohn's disease, Tsujikawa [/bib_ref]. Surgical treatment is necessary in cases where medical treatment is unsuccessful. It was reported that the surgical operation rate for hemostasis in patients with initial massive hemorrhaging was 20-90 %, and that the surgical operation rate in those with recurrent hemorrhage under medical treatment was 30-35 % [bib_ref] Severe gastrointestinal hemorrhage in Crohn's disease, Robert [/bib_ref] [bib_ref] Acute lower gastrointestinal bleeding in Crohn's disease: characteristics of a unique series..., Belaiche [/bib_ref]. ## V-10. abscesses CQ11: What diagnosis and treatment are used for abscesses due to CD? [bib_ref] The clinical characteristics and outcome of intraabdominal abscess in Crohn's disease, Yamaguchi [/bib_ref] [bib_ref] Ultrasound and magnetic resonance imaging in Crohn's disease: a comparison, Potthast [/bib_ref] [bib_ref] Percutaneous abscess drainage in Crohn disease: technical success and shortand long-term outcomes..., Gervais [/bib_ref] [bib_ref] Outcome of surgical versus percutaneous drainage of abdominal and pelvic abscesses in..., Gutierrez [/bib_ref] - Imaging examinations such as CT, US, and MRI are used to diagnose abscesses. B (JapanV, overseas IVb; 9). - Where possible, perform image-guided (e.g., CTguided) percutaneous drainage. B (Japan V, overseas IV; 8). - In patients with abscesses in the perianal region, perform incision and drainage. B* (Japan V, overseas V; 9). - In patients in whom abscesses recur after percutaneous drainage or in those with fistulas, surgical treatment is likely to be necessary. B* (Japan V, overseas V; 8). ## Comments In CD, abscesses may be found to be complicated with transmural lesions in the intestinal wall. A Japanese report has indicated that the frequency of such abscesses is approximately 10 % [bib_ref] The clinical characteristics and outcome of intraabdominal abscess in Crohn's disease, Yamaguchi [/bib_ref]. CT, MRI, and ultrasonographic examination are useful in diagnosing abscesses [bib_ref] Ultrasound and magnetic resonance imaging in Crohn's disease: a comparison, Potthast [/bib_ref]. For treatment, percutaneous drainage should be performed where possible. The drainage techniques include CT-guided percutaneous drainage, US-guided percutaneous drainage, or surgical drainage via a small incision. In patients having percutaneous drainage, administer an antimicrobial drug with a broad spectrum. Some overseas reports have indicated that percutaneous drainage avoided subsequent surgical operation in 50-69 % of the patients treated [bib_ref] Percutaneous abscess drainage in Crohn disease: technical success and shortand long-term outcomes..., Gervais [/bib_ref] [bib_ref] Outcome of surgical versus percutaneous drainage of abdominal and pelvic abscesses in..., Gutierrez [/bib_ref]. Patients with abscesses that cannot be controlled by percutaneous drainage require surgical treatment. ## V-11. extra-intestinal complications CQ12: What is the treatment for extra-intestinal complications of CD? [bib_ref] Crohn's disease associated with spondyloarthropathy: effect of TNF-alpha blockade with infliximab on..., Van Den Bosch [/bib_ref] [bib_ref] Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo..., Brooklyn [/bib_ref] [bib_ref] Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial, Braun [/bib_ref] - In patients with active intestinal lesions, treat the intestinal inflammation. C1 (Japan V, overseas V; 8). - In patientss with pyoderma gangrenosum or uveitis, administer steroids. C1 (Japan V, overseas V; 8). - In patients with extra-intestinal complications, the usefulness of infliximab was reported. A (overseas II; 8). ## Comments Extra-intestinal complications in CD include those related to the activity of the intestinal lesions (e.g., some types of peripheral arthritis, erythema nodosum, episcleritis, and intraoral aphthous ulceration) and those unrelated to the activity of the intestinal lesions (pyoderma gangrenosum, uveitis, sacral arthritis, and ankylosing spondylitis). For either category, it is necessary to intensively control the inflammation of the intestinal lesions. In patients with arthritis, a 5-ASA preparation such as SASP is the first choice. Avoid NSAIDs because they may exacerbate the intestinal lesions. Administer steroids for serious complications such as pyoderma gangrenosum and uveitis. Some randomized and non-randomized controlled studies, including those with non-CD patients, have indicated that infliximab was effective for treating complications such as pyoderma gangrenosum, arthritis, uveitis, and ankylosing spondylitis [bib_ref] Crohn's disease associated with spondyloarthropathy: effect of TNF-alpha blockade with infliximab on..., Van Den Bosch [/bib_ref] [bib_ref] Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo..., Brooklyn [/bib_ref] [bib_ref] Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial, Braun [/bib_ref]. VI. Remission maintenance treatment VI-1. General principles for preventing relapse CQ1: Are there any lifestyle factors that require attention to prevent relapse? [bib_ref] Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study, Felder [/bib_ref] [bib_ref] Smoking cessation and the course of Crohn's disease: an intervention study, Cosnes [/bib_ref] [bib_ref] Psychological stress in IBD: new insights into pathogenic and therapeutic implications, Mawdsley [/bib_ref] - If the patient smokes, advise them to refrain from smoking. B (overseas III; 9). - Advise the patient to avoid irregular lifestyle and eating habits, and to refrain from excessive alcohol drinking. C1 (overseas VI; 7). - Advise the patient to adopt a lifestyle without excessive mental stress, to have as little stress as possible. C1 (overseas IVb; 7). - Advise the patient that in using an analgesic or an antipyretic, wherever possible to avoid NSAIDs. C1 (overseas IVb; 7). ## Comments Although exacerbating factors common to all cases of CD cannot be specified, it has been shown that smoking contributes to the disease becoming refractory or relapsing, and that the disease is attenuated after smoking cessation [bib_ref] Smoking cessation and the course of Crohn's disease: an intervention study, Cosnes [/bib_ref]. Frequent or excessive alcohol drinking may damage the intestinal tract, and therefore drinking should be controlled. In view of the fact that nutritional therapies are beneficial for CD, irregular eating habits or unbalanced diets may precipitate relapse. It has also been shown that mental stress has some relationship with CD relapse [bib_ref] Psychological stress in IBD: new insights into pathogenic and therapeutic implications, Mawdsley [/bib_ref]. Patients with CD should be advised to live without mental stress as much as possible, and to adopt a lifestyle where stress does not accumulate. NSAIDs are known to cause gastrointestinal injuries, and also the relapse or exacerbation of CD. Therefore, wherever possible, they should be avoided. If analgesics or antipyretics need to be prescribed, acetaminophen would be an appropriate substitute [bib_ref] Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study, Felder [/bib_ref]. CQ2: Are there any distinctive features of CD that make the disease likely to relapse? [bib_ref] Predictors of Crohn's disease, Beaugerie [/bib_ref] [bib_ref] Long-term evolution of disease behavior of Crohn's disease, Cosnes [/bib_ref] - CD patients with fistulas, perforation, or perianal lesions, and those who have had resection of the intestinal tract, are more susceptible to relapses. C1 (Japan V, overseas V; 7). - Patients with CD who have required steroids for induction of remission are more susceptible to relapses. C1 (overseas IV; 7). ## Comments The pathophysiology and symptomatology of CD are complex, and it is difficult to predict the variable progress of each case. However, it has been shown that patients with fistula formation or intestinal perforation are more susceptible to relapses than those with the non-perforation type [bib_ref] Long-term evolution of disease behavior of Crohn's disease, Cosnes [/bib_ref]. Patients with CD with high disease activity who have required steroids for the induction of remission often have difficulty in withdrawing from the steroids and require immunomodulators. It has been shown that patients for whom steroids or immunomodulators are required are more susceptible to relapses than other patients [bib_ref] Predictors of Crohn's disease, Beaugerie [/bib_ref]. ## Vi-2. drug treatment CQ3: Which drugs are effective for maintaining remission of CD? [bib_ref] Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's disease, Akobeng [/bib_ref] [bib_ref] Azathioprine for maintaining remission of Crohn's disease, Pearson [/bib_ref] [bib_ref] 69 disease: the ACCENT I randomised trial, Hanauer [/bib_ref] [bib_ref] The evidence base for interventions used to maintain remission in Crohn's disease, Akobeng [/bib_ref] [bib_ref] Efficacy and safety of retreatment with antitumor necrosis factor antibody (infliximab) to..., Rutgeerts [/bib_ref] [bib_ref] Mesalamine in the maintenance treatment of Crohn's disease: a meta-analysis adjusted for..., Camma [/bib_ref] - AZA is effective in maintaining remission. A (overseas I; 9). - In patients in whom remission was induced by anti-TNF agents, the scheduled administration of anti-TNF agents is effective in maintaining remission. A (overseas II; 8). ## Comments Steroids are effective for inducing remission, but ineffective for maintaining remission. It has been shown that AZA and 6-MP have steroid-sparing effects in steroid tapering and complete withdrawal, as well as having a long-term effect in maintaining remission. The standard dose of AZA is 1.0-2.5 mg/kg daily, and that of 6-MP is half of that of AZA. A high dose of these drugs exhibits a more potent effect than a low dose [bib_ref] Azathioprine for maintaining remission of Crohn's disease, Pearson [/bib_ref] [bib_ref] The evidence base for interventions used to maintain remission in Crohn's disease, Akobeng [/bib_ref]. However, both AZA and 6-MP may produce serious side effects, and the doses that may produce the required effects and the adverse reactions differ individually. The recommended doses for these agents have been determined for patients in Western countries, and it is possible that lower doses in Japanese patients would produce the required effects and/or fewer adverse effects. It has been shown that infliximab exhibits a remission induction effect even in refractory or severe cases, and that administration of infliximab every 8 weeks to patients in whom remission was induced by the agent had a significant effect in preventing relapses for at least 1 year [bib_ref] 69 disease: the ACCENT I randomised trial, Hanauer [/bib_ref] [bib_ref] Efficacy and safety of retreatment with antitumor necrosis factor antibody (infliximab) to..., Rutgeerts [/bib_ref]. 5-ASA preparations have only a limited remission maintenance effect [bib_ref] Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's disease, Akobeng [/bib_ref] , but they are effective in controlling postoperative relapses [bib_ref] Mesalamine in the maintenance treatment of Crohn's disease: a meta-analysis adjusted for..., Camma [/bib_ref]. CQ4: How long should the treatment for remission be continued? [bib_ref] 69 disease: the ACCENT I randomised trial, Hanauer [/bib_ref] [bib_ref] Efficacy and safety of retreatment with antitumor necrosis factor antibody (infliximab) to..., Rutgeerts [/bib_ref] [bib_ref] A randomized, double-blind, controlled withdrawal trial in Crohn's disease patients in long-term..., Lemann [/bib_ref] - If effective, it is advisable to continue the administration of AZA or 6-MP* for 3-4 years. C1 (overseas VI; 8) Not covered by Japanese public health insurance for treatment of CD. - Scheduled administration of infliximab is effective for at least 1 year. A (overseas II; 8). Comments AZA and 6-MP, thiopurine derivatives, are known to have efficacy for long-term remission, and a meta-analysis showed that they were effective in maintaining remission for at least 1 year. Furthermore, it has been reported that the continued administration of these agents for more than 2 years is effective, and therefore it is advisable that they continue to be administered for 3-4 years as long as remission is maintained without the emergence of adverse effects [bib_ref] A randomized, double-blind, controlled withdrawal trial in Crohn's disease patients in long-term..., Lemann [/bib_ref]. In a study to evaluate the effect of the scheduled administration of infliximab at 8-week intervals for 1 year in patients in whom remission was induced by infliximab, the remission maintenance effect was significantly higher in the group receiving infliximab regularly at intervals of 8 weeks compared with placebo [bib_ref] 69 disease: the ACCENT I randomised trial, Hanauer [/bib_ref] [bib_ref] Efficacy and safety of retreatment with antitumor necrosis factor antibody (infliximab) to..., Rutgeerts [/bib_ref]. ## Vi-3. nutritional therapy CQ5: Is home enteral nutrition effective in maintaining remission? [bib_ref] Effectiveness of an 'half elemental diet' as maintenance therapy for Crohn's disease:..., Takagi [/bib_ref] [bib_ref] Impacts of long-term enteral nutrition on clinical and endoscopic disease activities and..., Yamamoto [/bib_ref] [bib_ref] Oral nutritional supplementation is effective in the maintenance of remission in Crohn's..., Verma [/bib_ref] - Replacing half of the daily caloric intake by enteral nutrients is effective in maintaining remission. A (Japan II, overseas II; 8). ## Comments Enteral nutrition as a long-term therapy for remission maintenance has an excellent safety profile, but often lacks acceptability and convenience. It is thus difficult for patients to receive total enteral feeding at home for a long period of time. Partial enteral feeding is more acceptable and more convenient for the patient, and the patient can enjoy eating as well. It was shown that replacing 30-50 % of the normal daily caloric intake by enteral nutrients had a significantly higher remission maintenance rate than a normal daily diet only [bib_ref] Effectiveness of an 'half elemental diet' as maintenance therapy for Crohn's disease:..., Takagi [/bib_ref] [bib_ref] Impacts of long-term enteral nutrition on clinical and endoscopic disease activities and..., Yamamoto [/bib_ref] [bib_ref] Oral nutritional supplementation is effective in the maintenance of remission in Crohn's..., Verma [/bib_ref]. CQ6: How long should nutritional therapy be continued? [bib_ref] Effectiveness of an 'half elemental diet' as maintenance therapy for Crohn's disease:..., Takagi [/bib_ref] [bib_ref] Impacts of long-term enteral nutrition on clinical and endoscopic disease activities and..., Yamamoto [/bib_ref] [bib_ref] Oral nutritional supplementation is effective in the maintenance of remission in Crohn's..., Verma [/bib_ref] - Replacing half of the daily caloric intake by enteral nutrients is effective in maintaining remission for at least one year. A (Japan II, overseas II; 8). ## Comments It was shown that replacing 30-50 % of the daily caloric intake by enteral nutrients had a significantly higher rate of remission maintenance at 1 year than a normal daily diet only [bib_ref] Effectiveness of an 'half elemental diet' as maintenance therapy for Crohn's disease:..., Takagi [/bib_ref] [bib_ref] Impacts of long-term enteral nutrition on clinical and endoscopic disease activities and..., Yamamoto [/bib_ref] [bib_ref] Oral nutritional supplementation is effective in the maintenance of remission in Crohn's..., Verma [/bib_ref] ; therefore, it is recommended to continue enteral nutrition for 1 year in patients in whom remission was induced by nutritional therapy. Although there is no evidence to favor enteral nutrition beyond 1 year, it may be advisable to continue this treatment for as long as possible, if no problems of acceptability or convenience emerge. CQ7: When is home parenteral nutrition (HPN) necessary, and how is it performed? [bib_ref] Management of the short bowel syndrome after extensive small bowel resection, Jutta [/bib_ref] - In patients with short-bowel syndrome for whom sufficient nutritional care by enteral feeding is not possible, supply nutrition by infusion through a central venous line. C1 (Japan VI, overseas VI; 8). ## Comments In CD patients with small-intestinal lesions where the remaining small intestine is short as a result of the resection of a large area or frequent resections, the bowel cannot digest and assimilate a sufficient amount of nutrition (i.e., if the remaining small intestine is 1 m or less, malabsorption is inevitable; even if the remaining small intestine is a little longer, malabsorption is likely to occur). Accordingly, to provide the patient with the required nutritional support, a catheter is placed in the central vein, and a home-based arrangement is made whereby the patient or the patient's family can manage nutrition drips [bib_ref] Management of the short bowel syndrome after extensive small bowel resection, Jutta [/bib_ref]. VII. Surgical treatment VII-1. Indication for surgery CQ1: How often is surgical treatment required for CD?- In Japan, the cumulative rate of surgical intervention for CD at 5 and 10 years after the onset is 30.3 and 70.8 %, respectively. The rates vary greatly from area to area in Europe and North America. C1 (Japan V, overseas V; 7). ## Comments In Japan, the cumulative rates of surgical treatment for CD at 5 and 10 years after the onset are 30.3 and 70.8 %, respectively (N = 361). Regarding the rate according to the disease location, there were no significant differences among the ileal, ileocolonic, and colonic types at 5 and 10 years after the disease onset. In Europe and North America, the rate of surgical treatment for CD varies from area to area. CQ2: What are the absolute indications and the relative indications for surgery? [bib_ref] The clinical characteristics and outcome of intraabdominal abscess in Crohn's disease, Yamaguchi [/bib_ref] [bib_ref] Cancer risk in inflammatory bowel disease, Ulman [/bib_ref] - Surgery is absolutely indicated in patients with perforation, massive hemorrhage, development of cancer, bowel obstruction not alleviated by medical therapies, and abscesses. B (Japan V, overseas V; 9). - Surgery is relatively indicated in patients with refractory stenosis or internal and external fistulas, and in those refractory to medical treatment, or with refractory extra-intestinal complications (e.g., growth retardation, pyoderma gangrenosum), and refractory perianal lesions. C1 (Japan V, overseas: V; 8). ## Comments Surgical indications in CD, in percentages according to the underlying lesions or clinical situations, are as follows: bowel obstruction and stenosis: 54 %; fistulas: 28 %; abscesses: 7 %; perforations: 4.5 %; cases refractory to medical therapies: 3.5 %; massive hemorrhage: 2 %; and colorectal cancer: 1 %. Toxic megacolon was also referred to as a surgical indication. Other surgical indications are: symptomatic fibrotic stenosis; enterocutaneous fistulas with excessive leaks of intestinal juices or with stenosis; symptoms due to bypass formation (e.g., duodenal/transverse colonic fistulas); intestinal fistulas involving a broad area of intact bowel; enterovesical fistulas refractory to medical therapies and with repeated urinary tract infection; intra-abdominal abscesses not responsive to medical therapies; and retroperitoneal abscesses [bib_ref] The clinical characteristics and outcome of intraabdominal abscess in Crohn's disease, Yamaguchi [/bib_ref]. The relative risks of colorectal cancer and small-intestinal cancer are significantly high in patients with CD [bib_ref] Cancer risk in inflammatory bowel disease, Ulman [/bib_ref]. In Japan, colorectal cancer in CD patients is more common in the form of rectal and anal fistula cancer, and small-intestinal cancer is more common in the ileum. With regard to gastric/duodenal lesions as complications of CD, surgical indications are fistulas starting at the colon or ileo-colonic anastomosis to the stomach, long duodenal stenosis, and duodenal fistulas that often occur arising from the adjacent lesions. ## Vii-2. refractory to medical treatment CQ3: What is the main principle guiding surgery on the intestine? [bib_ref] Effect of resection margins on the recurrence of Crohn's disease in the..., Fazio [/bib_ref] [bib_ref] The impact of disease pattern, surgical management, and individual surgeons on the..., Post [/bib_ref] - As CD involves the entire intestinal tract and often recurs, the intestinal tract should be preserved as much as possible. A (overseas II; 9). - Only the small portion of the intestinal tract causing stenosis or fistulas should be resected. Strictureplasty should be performed in patients with short fibrotic stenosis in the small intestine or in those with a short length of small intestine remaining. C1 (Japan V, overseas V; 9). ## Comments The postoperative recurrence of CD after resection of the intestine is unrelated to the distance between the lesion and the resected end [bib_ref] Effect of resection margins on the recurrence of Crohn's disease in the..., Fazio [/bib_ref] , or to the histological residue of the lesion at the resected ends [bib_ref] The impact of disease pattern, surgical management, and individual surgeons on the..., Post [/bib_ref]. Therefore, in principle, a short segment should be resected. In patients with an intestinal fistula induced by another intestinal lesion, the intestinal area of the principal lesion is resected, and the fistulized area is wedge-resected. Strictureplasty is performed to preserve the small intestine. Bypass operations result in a high incidence of malignant tumors in the diverted residual lesion, and a high rate of reoperation. In principle, therefore, only gastrojejunostomy for duodenal stenosis is performed in patients with CD. ## Vii-3. stenosis CQ4: What kind of surgery is used to treat stenosis? [bib_ref] Reoperative rates for Crohn's disease following strictureplasty. Long-term analysis, Ozuner [/bib_ref] [bib_ref] Extended strictureplasty for multiple short skipped strictures of Crohn's disease, Sasaki [/bib_ref] [bib_ref] Side-to-side isoperistaltic strictureplasty for multiple Crohn's strictures, Michelassi [/bib_ref] - Only the area of the lesion causing the stenosis should be resected. Strictureplasty should be performed for a short segment of fibrotic stenosis in the small intestine or in patients with a short length of small intestine remaining. B (Japan V, overseas IVb; 8). ## Comments It is a general opinion that there is little difference in postoperative recurrence rates between strictureplasty and intestinal resection [bib_ref] Reoperative rates for Crohn's disease following strictureplasty. Long-term analysis, Ozuner [/bib_ref]. In patients with a stenosis in a short segment, the Heineke-Mikulicz technique is applied; in those with stenosis over a long segment, the Finney technique or the Jaboulay technique is applied; and in those with stenoses close to one another, a more complex anastomosis technique is applied [bib_ref] Extended strictureplasty for multiple short skipped strictures of Crohn's disease, Sasaki [/bib_ref] [bib_ref] Side-to-side isoperistaltic strictureplasty for multiple Crohn's strictures, Michelassi [/bib_ref]. Furthermore, it is important to conduct a biopsy examination at the stenosis to exclude cancer. The effectiveness of strictureplasty on colonic stenosis is yet to be confirmed. ## Vii-4. perianal lesions CQ5: What kind of surgery is used to treat perianal lesions? [bib_ref] Perianal lesions in Crohn's disease, Hughes [/bib_ref] - Perianal lesions in CD are classified as primary lesions (cavitating ulcerative lesions due to CD), secondary refractory lesions (secondary lesions originating from a primary lesion via infection and other causes), and incidental lesions (lesions not associated with CD). C1 (overseas VI; 7). - For incidental lesions, use ordinary treatments generally appropriate for such lesions. C1 (Japan VI, overseas VI; 7). - Among the secondary refractory lesions, a Seton technique is used for low intersphincteric fistulas and ischiorectal fistulas. Consider creating a stoma in cases not responsive to the Seton technique or in those with fibrotic stenosis. C1 (Japan VI, overseas VI; 8). ## Comments In the diagnosis of perianal lesions in CD, determine whether the lesion is a secondary refractory lesion or an incidental lesion, on the basis of the presence or absence of a primary lesion characteristic of CD in the anal canal and the fistula (e.g., whether or not there are multiple fistulas, the location, and so on [bib_ref] Perianal lesions in Crohn's disease, Hughes [/bib_ref] ; refer to the Atlas of findings by visual observation of lesions in the anus of Crohn's disease. The refractory fistulas most frequent in CD are secondary lesions. Cancer complications are found more commonly in the rectum and anal canal (including fistulas) in patients with long-term progression of CD. CQ6: Is it possible to close a stoma later? [bib_ref] Efficacy and problems of fecal diversion for intractable anorectal complications of Crohn's..., Kogenei [/bib_ref] [bib_ref] Experience with ileostomy and colostomy in Crohn's disease, Post [/bib_ref] - In principle, a stoma that has been created because of rectal/anal lesions in CD is not closed because the lesions tend to recur frequently if it is closed. C1 (Japan V, overseas V; 7). ## Comments In a report of stoma closure surgery in 16 patients with symptomatic improvement out of 42 patients who underwent colostomies for refractory rectoanal lesions as complications of CD, 75 % required re-creation of the stoma [bib_ref] Efficacy and problems of fecal diversion for intractable anorectal complications of Crohn's..., Kogenei [/bib_ref]. It has been reported overseas that the cumulative rate of stoma closure in 5 years was 40 % [bib_ref] Experience with ileostomy and colostomy in Crohn's disease, Post [/bib_ref]. ## Vii-5. postoperative management CQ7: What is the relapse rate after surgical treatment? [bib_ref] Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative..., Rutgeerts [/bib_ref] [bib_ref] Recurrence of Crohn's disease after resection, Williams [/bib_ref] - Relapse after intestinal resection is frequently discovered early by means of endoscopic exploration. The cumulative reoperation rates were 16-43 % at 5 years and 26-65 % at 10 years. C1 (Japan V, overseas V; 8). ## Comments Postoperative relapse has been defined separately on the basis of endoscopic or contrast imaging findings, or on the basis of reoperation, and so the reported rates of relapse vary. The rate of relapse found by means of endoscopic exploration (in an ileocolonic anastomosis) seemed to be 72 % within 1 year after the operation [bib_ref] Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative..., Rutgeerts [/bib_ref] , indicating that the lesions tend to recur early. It was reported that the cumulative reoperation rates were 16-43 % at 5 years and 26-65 % at 10 years [bib_ref] Recurrence of Crohn's disease after resection, Williams [/bib_ref]. CQ8: What are the risk factors for a relapse? [bib_ref] Reoperative rates for Crohn's disease following strictureplasty. Long-term analysis, Ozuner [/bib_ref] [bib_ref] Recurrence of Crohn's disease after resection, Williams [/bib_ref] [bib_ref] Factors influencing recurrence in Crohn's disease. An analysis of a consecutive series..., Raab [/bib_ref] [bib_ref] Perforating and non-perforating indications for repeated operations in Crohn's disease: evidence for..., Greenstein [/bib_ref] [bib_ref] A meta-analysis comparing incidence of recurrence and indication for reoperation after surgery..., Simillis [/bib_ref] - Gender and the presence of granuloma are not significant risk factors. In patients who have had operations on the colonic lesions of CD, reoperation is not frequent. C1 (overseas V; 7). - The length of the uninvolved area in the resection margins is not a significant risk factor. C1 (overseas V; 7). - No consensus has been reached on the disease duration before the initial operation, the presence or absence of histological inflammation at the resection margins, or the types of anastomosis (end-to-end, end-to-side, or functional end-to-end) as risk factors. C1 (Japan VI, overseas VI; 8). - In patients where fistulization is the surgical indication, the reoperation rate may be higher in comparison with that in patients with a non-fistulizing type. B (overseas IVb; 8). - It was reported that there was little difference in terms of recurrence rates between strictureplasty and intestinal resection. C1 (overseas IVb: 7). ## Comments Risk factors for recurrence have not been determined. Gender and the presence or absence of granuloma are not significant risk factors. In patients who have had operations on the colonic lesions of CD, reoperation is not frequent [bib_ref] Recurrence of Crohn's disease after resection, Williams [/bib_ref]. The length of the intact area in the resection margins is not a significant risk factor [bib_ref] Factors influencing recurrence in Crohn's disease. An analysis of a consecutive series..., Raab [/bib_ref]. There are contradictory reports on the disease duration before the initial operation and the presence or absence of histological inflammation at the resection margins as risk factors. There is no consensus on the type of anastomosis (end-to-end, end-to-side, or functional end-to-end) as a risk factor. Reports about the types of surgical indication (perforating versus non-perforating) are also contradictory [bib_ref] Perforating and non-perforating indications for repeated operations in Crohn's disease: evidence for..., Greenstein [/bib_ref] ; however, a meta-analysis has indicated that the perforating type shows a higher reoperation rate [bib_ref] A meta-analysis comparing incidence of recurrence and indication for reoperation after surgery..., Simillis [/bib_ref]. It was reported that there was little difference in terms of recurrence rates between strictureplasty and intestinal resection [bib_ref] Reoperative rates for Crohn's disease following strictureplasty. Long-term analysis, Ozuner [/bib_ref]. CQ9: How can postoperative relapse be prevented? [bib_ref] Preventive effect of nutritional therapy against postoperative recurrence of Crohn disease, with..., Esaki [/bib_ref] [bib_ref] Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn's disease, Mcleod [/bib_ref] [bib_ref] Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal..., Rutgeerts [/bib_ref] [bib_ref] Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a..., Hanauer [/bib_ref] - There are no established measures to prevent relapse. C1 (Japan VI, overseas VI; 7). - 5-ASA, 6-MP, and metronidazole may be effective in preventing a postoperative relapse. B (overseas II; 7). *Not covered by Japanese public health insurance for treatment of CD. - The effect of postoperative nutritional therapies to prevent relapse is unclear. C1 (Japan V; 7). ## Comments The effects of surgical procedures, drug therapies, and nutritional therapies on relapse have been studied. With regard to surgical procedures, there are different views on the comparison between conventional end-to-end anastomosis and functional end-to-end anastomosis (in which the anastomotic site opening is wider in order to improve the retention of intestinal contents, which is considered to be a cause of relapse). 5-ASA (3,000 mg daily) exhibited significantly better results, in terms of clinical symptoms and relapse rate defined by endoscopy and contrast radiography, in comparison with a placebo group [bib_ref] Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn's disease, Mcleod [/bib_ref]. In patients who underwent ileal resection, metronidazole (20 mg/kg) was superior to placebo in terms of endoscopic relapse at 3 months after the operation, and in regard to the relapse rate at 1 year, but the relapse rates in the two groups were similar at 2 and 3 years after the operation [bib_ref] Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal..., Rutgeerts [/bib_ref]. In subjects with ileal resection, the 6-MP group (50 mg daily) exhibited significantly lower recurrence rates, according to the clinical symptoms, and endoscopic and contrast radiographic findings, at 2 years after the operation in comparison with the 5-ASA group and the placebo group [bib_ref] Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a..., Hanauer [/bib_ref]. Corticosteroids do not have efficacy to prevent postoperative relapse. Studies of the effects of anti-TNF agents to prevent postoperative recurrence have not been sufficient to reach definitive conclusions on such effects. The long-term application of nutritional therapy (approximately 1,000 kcal daily) is difficult in many cases. A report has indicated that nutritional therapies were effective in preventing postoperative relapse [bib_ref] Preventive effect of nutritional therapy against postoperative recurrence of Crohn disease, with..., Esaki [/bib_ref] , but the issue remains controversial. VIII. Follow-up VIII-1 Routine follow-up schedule CQ1: How are CD patients followed, and what kind of examinations are required? [bib_ref] Diagnosis of inflammatory diseases of the small intestine: comparison between double balloon..., Matsui [/bib_ref] [bib_ref] A simple biological score for predicting low risk of short-term relapse in..., Consigny [/bib_ref] - Advise patients to have regular examinations, and observe changes in the clinical symptoms (abdominal pain, diarrhea, fever, and others). C1 (Japan VI, overseas VI; 8). - CRP, ESR, complete blood counts, and serum albumin level correlate with the disease activity. C1 (Japan VI, overseas VI; 8). - If changes in disease activity are noted, employ imaging examinations to observe the lesions. C1 (Japan VI, overseas VI; 8). ## Comments Blood tests are convenient and are the first-line examination to observe progress. CRP and ESR in particular were reported to correlate with the disease activity. Anemia and hypoalbuminemia can be indices of broadly spread lesions or highly active lesions, and hypoproteinemia is often found, particularly in patients with smallintestinal lesions. When changes in the disease activity are noted (clinical relapse, bowel obstruction, abscess, fistula), it is advisable to conduct examinations according to the previous pathophysiological conditions (the disease extent and possibility of complications) [bib_ref] A simple biological score for predicting low risk of short-term relapse in..., Consigny [/bib_ref]. To determine the activity of intra-abdominal inflammation and the extent of active lesions, abdominal and pelvic CT and MRI are useful. To evaluate diffuse small-intestinal lesions, radiographic examinations are often more advantageous than endoscopy or capsule endoscopy [bib_ref] Diagnosis of inflammatory diseases of the small intestine: comparison between double balloon..., Matsui [/bib_ref]. ## Viii-2. morphological examination CQ2: When is endoscopy or contrast radiography necessary? [bib_ref] Long-term evolution of disease behavior of Crohn's disease, Cosnes [/bib_ref] - When changes in disease activity or pathophysiological conditions are noted (clinical relapse, or complications such as bowel obstruction, abscesses, and fistulas), it is advisable to perform diagnostic imaging such as endoscopy and contrast radiography to assess the disease. C1 (Japan VI, overseas VI; 8). ## Comments A study of the long-term prognosis of CD indicates that even in patients with the non-stricture and non-penetrating type without complications in their initial stage, approximately 30 % progressed to having stenosis or fistulas [bib_ref] Long-term evolution of disease behavior of Crohn's disease, Cosnes [/bib_ref]. It is not unlikely that the lesions progress even in patients with stable disease, and therefore, annual endoscopic examinations or contrast radiographic examinations, as far as possible, would be helpful in assessing the pathological conditions. ## Viii-3. cancer surveillance CQ3: Is the risk of cancer increased in CD, and can it be prevented? [bib_ref] Crohn's disease and intestinal cancer, Matsui [/bib_ref] [bib_ref] Risks and clinical features of colorectal cancer complicating Crohn's disease in Japanese..., Yano [/bib_ref] [bib_ref] Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease, Canavan [/bib_ref] [bib_ref] Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during..., Jess [/bib_ref] [bib_ref] Meta-analysis of risk of malignancy with immunosuppressive drugs in inflammatory bowel disease, Masunaga [/bib_ref] [bib_ref] Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a..., Rosh [/bib_ref] - Both colonic and ileocolonic CD have a higher risk of colorectal and/or anal cancer than that in the general population. B (Japan IVb, overseas IVa: 8). - The incidence of small-intestinal cancer in patients with CD is low, but the relative risk is high in such patients. C1 (overseas IVa; 7). - There is no evidence that the administration of immunomodulators increases the incidence of malignant tumors. C1 (overseas IVa; 7). - Preventive measures against the occurrence of cancer in patients with CD are not known, but control of the intestinal inflammation is considered to be important. C1 (Japan VI, overseas VI: 7). - There are no data to clearly show that 5-ASA reduces the risk of colorectal cancer in CD. C1 (overseas VI; 7). ## Comments A meta-analysis of analytical epidemiological studies indicated that the relative risk of colorectal cancer was 2.5 in all types of CD, and significantly higher, at 4.5, in colonic-type CD; the relative risk of small-intestinal cancer was extremely high, at 33.2, in all types of CD [bib_ref] Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease, Canavan [/bib_ref]. Another epidemiological study indicated similar results [bib_ref] Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during..., Jess [/bib_ref]. Although Japanese data on these risks are sparse, some studies of the colorectal/anal canal cancer and smallintestinal cancer complications of CD indicate that most cases are found as advanced cancer, but the incidence is not different from that in Europe and the United States [bib_ref] Crohn's disease and intestinal cancer, Matsui [/bib_ref] [bib_ref] Risks and clinical features of colorectal cancer complicating Crohn's disease in Japanese..., Yano [/bib_ref]. A meta-analysis of analytical epidemiological studies has reported that there was no significant difference in the occurrence of malignant tumors between groups with and without administration of immunomodulators [bib_ref] Meta-analysis of risk of malignancy with immunosuppressive drugs in inflammatory bowel disease, Masunaga [/bib_ref]. The TREAT study presents no evidence that a group in which infliximab was administered had an increased occurrence of malignant tumors. However, it has been reported that 13 cases of hepato-splenic T-cell lymphoma (HSTCL) occurred in a group in which infliximab and AZA were administered in combination [bib_ref] Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a..., Rosh [/bib_ref]. No causal relationship has been established between such drugs and cancer. It is assumed that controlling the intestinal inflammation is effective in preventing cancer in CD, as it is in UC. It has been suggested that 5-ASA has a suppressive effect on inflammatory carcinogenesis in UC, but there are no such data for CD. CQ4: How is cancer surveillance conducted? [bib_ref] Crohn's disease and intestinal cancer, Matsui [/bib_ref] [bib_ref] Screening and surveillance colonoscopy in chronic Crohn's colitis, Friedman [/bib_ref] - There is no effective cancer surveillance program at present. C1 (Japan VI, overseas VI; 8). ## Comments In patients with long-term disease, it is advisable to conduct endoscopic and contrast imaging examinations, as appropriate, as well as to check the condition of anal fistulas. However, there are patients in whom it is difficult to conduct examinations to evaluate the small intestine in detail in the presence of stenosis. Appropriate determination of a high-risk group and an effective screening program are awaited. In observing the progression of CD, it should be noted that the risks of small-intestinal cancer and colorectal cancer are high, particularly in the long-term progression of the disease, and that anal fistula cancer with diagnostic difficulty does occur, although the frequency is unknown. It was reported that surveillance endoscopy, like that for UC, was helpful in finding colorectal cancer [bib_ref] Crohn's disease and intestinal cancer, Matsui [/bib_ref] [bib_ref] Screening and surveillance colonoscopy in chronic Crohn's colitis, Friedman [/bib_ref]. However, several issues remain unsolved, such as how to conduct surveillance in patients with stenotic lesions, and therefore surveillance colonoscopy has not yet become a general practice. CQ5: Does CD increase the risk of extra-intestinal malignant tumors, and how is surveillance for such tumors conducted? [bib_ref] Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a..., Rosh [/bib_ref] [bib_ref] Tumour necrosis factor blockers do not increase overall tumour risk in patients..., Geborek [/bib_ref] [bib_ref] The effect of methotrexate and anti-tumor necrosis factor therapy on the risk..., Wolfe [/bib_ref] - A combination of infliximab and immunomodulators may increase the risk of malignant lymphoma. C1 (overseas V; 7). - There is no established program for the surveillance of malignant tumors in regions other than the intestinal tract. C1 (Japan VI, overseas VI; 8). ## Comments In patients with rheumatoid arthritis (RA), a study reported that it was unlikely that a combination of an anti-TNF agent with MTX raised the risk of lymphoma; on the other hand, another study indicated that the long-term use of a combination of an anti-TNF agent with an immunomodulator (AZA or 6-MP) did not raise the risk of solid cancer, but did raise the risk of malignant lymphoma [bib_ref] Tumour necrosis factor blockers do not increase overall tumour risk in patients..., Geborek [/bib_ref] [bib_ref] The effect of methotrexate and anti-tumor necrosis factor therapy on the risk..., Wolfe [/bib_ref]. In particular, it has been reported that HSTCL, which is extremely rare, occurred in CD groups receiving combination therapy [bib_ref] Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a..., Rosh [/bib_ref]. The pathophysiology of CD is different from that of RA, and the concomitant therapeutic drugs used and the clinical courses are different; because of these problems, no conclusion has been reached in regard to the risk of lymphoma with combination therapy in CD. ## Ix. pregnancy and delivery ## Ix-1. pregnancy CQ1: Is CD exacerbated during pregnancy or in relation to the menstrual cycle? [bib_ref] Inflammatory bowel disease and pregnancy: clinical study of mutual influence, clinical course..., Oriuchi [/bib_ref] - There is no evidence that CD is exacerbated by either pregnancy or the menstrual cycle. C1 (Japan VI, overseas V; 8). ## Comments Not many studies have been carried out to evaluate the effect of pregnancy on CD. A study involving a small number of pregnant CD patients (12 patients; 18 pregnancies) indicated that pregnancy was unlikely to be a factor exacerbating CD [bib_ref] Inflammatory bowel disease and pregnancy: clinical study of mutual influence, clinical course..., Oriuchi [/bib_ref]. Adherence with taking medications, however, may get worse due to the fear of taking drugs during pregnancy. It is necessary to explain the need for the medications to pregnant patients, so that the patients have a good understanding of the benefits and harms of the drugs. There are no reports on the relationship between the menstrual cycle and exacerbation of CD, and clinical experience indicates that the cycle has no significant effect on CD. However, there is a possibility that variations in estrogen secretion have some effect on the immune system, and this requires further study. CQ2: Do CD patients have different fertility rates from those of healthy individuals? [bib_ref] European survey of fertility and pregnancy in women with Crohn's disease: a..., Mayberry [/bib_ref] [bib_ref] The effects of chronic ill health and treatment with sulphasalazine on fertility..., Moody [/bib_ref] [bib_ref] Male infertility in inflammatory bowel disease, Narendranathan [/bib_ref] [bib_ref] Perceived sexual dysfunction amongst patients with inflammatory bowel disease, Moody [/bib_ref] - Many reports indicate that patients with CD have reduced fertility; on the other hand, some other reports show no significant differences from fertility rates in the general population. B (overseas IVb; 8). ## Comments Many reports have indicated that both male and female patients with CD have fewer children than the general population [bib_ref] European survey of fertility and pregnancy in women with Crohn's disease: a..., Mayberry [/bib_ref] [bib_ref] The effects of chronic ill health and treatment with sulphasalazine on fertility..., Moody [/bib_ref] [bib_ref] Male infertility in inflammatory bowel disease, Narendranathan [/bib_ref]. It was reported that the frequency of sexual intercourse was lower in female patients with CD because they were afraid of abdominal pain or fecal leaks [bib_ref] Perceived sexual dysfunction amongst patients with inflammatory bowel disease, Moody [/bib_ref]. There is a possibility that men who are administered SASP have reduced fertility [bib_ref] The effects of chronic ill health and treatment with sulphasalazine on fertility..., Moody [/bib_ref]. CQ3: Is modification of the treatment necessary for pregnant patients with CD? [bib_ref] Therapeutic drug use in women with Crohn's disease and birth outcomes: a..., Norgard [/bib_ref] [bib_ref] Pregnancy before and after the diagnosis of inflammatory bowel diseases: retrospective case-control..., Bortoli [/bib_ref] [bib_ref] Outcomes of infants born to mothers with inflammatory bowel disease: a population-based..., Dominitz [/bib_ref] [bib_ref] Increased risk of preterm birth for women with inflammatory bowel disease, Baird [/bib_ref] [bib_ref] The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a..., Francella [/bib_ref] [bib_ref] European evidence based consensus on the, Caprilli [/bib_ref] [bib_ref] Intentional infliximab use during pregnancy for induction or maintenance of remission in..., Mahadevan [/bib_ref] [bib_ref] Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment..., Katz [/bib_ref] [bib_ref] Pregnancy and inflammatory bowel disease, Present [/bib_ref] - Devise treatment strategies according to the disease activity, considering the benefits and harms of the drugs. C1 (Japan VI, overseas VI; 8). - Dominant overseas opinions are to treat pregnant CD patients similarly to non-pregnant patients. C1 (overseas VI; 8). - In Japan, 5-ASA preparations, small to medium doses of steroids, and nutritional therapies are considered to be relatively safe in pregnant patients, but it is desirable to avoid immunomodulators. C1 (Japan VI; 7). - When using nutritional therapies in pregnant patients, avoid excessive administration of vitamin A. C1 (Japan VI, overseas VI; 8). - There is a possibility that the administration of AZA or 6-MP is associated with pre-term delivery, low birth weight, and fetal malformation. C1 (overseas IVa; 7). - Infliximab has been reported to be relatively safe, but the relevant data are not sufficient. B (overseas IVb; 8). ## Comments Experts in Japan and overseas have different opinions concerning drug therapies for pregnant patients. Japanese specialists are cautious about using drugs because of the possibility of adverse effects, while overseas specialists assign priority to the benefits of the drugs unless they are confirmed to be harmful. Several reports have indicated that the relative risks of pre-term delivery, low birth weight, and fetal deformation were high in groups administered AZA and 6-MP [bib_ref] Therapeutic drug use in women with Crohn's disease and birth outcomes: a..., Norgard [/bib_ref] ; however, this does not exclude the possibility that other factors, such as high CD disease activity, were involved in these patients. Moreover, CD itself could pose such risks [bib_ref] Pregnancy before and after the diagnosis of inflammatory bowel diseases: retrospective case-control..., Bortoli [/bib_ref] [bib_ref] Outcomes of infants born to mothers with inflammatory bowel disease: a population-based..., Dominitz [/bib_ref] [bib_ref] Increased risk of preterm birth for women with inflammatory bowel disease, Baird [/bib_ref]. Recently, the number of reports overseas that have emphasized the safety of AZA has increased [bib_ref] The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a..., Francella [/bib_ref] [bib_ref] European evidence based consensus on the, Caprilli [/bib_ref]. Some reports have emphasized that the administration of infliximab or adalimumab in pregnancy was not associated with abnormal births; however, these reports were based on studies with a small number of subjects, and thus the safety of these drugs in pregnant patients could not be guaranteed [bib_ref] Intentional infliximab use during pregnancy for induction or maintenance of remission in..., Mahadevan [/bib_ref] [bib_ref] Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment..., Katz [/bib_ref]. It has been reported that 5-ASA preparations are comparatively safe in pregnancy [bib_ref] Pregnancy and inflammatory bowel disease, Present [/bib_ref]. CQ4: What is the treatment for CD exacerbation during pregnancy? [bib_ref] The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a..., Francella [/bib_ref] [bib_ref] European evidence based consensus on the, Caprilli [/bib_ref] [bib_ref] Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment..., Katz [/bib_ref] [bib_ref] Pregnancy and inflammatory bowel disease, Present [/bib_ref] [bib_ref] Issues of pregnancy and delivery in IBD, Kinjo [/bib_ref] - Devise treatment strategies according to the disease condition, considering the benefits and harms of the drugs. C1 (Japan VI, overseas VI; 8). - First increase the dose of a 5-ASA preparation, and reinforce nutritional therapy. C1 (Japan VI; 8). - If the result of the above is not sufficient, use steroids, an immunomodulator, and/or an anti-TNF agent, considering their benefits and harms. C1 (Japan VI; 7). ## Comments According to the FDA's pharmaceutical categories for safety in pregnancy, 5-ASA preparations and infliximab are in category B, oral prednisolone is in category C, and AZA and 6-MP are in category D [bib_ref] Issues of pregnancy and delivery in IBD, Kinjo [/bib_ref]. A study of 131 pregnant women (with RA or CD) who were treated with infliximab indicated that 15 % experienced birth abnormalities, and therapeutic abortion was induced in 19 %; these findings correspond to the expected values for the general American population [bib_ref] Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment..., Katz [/bib_ref]. Despite the information mentioned above, many overseas textbooks recommend that the risk of such drugs be compared with the risk of CD relapse if their administration is terminated. Specifically, many overseas opinions appear to consider the risk of relapse or exacerbation of CD to pose a greater risk to pregnancy. As a result, many consider that AZA and 6-MP are relatively safe, and that they should continue to be administered when the patient becomes pregnant [bib_ref] The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a..., Francella [/bib_ref] [bib_ref] European evidence based consensus on the, Caprilli [/bib_ref]. On the other hand, MTX is contraindicated for pregnant women [bib_ref] Pregnancy and inflammatory bowel disease, Present [/bib_ref]. ## Ix-2. lactation CQ5. What is the treatment for CD during a period of lactation? [bib_ref] Pregnancy and inflammatory bowel disease, Present [/bib_ref] [bib_ref] Disposition of olsalazine and metabolites in breast milk, Miller [/bib_ref] [bib_ref] Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine..., Esbjorner [/bib_ref] - Only a few drugs have been proven to be safe during breastfeeding, but nutritional therapy is considered safe. C1 (Japan VI, overseas VI; 8). - Devise treatment strategies according to the disease activity, considering the benefits and harms. C1 (Japan VI, overseas VI; 8). ## Comments Data are sparse on the transfer of therapeutic drugs for CD into breast milk and potential exposure to breastfed infants. It has been found that 5-ASA is transferred into breast milk [bib_ref] Disposition of olsalazine and metabolites in breast milk, Miller [/bib_ref] [bib_ref] Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine..., Esbjorner [/bib_ref]. However, there are many opinions that suggest it is safe in normal use. It is advisable to avoid administering a high dose of 5-ASA to lactating women. There are no relevant data with respect to AZA and 6-MP; on the other hand, MTX and cyclosporine are contraindicated in lactating women [bib_ref] Pregnancy and inflammatory bowel disease, Present [/bib_ref]. [fig] •: Target disease: Crohn's disease Users: Clinical practitioners in internal medicine, surgery, gastroenterology, and general practice Purpose: To provide appropriate clinical indicators to practitioners Scope of clinical indicators: Concept of Crohn's disease, epidemiology, classifications, diagnosis, treatment, follow up, and special situations Intervention: Diagnosis (interview, physical examination, clinical laboratory tests, imaging, and pathology) and treatment (lifestyle guidance, drug therapy, nutritional therapy, surgery, etc.) Outcome assessment: Attenuation of symptoms, induction and maintenance of remission, imaging findings, quality of life (QOL), prevention of complications and harm of therapy Methods for developing these guidelines: Described in the text Basis of recommendations: Integration of evidence level and consensus of experts Cost-benefit analysis: Not implemented Evaluation of effectiveness: Yet to be confirmed Status of guidelines: Updated version of the first Guidelines published in 2010 Publication sources: Printed publication available and electronic information in preparation Patient information: Not available Date of publication: October 2011 [/fig] [fig] Figure 1: Diagnostic [/fig] [fig] Figure 2: Treatment of Crohn's disease (CD). 5-ASA 5-Aminosalicylic acid, SASP salazosulfapyridine, TNF-a tumor necrosis factor-a [/fig] [table] Table 1: Evidence levels of literature-based information [/table] [table] Table 2: Criteria for setting recommendation grades Level of evidence Consensus (median value of Delphi evaluation) [/table] [table] Table 3: Interpretations of recommendation grades [/table] [table] Table 5: Proposed diagnostic criteria for Crohn's disease in Japan (as revised in February 2011)[39] Minor findings a. Irregular-shaped and/or quasi-circular ulcers or aphthous ulcerations found extensively in the gastrointestinal tract c b. Characteristic perianal lesions d c. Characteristic gastric and/or duodenal lesions e In the small intestine, the ulcer occurs more commonly on the mesentery side [/table] [table] Table 6: Classification of disease severity [/table]	None	https://link.springer.com/content/pdf/10.1007/s00535-012-0673-1.pdf	None
116e8cd9188dd5032609d267db208c652b74f14b	pubmed	Treatment of Adult Patients with Renal Failure: Recommended Standards and Audit Measures	Treatment of Adult Patients with Renal Failure: Recommended Standards and Audit Measures ## Physicians In 1990 the Renal Association resolved to produce two policy documents on the treatment of adult patients with renal failure. The first document Provision of treatment for chronic renal failure was published in 1991 [1] and describes the required resources. This second complementary document, produced in collaboration with the Royal College of Physicians of London, is a consensus statement of recommended standards for good practice in the treatment of adult patients with renal failure. Its first aim is to protect patients from the effects of substandard treatment and to improve the general quality of their care. It will also educate patients on what to expect, providers on what to provide and purchasers on what they should buy, and will therefore help in the process of contracting for renal services in the National Health Service. SETTING STANDARDS 1. Minimum standards are set where evidence for them is strong. Where it is lacking or inconclusive, recommendations are made and more research is called for. Much of this research will consist of data collection through the National Renal Registry, which is now being set up, and comparative audit. Standards will be revised at regular intervals in the light of this new knowledge. 2. Standards and comparative audit will only be meaningful if these are carried out in a well defined population of patients. Consequently, the time of initiation of regular dialysis is precisely defined and the report recommends collection of data on all the patient characteristics that are known to have a substantial effect on outcome (eg age, primary disease) and the other patient characteristics and co-morbidity which are important but whose effect is not so well quantified (eg race, left ventricular failure). The long-term aim is to devise a comprehensive co-morbidity score for use in comparative audit. 3. The report addresses specific areas of concern. Simple methods of measuring adequacy of dialysis are recommended pending evaluation of more refined methodology. Standard methods for measuring some variables (eg serum albumin) will be required for comparative audit; as an interim measure the method should be recorded. Measuring quality and achieving targets will have a cost which should be made explicit in the contracting process. ## Patients and treatment The document sets standards and recommends comparative audit of patients managed by haemodialysis, peritoneal dialysis and transplantation. Those with acute renal failure, pre-dialysis and general nephrology are covered in less detail. ## Recommendations for endstage ## Renal failure 1. Acceptance of new patient intake of at least 80 per million population, adjusted as necessary for the race and age distribution of the population. 2. Comorbidity scoring, to incorporate at least age, presence of diabetes mellitus and heart disease.. Equity of access to all forms of therapy and consideration of patient preference after informed guidance on dialysis options and transplantation. Haemodialysis and peritoneal dialysis Minimum or recommended standards are suggested for: biomedical equipment, water purity for dialysis (inorganic and microbiological contaminants), type of membrane, reuse of dialysers and use of bicarbonate dialysis fluids. For peritoneal dialysis patients a firm target is advocated for the universal use of the disconnect system, which has a major impact on peritonitis and quality of life. ## Correction of anaemia It is recommended that a haemoglobin concentration of 10-12 g/dl should be achieved in at least 80% of the dialysis population, if necessary by the use of recombinant human erythropoietin. Dialysis and Transplant Association have been adopted as the basis for such targets, which will be revised in the light of comparative audit. ## Audit The document recommends that audit initiatives concentrate on outcome measures and on measurements which have a proven place in determining morbidity and mortality in renal failure patients. ## Transplantation The supply of donors is far outstripped by the demand for transplants; the recommendations consequently deal with equity as well as effective use. 1. There should be equity of access to transplantation geographically and for patients with unusual tissue types. 2. Distribution of donor kidneys should continue to be based on MHC (HLA) matching. 3. Recommended targets for survival of patient and graft are proposed, based on comorbidity at the time of transplantation, the degree of sensitisation and the HLA matching, and an immunosuppressive regime. 4. It is envisaged that a more complete set of standards and audit guidelines will be formulated in conjunction with the British Transplantation Society. ## Acute renal failure The incidence of acute renal failure requiring dialysis is about 70 per million population per year. Outcome is heavily dependent on organ failure, worsening with increasing number of organs failing and with a rising APACHE (acute physiology and chronic health evaluation) score [bib_ref] Organ system dysfunction and risk prediction, Rnaus [/bib_ref] -The document recommends: 1. Patients with other organ failures should be managed in intensive care units with the close involvement of the nephrologist. 2. Dialysis needs should be met by haemofiltration, which is usually the treatment of choice, or by dialysis in a renal unit. Peritoneal dialysis should be employed as elective treatment only in patients who are not hypercatabolic. It should not be used as a substitute for more effective measures in centres that lack them. Future of this documentThis is the second in a series of documents being produced by the	None	None	L'A. resume le second texte prepare par la Renal Association et le Royal College of Physicians of london en vue d'etablir les normes du traitement des insuffisances renales chez l'adulte
a95cd14e9d03d37b7326a053480a95a4f585b26a	pubmed	Italian guidelines for management and treatment of hyperbilirubinaemia of newborn infants ≥ 35 weeks’ gestational age	Italian guidelines for management and treatment of hyperbilirubinaemia of newborn infants ≥ 35 weeks’ gestational age Hyperbilirubinaemia is one of the most frequent problems in otherwise healthy newborn infants. Early discharge of the healthy newborn infants, particularly those in whom breastfeeding is not fully established, may be associated with delayed diagnosis of significant hyperbilirubinaemia that has the potential for causing severe neurological impairments. We present the shared Italian guidelines for management and treatment of jaundice established by the Task Force on hyperbilirubinaemia of the Italian Society of Neonatology. The overall aim of the present guidelines is to provide an useful tool for neonatologists and family paediatricians for managing hyperbilirubinaemia. # Background Hyperbilirubinaemia is a very common condition. The prevention, detection and management of jaundice remains a challenge especially because of early discharge of healthy late preterm and full term newborn infants [bib_ref] Length of stay, jaundice, and hospital readmission, Maisels [/bib_ref] [bib_ref] Discharge criteria for the term newborn, Friedman [/bib_ref] [bib_ref] Improving newborn preventive services at the birth hospitalization: a collaborative, hospital-based quality-improvement..., Mercier [/bib_ref]. Early discharge of the healthy newborn, particularly those in whom breastfeeding is not fully established, may be associated with delayed diagnosis of severe hyperbilirubinaemia [bib_ref] Length of stay, jaundice, and hospital readmission, Maisels [/bib_ref] [bib_ref] Association between duration of neonatal hospital stay and readmission rate, Lee [/bib_ref] [bib_ref] Hospital readmission due to neonatal hyperbilirubinemia, Seidman [/bib_ref]. A recent survey performed by Dani et al. [bib_ref] Current Italian practices regarding the management of hyperbilirubinaemia in preterm infants, Dani [/bib_ref] showed that the management of hyperbilirubinaemia is not homogeneous in Italy. Therefore the Task Force on hyperbilirubinaemia of the Italian Society of Neonatology drew up national guidelines for management of jaundice in the newborn and established a national registry of kernicterus and hyperbilirubinaemia in order to monitor the incidence of cases of kernicterus and severe hyperbilirubinaemia in Italy over time. ## Focus of guidelines The overall aim of this guidelines is to provide an useful tool for neonatologists and family paediatricians for managing hyperbilirubinaemia. These recommendations promote an approach based on the importance of universal systematic assessment for the risk of severe hyperbilirubinaemia, close follow-up, and prompt intervention when indicated. The statement fully applies to the care of infants at 35 or more weeks of gestation, while only some recommendations could be used for newborn infants with lower gestational age (GA). ## Methods of statement development Literature searches were last updated in September 2013. Guidelines from AAP [bib_ref] Hyperbilirubinemia in the newborn infant > or =35 weeks' gestation: an update..., Maisels [/bib_ref] [bib_ref] American Academy of P: Phototherapy to prevent severe neonatal hyperbilirubinemia in the..., Bhutani [/bib_ref] , NICE [bib_ref] Review of the NICE guidance on neonatal jaundice, Atkinson [/bib_ref] , Canadian Pediatric Association, Nederland Neonatal Research Network [bib_ref] Bartrial study group NNRN: Uniform treatment thresholds for hyperbilirubinemia in preterm infants:..., Van Imhoff [/bib_ref] , Norwegian Pediatric Society [bib_ref] National guidelines for treatment of jaundice in the newborn, Bratlid [/bib_ref] , Israel [bib_ref] Israel guidelines for the management of neonatal hyperbilirubinemia and prevention of kernicterus, Kaplan [/bib_ref] , New Zealand, Australia (Queensland), India, Spain, Switzerland [bib_ref] Assessment and treatment of jaundice newborn infants 35 0/7 or more weeks..., Arlettaz [/bib_ref] were considered. Studies conducted in the neonatal units of Lazio were also evaluated to obtain recommendations more suitable for Italian population [bib_ref] Skin bilirubin nomogram for the first 96 h of life in a..., De Luca [/bib_ref] [bib_ref] Validation of transcutaneous bilirubin nomogram in identifying neonates not at risk of..., Romagnoli [/bib_ref] [bib_ref] Development and validation of serum bilirubin nomogram to predict the absence of..., Romagnoli [/bib_ref]. The hierarchy of evidence from the Centre for Evidence-Based-Medicine was applied (see [fig_ref] Table 1: The hierarchy of evidence from the centre for evidence-based-medicine [/fig_ref]. ## Acute bilirubin encephalopathy The main aim of these guidelines is to avoid cases of acute bilirubin encephalopathy (ABE) by establishing levels of serum bilirubin at risk of neurologic damage. A total serum bilirubin (TSB) of 20 mg/dl should not be exceeded in the first 96 hours of life in term newborns. After 96 hours of life a TSB of 25 mg/dl should be avoided (evidence level 2b), since the efficacy of Blood-brain-Barrier increases with postnatal age. The safe bilirubin level is lower for preterm infants: 12 mg/dl for babies with GA ≤ 30 weeks and 15 mg/dL for babies with GA 31-36 weeks [bib_ref] Treatment of jaundice in low birthweight infants, Maisels [/bib_ref] [bib_ref] Jaundice in low birthweight infants: pathobiology and outcome, Watchko [/bib_ref]. Apart from TSB level, gestational age and postnatal age, some more risk factors for ABE should also be considered: Birth asphyxia Severe hypothermia (Tc < 36°C for > 6 hours) Respiratory failure (RDS, pneumonia, meconium aspiration syndrome) Prolonged acidosis (pH < 7.20 for > 6 hours) Severe hypoglycaemia (glucose < 45 mg/dl for > 12 hours) Severe haemolysis Sepsis and meningitis Drugs impairing bilirubin/albumin binding ## Bilirubin measurement All infants should be routinely monitored for the development of jaundice. The ability of physicians and other health care providers to recognise clinically significant jaundice and predict bilirubin levels based on the coephalo-caudal progression of jaundice is limited (evidence level 1b) [bib_ref] Accuracy of clinical judgment in neonatal jaundice, Moyer [/bib_ref] [bib_ref] The joint use of human and electronic eye: visual assessment of jaundice..., De Luca [/bib_ref] [bib_ref] Is visual assessment of jaundice reliable as a screening tool to detect..., Riskin [/bib_ref] [bib_ref] The influence of the reserve albumin concentration and pH on the cephalocaudal..., Knudsen [/bib_ref] [bib_ref] Skin colour and bilirubin in neonates, Knudsen [/bib_ref]. Therefore each jaundiced newborn should receive a bilirubin measurement. Transcutaneous bilirubin (TcB) can be used as first step in order to reduce the number of invasive and painful blood sampling. BiliCheck TM (Respironics, Marietta, GA -USA) and JM-103 (Drager Medical Inc, Telford, Pennsylvania) are the two most used bilirubinometers in the studies conducted in the Italian population and both had good correlation with TSB values [bib_ref] Skin bilirubin nomogram for the first 96 h of life in a..., De Luca [/bib_ref] [bib_ref] Validation of transcutaneous bilirubin nomogram in identifying neonates not at risk of..., Romagnoli [/bib_ref] [bib_ref] BiliCheck vs JM-103 in identifying neonates not at risk of hyperbilirubinaemia, Romagnoli [/bib_ref] [bib_ref] Transcutaneous bilirubin measurement: comparison of Respironics BiliCheck and JM-103 in a normal..., Romagnoli [/bib_ref]. TSB measurement is always necessary when the level of bilirubin is high and for therapeutic decisions (evidence level 1b). ## Prediction of hyperbilirubinaemia The evaluation of jaundice is now facilitated by the availability of different nomograms for both serum [bib_ref] Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia..., Bhutani [/bib_ref] and transcutaneous bilirubin [bib_ref] Skin bilirubin nomogram for the first 96 h of life in a..., De Luca [/bib_ref] [bib_ref] Transcutaneous bilirubin nomogram for predicting neonatal hyperbilirubinemia in healthy term and late-preterm..., Yu [/bib_ref] [bib_ref] Transcutaneous bilirubin nomogram for prediction of significant neonatal hyperbilirubinemia, Varvarigou [/bib_ref]. However, a nomogram could not perform well in one specific setting if the racial, genetic and environmental background of that setting are too different from that of the reference population. Furthermore, predictive tools should be developed in one sample and validated in another one. Hour-specific percentile based nomograms have been developed in cohorts of healthy Italian full term neonates or Italian neonates with ≥ 35 weeks' gestational age using serial measurements of TcB and TSB [fig_ref] Table 2: Values of TcB corresponding at the 50th and 75th percentile of the... [/fig_ref] ; [fig_ref] Figure 1: Depicts hour-specific percentile based nomograms for TcB [/fig_ref] [bib_ref] Skin bilirubin nomogram for the first 96 h of life in a..., De Luca [/bib_ref] [bib_ref] Development and validation of serum bilirubin nomogram to predict the absence of..., Romagnoli [/bib_ref]. In a second phase the predictive ability of these nomograms has been evaluated. Sensitivity, specificity, positive and negative predictive value of percentiles in predicting significant hyperbilirubinaemia (defined as TSB > 17 mg/dL or need for phototherapy) are listed in [fig_ref] Table 4: Ability of TcB measurements over the 50th, the 75th and the 90th... [/fig_ref]. On the base of these studies the Task Force on hyperbilirubinaemia of the Italian Society of Neonatology drew up the following recommendations for infants with GA ≥ 35 weeks (evidence level 1b). ## Recommendations: All jaundiced newborn infants should be tested with a TcB measurement and the value should be plotted on the hour-specific nomogram for TcB measurements [fig_ref] Table 2: Values of TcB corresponding at the 50th and 75th percentile of the... [/fig_ref]. If the TcB measurement is > 75th percentile, a serum determination of bilirubin should be performed and the value should be plotted on the nomogram for TSB measurements ( At present, there are no nomograms able to predict hyperbilirubinaemia in infants with GA < 35 weeks. Therefore bilirubin measurements should be decided according to GA and treatment thresholds (evidence level 5). ## Treatment: phototherapy There is no reliable evidence to inform the choice of thresholds for starting phototherapy. For this reasons guidelines report different recommendations. In determining theValues of TSB corresponding at the 50th, 75th and 90th percentile of the hour-specific nomogram h 50th 75th 90th h 50th 75th 90th h 50th 75th 90th bilirubin thresholds for treatment, the Italian Society of Neonatology considered as primary aim to choose a threshold allowing a large margin of safety, being the threshold for starting phototherapy less than that for performing exchange transfusion, and not so low to become unnecessary. The thresholds for phototherapy are showed in a graph in which total bilirubin is plotted against age in hours. The groups of GA (GA < 30; 30-31; 32-34; 35-37; > 37) are represented by different lines . ## Recommendations: Phototherapy should be administered for irradiating the most of the infant's skin. Intensive phototherapy with an irradiance > 35 μW/ cm 2 /nm is recommended. Daylight, blue light, conventional or blue LED phototherapy can be used (evidence level 1a). Fiberoptic phototherapy can be used even if it is less effective than conventional phototherapy and require more prolonged treatment (evidence level 1a) [bib_ref] Fibreoptic phototherapy for neonatal jaundice, Mills [/bib_ref]. Serum bilirubin should be tested 4-8 hours after the beginning of phototherapy or earlier if TSB < 3 mg/dL less than threshold for exchange transfusion. Subsequently, TSB should be assessed every 12-24 hours to monitor the treatment effectiveness. In case of treatment failure, multiple phototherapy should be started adding a fiberoptic device to the conventional treatment to increase the skin's exposure (evidence level 1a) [bib_ref] Fibreoptic phototherapy for neonatal jaundice, Mills [/bib_ref]. Phototherapy should be discontinued once the bilirubin levels are below the threshold value for treatment on two consecutive measurements, 6-12 h apart. This would avoid keeping babies under phototherapy longer than necessary [bib_ref] When should phototherapy be stopped? A pilot study comparing two targets of..., Barak [/bib_ref] (evidence level 1b). Serum bilirubin should be checked 12-24 hours after discontinuation of phototherapy the occurrence of post-phototherapy bilirubin rebound [bib_ref] Post-phototherapy neonatal bilirubin rebound: a potential cause of significant hyperbilirubinaemia, Kaplan [/bib_ref] (evidence level 4). Infants with either Rhesus or ABO haemolytic disease should be immediately treated with phototherapy once the diagnosis is made. Hydration status should be monitored during phototherapy by daily weighing of the baby, assessing wept nappies and, if required, monitoring electrolytaemia. Breastfeeding should not be discontinued, because its interruption is associated with an increased frequency of stopping breastfeeding by one month (evidence level 2b) [bib_ref] Jaundice, terminating breast-feeding, and the vulnerable child, Kemper [/bib_ref]. Italian Society of Neonatology suggests brief suspensions (up to 30 minutes) of phototherapy for allowing breastfeeding. Breastfed babies should not be routinely supplemented with formula, water or dextrose water for the treatment of jaundice (evidence level 1b). The need for additional fluids during phototherapy should be considered only when the daily weight loss is higher then 5%, or when breast milk is not sufficient to permit the full feeding. The graph shows the thresholds for phototherapy. Total bilirubin was plotted against age in hours. The groups of GA were represented with different lines. ## Exchange transfusion (et) Exchange Transfusion is recommended for newborn infants with TSB levels at risk of neurologic damage and with clinical signs and symptoms of ABE. However, available guidelines suggest different thresholds for ET, without differences between haemolytic and non haemolytic jaundice. TSB threshold for ET in newborns with non haemolytic jaundice are generally 5-6 mg/dL higher than TSB threshold for phototherapy . The TSB threshold for ET in newborns with Rh or ABO haemolytic jaundice is lower than that of newborns with non haemolytic jaundice . The more conservative approach to the treatment of ABO haemolytic disease compared to Rh haemolytic disease is due to its less aggressive development. ## Recommendations (see additional file 1): ET should be performed only by trained personnel in a neonatal intensive care unit with fully monitoring and resuscitation capabilities. Heart rate, breath rate, SpO 2 and body temperature should be monitored during ET and for 12-24 hours after the end of the procedure. The most common adverse effects of ET are thrombocytopenia, haemolysis, hypocalcaemia, hypotension, venous thrombosis, hypokalaemia and hypoglycaemia and should be carefully monitored. Measurement of TSB should be performed before ET and at the end of the procedure. The graph shows the thresholds for exchange transfusion. Total bilirubin was plotted against age in hours. The groups of GA were represented with different lines. The graph shows the thresholds for exchange transfusion in case of haemolytic disease. Total bilirubin was plotted against age in hours. As bilirubin levels may continue to rise after an ET we recommend that TSB is measured every 4-6 hours, and that phototherapy is continued. It is recommended to discontinue enteral feeding during ET and for 6 hours from the end of the procedure (evidence level 5). Infants underwent ET should be followed up for the development of anaemia after discharge. ## Other therapies Intravenous immunoglobulins (IVIG) act by preventing haemolysis. IVIG contain pooled IgG immunoglobulins extracted from the plasma of over 1000 blood donors. IVIG at a dose of either 500 mg/kg or 1 gr/kg over 2-4 hours reduce TSB in newborn infants with immune haemolytic jaundice [bib_ref] Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates, Alcock [/bib_ref] [bib_ref] Intravenous immunoglobulin G (IVIG) therapy for significant hyperbilirubinemia in ABO hemolytic disease..., Miqdad [/bib_ref] and reduce the need for ET (evidence level 1a). IVIG should be administered in the first hours of life to infants with Rhesus haemolytic disease or ABO haemolytic disease when the serum bilirubin continues to rise by more than 0.5 mg/dL per hour. ## Italian registry of kernicterus and hyperbilirubinaemia The Italian Society of Neonatology instituted the Italian Registry of Kernicterus and Hyperbilirubinaemia (RIKI: Registro Italiano del Kenicterus e dell'Iperbilirubinemia) for monitoring the incidence of kernicterus and severe hyperbilirubinaemia (TSB > 20 mg/dL or need for ET) in Italy. Each new case can be reported through the website of the Italian Society of Neonatology (www.neonatologia.it). The objective of this registry is to provide evidences of the guidelines effectiveness through the evaluation of severe hyperbilirubinaemia and kernicterus rate. # Conclusion The development of national guidelines provide standardisation of the management of neonatal jaundice. Severe hyperbilirubinaemia in both healthy term or preterm newborn infants continues to carry the potential for complications from ABE. The careful assessment of involved risk factors and the systematic approach to the management of hyperbilirubinaemia are essential to decrease the occurrence of kernicterus. ## Additional file Additional file 1: Exchange transfusion procedure. Abbreviations ABE: Acute bilirubin encephalopathy; B/A: Bilirubin/albumin ratio; ET: Exchange transfusion; GA: Gestational age; IVIG: Intravenous immunoglobulin; RBCs: Red blood cells; TSB: Total serum bilirubin; TcB: Transcutaneous bilirubin. [fig] Figure 1: Depicts hour-specific percentile based nomograms for TcB. [/fig] [fig] Figure 2: Depicts hour-specific percentile based nomograms for TSB. [/fig] [table] Table 1: The hierarchy of evidence from the centre for evidence-based-medicine [/table] [table] Table 2: Values of TcB corresponding at the 50th and 75th percentile of the hour-specific nomogram [/table] [table] Table 4: Ability of TcB measurements over the 50th, the 75th and the 90th percentile of TcB nomogram to predict significant hyperbilirubinaemia, for designated time periods [/table] [table] Table 5: Ability of TSB measurements over the 50th, the 75th and the 90th percentile of TSB nomogram to predict significant hyperbilirubinaemia, for designated time periods [/table]	None	https://ijponline.biomedcentral.com/counter/pdf/10.1186/1824-7288-40-11	None
ed9bd3f0697b9275e9224a4fc888a3d4098f7e19	pubmed	Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update	Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update Background: The management of minimal, mild and moderate head injuries is still controversial. In 2000, the Scandinavian Neurotrauma Committee (SNC) presented evidence-based guidelines for initial management of these injuries. Since then, considerable new evidence has emerged. Medicine (CEBM) quality ratings. Based upon the results, GRADE recommendations, guidelines and discharge instructions were drafted. A modified Delphi approach was used for consensus and relevant clinical stakeholders were consulted. Conclusions: We present the updated SNC guidelines for initial management of minimal, mild and moderate head injury in adults including criteria for computed tomography (CT) scan selection, admission and discharge with suggestions for monitoring routines and discharge advice for patients. The guidelines are designed to primarily detect neurosurgical intervention with traumatic CT findings as a secondary goal. For elements lacking good evidence, such as in-hospital monitoring, routines were largely based on consensus. We suggest external validation of the guidelines before widespread clinical use is recommended. # Background Traumatic brain injury (TBI) is one of the most common reasons for emergency department (ED) care [bib_ref] Incidence, risk factors and prevention of mild traumatic brain injury: results of..., Cassidy [/bib_ref]. Cases of TBI account for over 1 million visits per year in both the USA and the UK [bib_ref] Warfarin and the apparent minor head injury, Saab [/bib_ref] [bib_ref] Incidence of traumatic brain injury in the United States, Rutland-Brown [/bib_ref] and are responsible for twothirds of all trauma deaths [bib_ref] Epidemiology and contemporary patterns of trauma deaths: changing place, similar pace, older..., Soreide [/bib_ref]. Only a small proportion of these are classed as severe head injury [bib_ref] Incidence, risk factors and prevention of mild traumatic brain injury: results of..., Cassidy [/bib_ref] , with a Glasgow Coma Scale (GCS) score of 3 to 8. The majority of patients are instead classed as minimal, mild and moderate head injuries [bib_ref] Scandinavian guidelines for initial management of minimal, mild, and moderate head injuries...., Ingebrigtsen [/bib_ref] and are generally conscious in the ED with varying degrees of neurological symptoms. A minority of these patients will have intracranial pathology on computed tomography (CT) scanning and an even smaller proportion will need neurosurgical intervention [bib_ref] Indications for computed tomography in patients with minor head injury, Haydel [/bib_ref] [bib_ref] Mild head injury-mortality and complication rate: meta-analysis of findings in a systematic..., Af Geijerstam [/bib_ref]. In particular, the intermediate risk group of mild head injury (MHI) has been notoriously difficult to manage as these patients have a very low, but not negligible, risk of needing neurosurgical intervention [bib_ref] Mild head injury-mortality and complication rate: meta-analysis of findings in a systematic..., Af Geijerstam [/bib_ref] [bib_ref] Head computed tomography use in the emergency department for mild traumatic brain..., Morton [/bib_ref]. Over the past decade, initial management strategies have become focused on selective CT use based upon presence or absence of specific aspects of patient history and/or clinical examination [bib_ref] Indications for computed tomography in patients with minor head injury, Haydel [/bib_ref] [bib_ref] Developing a decision instrument to guide computed tomographic imaging of blunt head..., Mower [/bib_ref] [bib_ref] The Canadian CT Head Rule for patients with minor head injury, Stiell [/bib_ref] [bib_ref] Predicting intracranial traumatic findings on computed tomography in patients with minor head..., Smits [/bib_ref] , in order to effectively use health care resources. This selective management has received more attention following reports of increased cancer risks from CT scans, estimated at 1 in 5,000 to 10,000 for a single head CT scan in young adults [bib_ref] Radiation dose associated with common computed tomography examinations and the associated lifetime..., Smith-Bindman [/bib_ref]. Following a normal CT scan after mild head injury, consensus is generally to discharge patients from the hospital [bib_ref] American College of Emergency Physicians; Centers for Disease Control and Prevention: Clinical..., Jagoda [/bib_ref] [bib_ref] Mild head injury: reliability of early computed tomographic findings in triage for..., Af Geijerstam [/bib_ref] , although subgroups of patients may still be at risk of developing delayed intracranial complications of varying significance [bib_ref] Secondary intracranial hemorrhage after mild head injury in patients with low-dose acetylsalicylate..., Tauber [/bib_ref] [bib_ref] Emergency department discharge of patients with a negative cranial computed tomography scan..., Livingston [/bib_ref]. In 2000, the Scandinavian Neurotrauma Committee (SNC) presented evidence-based guidelines for the initial management of minimal, mild and moderate head injuries [bib_ref] Scandinavian guidelines for initial management of minimal, mild, and moderate head injuries...., Ingebrigtsen [/bib_ref]. Although external and independent validation has shown the guidelines to function favorably [bib_ref] A critical comparison of clinical decision instruments for computed tomographic scanning in..., Stein [/bib_ref] [bib_ref] Minor head injury: guidelines for the use of CT-a multicenter validation study, Smits [/bib_ref] , it is likely that new evidence exists which needs to be considered. The SNC has therefore mandated an update of the guidelines. The aim of the present report is to present these updated guidelines for adults, including the methodology and considerations behind the workflow. # Methods The overall policy was to follow the Appraisal of Guidelines for Research and Evaluation (AGREE) II guideline development framework [bib_ref] AGREE Next Steps Consortium: AGREE II: advancing guideline development, reporting and evaluation..., Brouwers [/bib_ref] , complemented by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [bib_ref] GRADE Working Group: Grading quality of evidence and strength of recommendations for..., Schünemann [/bib_ref]. Consensus was that these two aids would result in a transparent and systematic methodology and the best possible workflow from available evidence to guideline construction and implementation. The overall workflow process is shown in [fig_ref] Figure 1: Flow diagram showing the overall work process [/fig_ref]. ## Task force, working group and stakeholders The SNC consists of neurosurgeons and anesthesiologists from Scandinavia with expertise in neurotrauma. A task force was initiated within the SNC, consisting of three authors with experience within the field (JU, TI, BR), to propose evidence-based recommendations and a draft for the updated guidelines. For the consensus stage of development, a working group was formed consisting of SNC members. Important stakeholders from general surgery, emergency medicine and orthopedics were also involved in this process. These specialties initially manage the vast majority of head injury patients in Scandinavia. We also considered including members of the public in the process but unanimously decided against this as we did not believe it would facilitate optimal guideline development in the present scenario. ## Scope, purpose and target population The objective of the guidelines created in the present work would be to assist ED physicians with initial (the first 24 h) management of all adult patients with minimal, mild and moderate head injury, specifically to decide which patients are to receive CT scanning, admission or discharge (or combinations of these) from the ED. Head injury severity was predefined according to the Head Injury Severity Score (HISS [bib_ref] The Head Injury Severity Scale (HISS): a practical classification of closed-head injury, Stein [/bib_ref] where minimal represents patients with a GCS score of 15 and no risk factors, mild is a GCS score of 14 or 15 with risk factors (such as amnesia or loss of consciousness (LOC)) and moderate is a GCS score of 9 to 13. The rationale was primarily to identify all patients needing neurosurgical intervention, including medical intervention for high intracranial pressure (assigned a critical level with regard to patient-important outcomes). The secondary goals (assigned important, but not critical, with regard to patient-important outcomes) were identification of non-neurosurgical intracranial traumatic complications and also strong consideration of resource use with minimization of unnecessary (normal) CT scans and/or admission. The task force decided a priori to make an attempt to keep the guidelines applicable to the complete patient spectrum within EDs, that is, to ensure that all adult patients with minimal, mild and moderate head injury can be managed according to the guidelines. Certain assumptions were also made a priori concerning aspects of management that were deemed unnecessary for critical review. The task force all agreed that magnetic resonance imaging (MRI) would not be considered in these guidelines concerning initial management and that in-hospital observation, instead of CT, would be regarded only as a secondary management option. The use of plain skull films was addressed and rejected in the previous guidelines. Additionally, we chose not to consider later aspects of management, such as detection and treatment of post-concussion syndrome (PCS) and chronic subdural hematomas. We also agreed that all pathological findings on head CT should lead to hospital admission. Finally, we would not address the surgical or medical management of intracranial complications. The task force was unclear concerning the selection of patients for CT scanning or discharge, following minimal, mild and moderate head injuries. We were also unclear concerning which patients, irrespective of initial CT scan results, should have hospital admission for clinical observation, a repeat CT scan, or both. Therefore, consensus was achieved to address two important clinical questions that would require systematic review of evidence and would form the basis of the updated guidelines, shown below. Clinical question 1: 'Which adult patients with minimal, mild and moderate head injury need a head CT and which patients may be directly discharged?'. Clinical question 2: 'Which adult patients with minimal, mild and moderate head injury need in-hospital observation and/or a repeat head CT?'. ## Search strategy In order to address the clinical questions we performed two separate systematic reviews of the literature, in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [bib_ref] The PRISMA statement for reporting systematic reviews and meta-analyses of studies that..., Liberati [/bib_ref]. Both utilized broad searches of the MEDLINE and EMBASE databases, from 1985 until January 2010 and then complemented to July 2012, using prespecified Medical Subject Headings (MeSH) terms and key words depicted by the task force. MeSH terms were pretested for validity through identification of several key articles. It was deemed unlikely that studies prior to 1985 would be useful considering the wide-scale introduction of CT scanning around this period. We did not apply any other limitations to the search. For the first clinical question, the MeSH terms and keywords were; ((head trauma) OR (brain injury) OR (head injury) OR (traumatic head injury) OR (traumatic brain injury)) AND (minimal OR mild OR minor OR moderate) AND (management OR predictors OR predictor). For the second clinical question we used; ((head trauma) OR (brain injury) OR (head injury) OR (traumatic head injury) OR (traumatic brain injury)) AND In text Additional file 1: GRADE Deplhi process [fig_ref] Table 2: A priori established seven-point response scale and criteria to determine acceptance, rejection... [/fig_ref] In text Additional files 6-7: Figures S1-2 OR multiple OR serial OR follow-up) AND (CT OR CCT OR computed tomography)). Additional papers were identified by hand-searching bibliographies of retrieved studies. ## Selection criteria and study eligibility Titles were examined by one author (JU) and borderline titles were included. Titles that were obviously not relevant were excluded. Abstracts were examined independently by two authors (JU, BR) and the third (TI) was consulted when discrepancies arose. Selected full papers were independently reviewed by all authors (JU, TI, BR) and discrepancies were resolved through discussion. Review articles, letters, expert opinion and editorials could be retrieved for examination of bibliographies but were excluded from the analysis. Papers reporting only children (<18 years) were excluded in both searches. In cases where essential data was missing or unclear, we made an attempt to contact corresponding authors for clarification. Studies including patients with all severities of head injury were only included if at least 50% of patients were within the GCS 9 to 15 range. For the first clinical question, we included studies reporting patients with admission/initial GCS scores ≥9 and that included one or more predictive risk factors for the reference standards of CT findings, intracranial injury (ICI) and/or neurosurgical intervention. We decided a priori to only include studies where information concerning true positives (TP), false positives (FP), true negatives (TN) and false negatives (FN) could be extracted. This information would be necessary to fully appreciate the possible clinical effect and role of a risk factor, allowing consideration of other effects than the positive predictive power. Studies reporting less than 50 patients were excluded. Definitions for risk factors were defined a priori. For the second clinical question, we included studies reporting patients with admission/initial GCS scores ≥9 with an initial CT scan (normal or abnormal) and contained information regarding clinical characteristics that were associated with a positive or worsening repeat CT scan, ICI and/or neurosurgical intervention within 1 week following trauma. CT findings were defined as any traumatic finding on head CT. ICI was defined as any intracranial (isolated non-depressed cranial fractures not included) traumatic finding on CT. Also, since not all patients can be subjected to CT, absence of ICI was defined as relevant and robust clinical follow-up suggestive of normal neurological functioning (with the exception of classical PCS symptoms). The decision to consider any CT findings and ICI as separate reference standards was due to the difference in clinical importance of these measures. This approach should also stratify reference standards in a more homogenous selection compared to a combined definition. Finally, neurosurgical intervention was defined as any neurosurgical procedure for a cranial or intracranial injury within the first week following trauma. Medical treatment for elevated intracranial pressure, within the first week following trauma, was also included in this group since some patients with diffuse brain injury cannot be managed surgically. ## Data extraction and quality assessment Data was extracted by one author (JU) and checked by another (BR). Data was entered into a predefined protocol and then inputted into Excel (Microsoft; Redmond, WA, USA). Evidentiary tables were constructed to summaries the studies. We decided to address the quality of papers in different phases, due to the nature of the studies and the phase of assessment. Firstly, all retrieved studies were independently graded by all authors in the task force (JU, TI, BR) according to the Centre of Evidence Based Medicine (CEBM) diagnosis criteria. Discrepancies in grading were resolved through discussion. Quality ratings ranged from 1 (strongest evidence, for instance reports of clinical decision rules and high quality validation studies) to 5 (weakest evidence, often expert opinion). Studies receiving CEBM scores of 5 were excluded. Studies were then graded according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool [bib_ref] The development of QUADAS: a tool for the quality assessment of studies..., Whiting [/bib_ref] , which was modified for the purpose of the review. This tool considers 14 criteria relevant to diagnostic studies accounting for bias (items 3 to 7, 10 to 12), variability (items 1 and 2) and reporting (items 8 and 9). Items 4 (regarding the time period between index and reference test) and 7 (regarding the independency of the reference test) were omitted with regard to the selection criteria and the previously applied CEBM criteria. Additionally, item 3 (regarding the ability of the reference test to correctly classify the target condition) was applied to CT findings, ICI and neurosurgery separately. # Data analysis Although extracted data regarding the first clinical question, predictors of CT findings, ICI and neurosurgery, could theoretically be summarized in a meta-analysis, the task force decided a priori not to perform such an analysis for the purpose of development of the guidelines, independent of heterogeneity between studies. We felt combining the data in this way could mislead the working group in the consensus process and opted to instead present uncombined data for studies including their quality assessment. We therefore calculated individual positive likelihood ratios (PLR) and negative likelihood ratios (NLR) for each risk factor with respect to the corresponding reference test (CT, ICI or neurosurgery) and the prevalence of both the reference test and the risk factor in the population. We felt that these indices would represent the most relevant clinical applications for the working group when considering the recommendations. For the second clinical question, we presented only descriptive analysis. ## Evidence summary and recommendations draft Recommendations were formed by the task force (JU, TI, BR) based upon the evidence in accordance with the GRADE system [bib_ref] GRADE Working Group: Grading quality of evidence and strength of recommendations for..., Schünemann [/bib_ref] [bib_ref] Going from evidence to recommendations, Guyatt [/bib_ref]. This system is increasingly been used in the development of recommendations and allows consideration of aspects other than level of evidence in determining the strength of a recommendation [bib_ref] Going from evidence to recommendations, Guyatt [/bib_ref]. Clinical predictors were chosen based upon the summarized evidence (see Additional file 1, . Focus was put on the more severe outcome variables (need for neurosurgery being of critical importance), but ICI and any CT findings were also considered, especially in cases where the evidence concerning neurosurgery was poor and/or inconsistent. We also considered the prevalence of the risk factors in the studied cohorts. Risk factors relatively common in a population would lead to many CT scans and these risk factors would therefore need to show high predictive abilities to be included. The summarized quality of evidence, from studies forming the basis of a recommendation, was graded from high quality to very low quality, see . Evidence was initially considered high quality when derived from cohort studies reporting patients with diagnostic uncertainty and appropriate reference standards, as described earlier. Evidence could be downgraded due to risk of bias (selection (population indirectness), verification, observer and reporting), outcome indirectness (balance between the presumed influence on patient outcome of the test result (combination of risk factors) in relation to the complications and resource use of the test), inconsistency (large differences in prevalence of reference tests, prevalence of risk factors, PLR or NLR) or differing general results between studies), impreciseness (studies with small number of patients and few positive CT, ICI or neurosurgery events) and suspicion of publication bias (small number of studies, industry funding). Recommendations, relating to the clinical questions, were classed as strong (we recommend...), weak (we suggest...) or uncertain (we cannot recommend...) (see . For this process, careful consideration was again made to risk/benefit aspects of patient-important outcomes (need for neurosurgery was classed as the most important) in relation to test results, including assumptions for pretest probabilities (different magnitudes of risk for a positive reference result of CT, ICI or neurosurgery) for different patients, quality of evidence, uncertainty of the preferences and values for outcomes and the use of health care resources. Therefore, it is theoretically possible to achieve a strong recommendation despite low quality evidence or vice versa. ## Recommendations and guideline development Based upon the recommendations, a draft for the updated guidelines was constructed by the task force. Following this, a modified Delphi process was used [bib_ref] Consensus methods for medical and health services research, Jones [/bib_ref] , involving the working group previously described, consisting of at least two rounds of consensus. The a priori criteria to determine acceptance, rejection or lack of consensus are shown in [fig_ref] Table 2: A priori established seven-point response scale and criteria to determine acceptance, rejection... [/fig_ref]. In the first round, the recommendations, including data from included studies with CEBM, QUADAS and GRADE evaluations together with a guideline draft were sent via email to the working group. Ratings, including feedback, were anonymously collected. The task force adjusted the recommendations and draft based upon these responses. Then, in conjunction with a 2-day SNC meeting in September 2012 outside Copenhagen, Denmark, results were discussed and suggestions for improvements made. Following this, the second round of Delhi was completed via email. Additional rounds would be undertaken if necessary. The task force and working group were urged to consider the GRADE aspects previously mentioned, especially health risk/benefit aspects including resource use, as well as side effects and risks (misclassification of patients), at all stages of development. The final guidelines were evaluated, independently of the task force and working group, in the ED of Skane University Hospital, Malmo, Sweden, to judge clarity of presentation and ease of use. Simultaneously, the guidelines were evaluated by important stakeholders from specialties directly involved in the everyday management of these patients. Feedback was documented and appropriate changes were made, if necessary, but only to consensus aspects. Finally, the working group reapproved the guidelines after presentation of changes and feedback from the evaluation. ## Implementation, monitoring and future updates Guidelines will only be successful if they are used correctly and on a wide scale. Previous experience with the 2000 Scandinavian guidelines has shown poor compliance and varying degrees of implementation success [bib_ref] An observational study of compliance with the Scandinavian guidelines for management of..., Heskestad [/bib_ref] [bib_ref] Guideline compliance in management of minimal, mild, and moderate head injury: high..., Heskestad [/bib_ref]. Implementation and monitoring strategies were discussed within the working group in order to facilitate long-term successful use of the guidelines in Scandinavia. Focus was put on overcoming barriers to application and effectively using available resources. The working group also outlined a procedure and approximate time period for updating the guidelines. # Results The search and selection process is shown in [fig_ref] Figure 2: Adapted Preferred Reporting Items for Systematic Reviews and Meta-Analyses [/fig_ref] for the two clinical questions. For the first clinical question, we found 72 studies that adhered to our inclusion criteria (see Additional File 2, [fig_ref] Table 2: A priori established seven-point response scale and criteria to determine acceptance, rejection... [/fig_ref] for evidentiary information). These studies included 226,606 individual patients. The level of evidence according to CEBM was variable and overall judged to be moderate (see Additional file 2, [fig_ref] Table 2: A priori established seven-point response scale and criteria to determine acceptance, rejection... [/fig_ref]. Quality assessment with the QUADAS tool (see Additional file 3, [fig_ref] Table 3: Results of the modified Delphi process, round 1 [/fig_ref] showed substantial bias in the studies, particularly concerning the representativeness of the studied population (selection bias, criteria 1), blinding of the index test (criteria 8) and withdrawals (criteria 12). Studies scored better regarding the reporting of selection criteria (criteria 2) and most had acceptable reference standards (criteria 3), although they were often described poorly. Clinical predictors, with according source study, PLR, NLR, reference test prevalence and risk factor prevalence are shown in Additional file 1, . With regard to the second clinical question, we found 21 studies adhering to our inclusion criteria (see Additional file 4, [fig_ref] Table 4: Results of the modified Delphi process, round 2 [/fig_ref] for evidentiary information and relevant results). The CEBM rating was generally low, with several studies reporting non-independent reference standards (see Additional file 4, [fig_ref] Table 4: Results of the modified Delphi process, round 2 [/fig_ref]. QUADAS assessment showed selection bias in most studies (criteria 1). Other consistent weaknesses of the studies were a lack of reference test description and blinding (see Additional file 5, for details). ## Recommendations Based upon the evidence, drafts for recommendations, guidelines and written discharge advice were constructed by the task force. These, with according presentation of the evidence (Additional files 1, 2, 3, 4, 5, Tables S1-S5), were reviewed by the working group using the predefined Delphi process. Following round 1 (see [fig_ref] Table 3: Results of the modified Delphi process, round 1 [/fig_ref] , discussion in the working group concerned points 4 and 7. Since point 7 regarded the overall guidelines, minor adjustments were also made to other points. Only consensus points were changed (the risk factors shunt-treated hydrocephalus and the combination of age >65 and antiplatelet medication were added, discharge advice was simplified, monitoring routines were adjusted and the graphical layout of the guidelines was improved). Following round 2 (see [fig_ref] Table 4: Results of the modified Delphi process, round 2 [/fig_ref] , consensus was achieved in favor of all recommendations, the guidelines and the discharge instructions. One recommendation, concerning Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [bib_ref] The development of QUADAS: a tool for the quality assessment of studies..., Whiting [/bib_ref] for rating quality of evidence and strength of recommendation ## Factor description Evidence: High quality Considerable confidence of the estimate of effect. Further research is very unlikely to change our confidence in the estimated effect. Moderate quality Confidence that the estimate is close to the truth. Further research is likely to have an important impact on our confidence in the estimate effect and may change the estimate. Low quality Limited confidence in the effect. Further research is likely to have an important impact on our confidence in the estimate effect and is likely to change the estimate. Very low quality Little confidence in the effect estimate. Any change of effect is uncertain. ## Recommendation: Strong: 'We recommend...' A strong recommendation indicates that most well informed people will make the same choice Weak: 'We suggest...' A weak recommendation indicates that the majority of well informed people will make the same choice but a substantial minority will not Uncertain: 'We cannot recommend...' ## No specific recommendation for or against Factors influencing the strength of the recommendation include evidence quality, risk/benefit aspects of presumed patient-important outcomes, costs and uncertainty concerning values and preferences. (1) We recommend that adult patients after mild and moderate head injury with GCS ≤14, loss of consciousness, repeated (≥2) vomiting, anticoagulant therapy or coagulation disorders, clinical signs of depressed or basal skull fracture, post-traumatic seizures or focal neurological deficits should have a CT scan (moderate quality, strong recommendation). ## Excluded by title n=3295 Abstracts n=401 ## Titles initially screened n=3696 ## Full-text papers n=201 Additional papers from reference lists of retrieved papers n=27 Excluded by abstract n=200 ## Papers included in review n=72 Excluded by full-text n=156 - Not relevant n=79 - No data n=24 - Reporting only children n=43 - <50 patients n=6 - Duplicate data n=4 Full-text papers n=228 The evidence was initially of high quality but was downgraded due to limitations in study design (mostly selection bias), indirectness (outcomes were rarely reported) and impreciseness (different magnitudes of predictive power of risk factors between studies). However, the strength of the recommendation was view as strong by the working group, considering the seriousness of the complication and health/economic impact of missing a patient with a neurosurgical lesion. The working group also discussed older age (≥60 years and ≥65 years) as well as antiplatelet medication as risk factors of importance, partly due to the presence of these criteria in other guidelines and decision rules. However, the predictive ability was only moderate and these individual risk factors would lead to an unacceptable CT increase and so consensus was not to include these in our recommendation. (2) We recommend that adult patients after mild head injury with GCS 14 and no risk factors (anticoagulant therapy or coagulation disorders, post-traumatic seizures, clinical signs of depressed or basal skull fracture, focal ## Excluded by title n=2795 Abstracts n=131 ## Titles initially screened n=2926 ## Full-text papers n=33 Additional papers from reference lists of retrieved papers n=12 Excluded by abstract n=98 ## Papers included in review n=21 Excluded by full-text n=24 - Not relevant n=20 - No data n=2 - Reporting only children n=2 Full-text papers n=45 neurological deficits), or GCS 15 with loss of consciousness or repeated (≥2) vomiting and no other risk factors, be sampled for analysis of S100B if less than 6 h have elapsed following trauma. If S100B is less than 0.10 μg/l, the patient may be discharged without a CT (moderate quality, strong recommendation). The evidence was initially of high quality but was downgraded due to study design (mostly selection bias) and indirectness (outcomes were rarely reported). However, studies consistently show that low S100B levels can be used to select patients who do not need a CT scan and, hence, may save valuable resources. Of the few missed patients in the literature, almost all are nonneurosurgical lesions. Some studies include risk factors such as GCS 13, anticoagulation and focal neurological deficits in the inclusion criteria. The working group, however, found these risk factors to be too predictive of intracranial injury. This recommendation may seem conflicting with recommendation 1, above. However, S100B is recommended as an option for reducing unnecessary CT scans in a subgroup of Mild head injury patients with low risk for intracranial complication and/or neurosurgical intervention. (3) We recommend that adult patients after minimal and mild head injury with GCS 15 and without risk factors (loss of consciousness, repeated (≥2) vomiting, anticoagulation therapy or coagulation disorders, posttraumatic seizures, clinical signs of depressed or basal skull fracture, focal neurological deficits) can be discharged from the hospital without a CT scan (moderate quality, strong recommendation). The evidence was initially of high quality but was downgraded due to limitations in study design (mostly selection bias), indirectness (outcomes were rarely reported) and impreciseness (different magnitudes of predictive power of risk factors between studies). The working group felt, however, that the large proportion of patients with head injury would fall into this category and that a CT policy in all these patients would not be health/economically viable considering the very low risk of intracranial injury, and even lower risk of neurosurgery, in this patient group. As previously discussed, older age and antiplatelet medication was again considered but rejected by the working group. Clinical question 2: 'Which adult patients with minimal, mild and moderate head injury need in-hospital observation and/or a repeat head CT?' (1) We suggest that all adult patients after head injury with GCS ≤13, clinical signs of depressed or basal skull fracture, anticoagulation therapy or coagulation disorder, post-traumatic seizure or focal neurological deficit should have a CT scan and be admitted to hospital for observation, irrespective of CT findings (low quality, weak recommendation). The evidence was sparse and also of low quality due to study limitations (selection bias) and inconsistency in findings. The working group felt that it would not be good clinical practice to discharge patients with any of these risk factors, despite the low quality of evidence. (2) We recommend that repeat CT scans should be performed in patients with neurological and/or GCS (≥2 points) deterioration (low quality, strong recommendation). The evidence was of moderate quality and was downgraded due to serious limitations in study design and some inconsistency. Most of the evidence indicates that routine repeat CT of these patients with or without CT findings is unnecessary in the absence of clinical deterioration, specifically deterioration of GCS >2 points and/or neurological status. A strong recommendation was chosen in spite of weak evidence due to the seriousness of the condition. Clinical aspects such as anticoagulation and persistent neurological findings were discussed but the working group could not reach consensus on a recommendation for follow-up scans in these patients. ## Guidelines Based upon the recommendations, guidelines were constructed. The addition of shunt-treated hydrocephalus was based upon consensus in the working group with little evidence to support this. The working group discussed risk factors relating to trauma mechanism and multitrauma injuries but found these difficult to recommend, mainly due to practical issues with clinical application. We considered serious extracranial injuries (defined as Abbreviated Injury Score (AIS) >3 to any organ system, for instance large (for example, femur) fractures or serious thoracic or abdominal injuries) as a risk factor due to the probability of a higher magnitude of trauma, need for extracranial CT and the poorer prognosis of brain injury in these patients. However, we finally decided to omit this as a risk factor primarily due to the difficulty of classifying this risk factor in a busy clinical scenario. Additionally, predictive ability was generally only moderate for these risk factors. Also, loss of consciousness was expanded to suspected/confirmed loss of consciousness, as it is often difficult to confirm this finding in the clinical setting. Patients who could not clearly deny any loss of consciousness should be classed as suspected. Finally, the working group could not recommend older age or antiplatelet medication as individual risk factors due to the unacceptable CT increase such a recommendation would cause, in combination with only moderate predictive abilities. However, consensus was reached to combine these into one risk factor, namely age ≥65 years and antiplatelet medication. Written instructions for patients being discharged were adapted from the 2000 guidelines with consideration of the National Institute of Clinical Excellence (NICE) instructions [bib_ref] Assessment, investigation, and early management of head injury: summary of NICE guidance, Yates [/bib_ref] and a proposal for evidence-based instructions from Fung et al. [bib_ref] A proposal for an evidencedbased emergency department discharge form for mild traumatic..., Fung [/bib_ref] , (see Additional file 6, [fig_ref] Figure 1: Flow diagram showing the overall work process [/fig_ref]. With the Scandinavian setting in mind, the discharge sheet was heavily simplified for clarity. Observation and monitoring routines for admitted patients were based on consensus in the working group. We discussed the intensity of monitoring routines in relation to the severity of the complications and burden on hospital wards and finally decided that these should be relatively frequent shortly after trauma (the first 4 h) with de-escalation over time. Reasonably, most admitted patients will arrive to a ward after at least 4 h and hence already have passed the 15-minute interval period. Also, these monitoring routines will only be used in small minority of patients as moderate and high-risk patients are relatively uncommon and other patients should preferentially have a CT. Feedback from ED evaluation and from stakeholders resulted in minor changes to wording and general appearance of the guidelines. All stakeholders and the working group approved the final version, see Additional file 7, [fig_ref] Figure 2: Adapted Preferred Reporting Items for Systematic Reviews and Meta-Analyses [/fig_ref]. ## Implementation, monitoring and future updates The working group decided on implementation by SNC members in their respective countries. This would be performed through a combination of written and oral presentations in national medical journals and national meetings, respectively. We discussed barriers to implementation and decided that the most important of these was probably the absence of sufficient education concerning head injury management in Scandinavia. We would attempt to further facilitate implementation by printing flyers and placards with the guidelines and to send these to Scandinavian hospitals. We would also initiate national training initiatives within the respective Scandinavian countries. With respect to monitoring aspects, the working group decided to plan a questionnaire to Scandinavian physicians treating head injury to determine the present use of guidelines, similar to previous efforts [bib_ref] Survey of the management of patients with minor head injuries in hospitals..., Bellner [/bib_ref]. At 1 year following implementation, a follow-up questionnaire will be sent out to establish changes in management routines. We will also initiate studies examining compliance with the guidelines, as previously established in Norway [bib_ref] An observational study of compliance with the Scandinavian guidelines for management of..., Heskestad [/bib_ref] [bib_ref] Guideline compliance in management of minimal, mild, and moderate head injury: high..., Heskestad [/bib_ref] , and attempt to improve insufficient use of the guidelines depending on these results. Finally, we will initiate a prospective validation study, also comparing the performance of our guidelines with other guidelines, decision rules and, importantly, unstructured physician judgment [bib_ref] Medical decisionmaking: let's not forget the physician, Schriger [/bib_ref]. The working group decided that an update of the guidelines would be necessary in 2015. This would include evidence updates concerning the clinical questions addressed in the present update and would further examine the observation and monitoring routines for admitted patients. # Discussion Since 2000, considerable evidence has emerged concerning the initial management, particularly risk factors for CT selection, of minimal, mild and moderate head injury. The work presented here is, in contrast to our previous guidelines, confined to adults but a similar effort regarding management of children is underway. Although these guidelines can theoretically be used in any setting, they were designed with the Scandinavian emergency care setting in mind. They are also designed to primarily identify patients needing neurosurgical or medical intervention, with traumatic CT findings being the secondary identification goal. In summary, the evidence was of reasonable quality referring to the predictive ability of risk factors for complications following head injury in these patients. Unsurprisingly, many of the risk factors included here are also found in other guidelines and decision rules [bib_ref] Indications for computed tomography in patients with minor head injury, Haydel [/bib_ref] [bib_ref] Developing a decision instrument to guide computed tomographic imaging of blunt head..., Mower [/bib_ref] [bib_ref] The Canadian CT Head Rule for patients with minor head injury, Stiell [/bib_ref] [bib_ref] Predicting intracranial traumatic findings on computed tomography in patients with minor head..., Smits [/bib_ref] [bib_ref] Assessment, investigation, and early management of head injury: summary of NICE guidance, Yates [/bib_ref] [bib_ref] European Federation of Neurological Societies: Mild traumatic brain injury, Vos [/bib_ref]. However, several differences can be noted. We found that the predictive power of amnesia was too low to be included. This risk factor was present in the SNC guidelines from 2000, mostly due to the difficultly in ruling out loss of consciousness in some patients. For this reason, we include suspected loss of consciousness as a risk factor. Risk factors such as intoxication, trauma above the clavicles, nausea, vertigo and headache were not included due to poor predictive ability combined with a high prevalence of these factors in the head injury population. The working group found injury mechanisms complicated to use practically in initial management and decided not to include these as risk factors. Older age, most often defined as ≥60 or ≥65 years, is often included in other guidelines. The predictive ability of this risk factor was only moderate and there was considerable uncertainty in the group with regard to patient important outcomes and resource use. The number of people in older age groups in industrialized countries is increasing [bib_ref] The coming acceleration of global population ageing, Lutz [/bib_ref] and the increased CT rate that would be associated with this risk factor was deemed unacceptable. Also, the risk factor is common in the head injury cohorts, with between 10% and 45% of patients being over 65 years of age in reported cohorts of mild [bib_ref] The Canadian CT Head Rule for patients with minor head injury, Stiell [/bib_ref] [bib_ref] Reliability of clinical guidelines in the detection of patients at risk following..., Ibanez [/bib_ref] [bib_ref] S100-B protein as a screening tool for the early assessment of minor..., Zongo [/bib_ref] [bib_ref] Indications for computed tomography in patients with mild head injury, Ono [/bib_ref] [bib_ref] Impact of age and anticoagulation: need for neurosurgical intervention in trauma patients..., Moore [/bib_ref] and moderate [bib_ref] Early predictors of unfavourable outcome in subjects with moderate head injury in..., Fabbri [/bib_ref] TBI. Fabbri et al. recently presented results considering the combination of older age and antiplatelet agents [bib_ref] Predicting intracranial lesions by antiplatelet agents in subjects with mild head injury, Fabbri [/bib_ref]. Despite the lack of good evidence for this combination, consensus was reached to include age ≥65 years in combination with any antiplatelet agent as a risk factor. It is reasonable to expect that the combination would be more predictive of complications after head injury and result in a smaller CT rate increase when compared to the risk factors used individually. Additionally, it has been suggested that antiplatelet medication may be at least partly responsible for the higher risks for intracranial complications seen after head injury in older patients [bib_ref] Predicting intracranial lesions by antiplatelet agents in subjects with mild head injury, Fabbri [/bib_ref]. Shunt-treated hydrocephalus was added purely based on consensus, with evidence derived from expert opinion in the group. We acknowledge the poor evidence-based background to this decision but this patient group is uncommon and will not lead to a noticeable increase in CT scanning. Evidence concerning repeat CT was reasonable but lacking concerning both written discharge advice and observation routines. These aspects were therefore based heavily upon consensus with special weight put on adaptation to the Scandinavian health care system. Since in-hospital observation consumes valuable resources, there is a need for stronger evidence examining the need and magnitude of these routines. For the first time, a brain biomarker has been introduced into clinical practice guidelines. Using a low cutoff of 0.10 μg/l, the biomarker has shown considerable ability to predict the absence of CT pathology and neurosurgical intervention [bib_ref] S100-B protein as a screening tool for the early assessment of minor..., Zongo [/bib_ref] [bib_ref] Serum S-100B concentration provides additional information fot the indication of computed tomography..., Biberthaler [/bib_ref] [bib_ref] Can low serum levels of S100B predict normal CT findings after minor..., Unden [/bib_ref]. This negative prediction is welcomed since all other risk factors are of positive predictive nature. S100B allows for a safe reduction in CT scans in a subpopulation of patients with mild head injury. In order to maintain the theoretical safety and cost-saving ability, the biomarker should primarily not exhibit false negative results. Also, the biomarker should only be taken in patients that would usually receive a CT scan and the fraction of negative S100B results (below cut-off) should be as large as possible. S100B is clinically unspecific [bib_ref] Raised serum S100B levels after acute bone fractures without cerebral injury, Unden [/bib_ref] [bib_ref] Hemorrhagic shock induces an S 100 B increase associated with shock severity, Pelinka [/bib_ref] and has a short half-life [bib_ref] Elimination of S100B and renal function after cardiac surgery, Jonsson [/bib_ref]. Therefore, patients with extracranial injuries and those seeking care more than 6 h after trauma are not good candidates for S100B sampling due to a risk of false positives and negatives, respectively. Some patients have risk factors with higher predictive abilities and also factors that would usually warrant admission irrespective of CT findings. This group is therefore also not suitable for S100B sampling. Despite the relatively good evidence for S100B in this setting, biomarkers have historically had different effects in actual management and the clinical impact and health economic implications may alter future recommendations. Based upon the current evidence and clinical setting, however, this biomarker should safely reduce resource use if used correctly since low levels are very uncommon in patients needing neurosurgical intervention in this setting. There are limitations to the process outlined in this paper. Although the recommendations are based upon evidence, there were elements of consensus input to the final guidelines. This is inevitable when dealing with these injuries and we attempted to minimize the negative effects of this through our stringent and extensive methodology using the best available tools. Particularly, the GRADE system [bib_ref] GRADE Working Group: Grading quality of evidence and strength of recommendations for..., Schünemann [/bib_ref] allows consideration of other important aspects other than the level of evidence in recommendations. The derivation and validation of predictive risk factors as performed by other authors [bib_ref] Indications for computed tomography in patients with minor head injury, Haydel [/bib_ref] [bib_ref] The Canadian CT Head Rule for patients with minor head injury, Stiell [/bib_ref] [bib_ref] Minor head injury: guidelines for the use of CT-a multicenter validation study, Smits [/bib_ref] would hardly be feasible in Scandinavia and would only account for one aspect of the management guidelines. Our methodology was judged as the most feasible considering the target population. However, external clinical validation of our guidelines is welcomed and would naturally support successful implementation. Finally, these guidelines are, by definition, guidelines and should be utilized accordingly. They are primarily designed as evidence and consensus-based guidance for physicians who are not experts in the field. Physicians who have considerable experience with these patients should naturally be allowed to defer from the guidelines according to clinical judgment. # Conclusions We present guidelines for initial management of adults with minimal, mild and moderate head injury based upon a thorough evidence and consensus-based methodology. The guidelines are primarily designed to detect complications after head injury needing either neurosurgical or medical intervention. They can be applied to all adult patients and include aspects such as CT and admission selection, repeat CT selection, monitoring routines and discharge aspects. However, we suggest external validation before they are widely implemented. Furthermore, areas with poor evidence, such as clinical monitoring routines for patients following head injury, should be addressed in future studies. [fig] Figure 1: Flow diagram showing the overall work process. [/fig] [fig] Figure 2: Adapted Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram showing the review process with reference to the clinical question: 'Which adult patients with minimal, mild and moderate head injury need a head CT and which patients may be directly discharged?'. [/fig] [fig] Figure 3: Adapted Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram showing the review process with reference to the clinical question: 'Which adult patients with minimal, mild and moderate head injury need in-hospital observation and/or a repeat head CT?'. [/fig] [table] Table 2: A priori established seven-point response scale and criteria to determine acceptance, rejection or lack of consensus for recommendations and guidelines for the working group using a modified Delphi process[25] Clinical question 1: 'Which adult patients with minimal, mild and moderate head injury need a head CT and which patients may be directly discharged?' [/table] [table] Table 3: Results of the modified Delphi process, round 1 [/table] [table] Table 4: Results of the modified Delphi process, round 2 [/table]	None	https://bmcmedicine.biomedcentral.com/track/pdf/10.1186/1741-7015-11-50	None
3a7dffe391270d5edc57ee476a4e74d21873fbe0	pubmed	Expert Consensus on the Management of Adverse Events from EGFR Tyrosine Kinase Inhibitors in the UK	Expert Consensus on the Management of Adverse Events from EGFR Tyrosine Kinase Inhibitors in the UK Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib are standard-of-care for first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC). These drugs have a proven benefit in terms of higher response rate, delaying progression and improvement of quality of life over palliative platinumbased chemotherapy. The most common adverse events (AEs) are gastrointestinal (GI) (diarrhoea and stomatitis/mucositis) and cutaneous (rash, dry skin and paronychia). These are usually mild, but if they become moderate or severe, they can have a negative impact on the patient's quality of life (QOL) and lead to dose modifications or drug discontinuation. Appropriate management of AEs, including prophylactic measures, supportive medications, treatment delays and dose reductions, is essential. A consensus meeting of a UKbased multidisciplinary panel composed of medical and clinical oncologists with a special interest in lung cancer, dermatologists, gastroenterologists, lung cancer nurse specialists and oncology pharmacists was held to develop guidelines on prevention and management of cutaneous (rash, dry skin and paronychia) and GI (diarrhoea, stomatitis and mucositis) AEs associated with the administration of EGFR-TKIs. These guidelines detail supportive measures, treatment delays and dose reductions for EGFR-TKIs. Although the focus of the guidelines is to support healthcare professionals in UK clinical practice, it is anticipated that the management strategies proposed will also be applicable in non-UK settings. # Introduction Lung cancer remains the leading cause of cancer-related death worldwide [bib_ref] Cancer statistics, Siegel [/bib_ref]. Non-small cell lung cancer (NSCLC) represents 85 % of all lung cancer diagnoses and is a heterogeneous disease with several biological events driving tumour growth and progression [bib_ref] Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment..., Peters [/bib_ref]. Activating epidermal growth factor receptor (EGFR) gene mutations have emerged as the most relevant predictor of response to the EGFR tyrosine kinase inhibitors (EGFR-TKIs) gefitinib, erlotinib and afatinib [bib_ref] Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell..., Lynch [/bib_ref] [bib_ref] EGF receptor gene mutations are common in lung cancers from ''never smokers''..., Pao [/bib_ref] [bib_ref] EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy, Paez [/bib_ref]. These mutations are present in 10-35 % of NSCLC patients and more frequent in never/light smokers, women, patients with adenocarcinoma histology and patients with East Asian ethnicity. Several randomised phase III trials have consistently shown that gefitinib, erlotinib and, more recently, afatinib are more effective in terms of response rate (RR) and progression-free survival (PFS), less toxic and better tolerated than standard platinum-based doublet chemotherapy when given to untreated advanced NSCLC patients harbouring an activating EGFR mutation [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref]. Furthermore, after a median follow-up of 36.5 months, a prespecified analysis of LUX-Lung 3 and LUX-Lung 6 studies demonstrated longer overall survival (OS) favouring the afatinib arm over chemotherapy for patients with a tumour harbouring an exon 19 deletion (LUX-Lung 3: 33.3 vs. 21.1 months, p = 0.0015; LUX-Lung 6: 31.4 vs..4 months, p = 0.02) [bib_ref] Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer..., Yang [/bib_ref]. On the basis of these phase III clinical data [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref] , the American Society of Clinical Oncology (ASCO) [bib_ref] American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor..., Keedy [/bib_ref] and European Society for Medical Oncology (ESMO) [bib_ref] Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment..., Peters [/bib_ref] recommend EGFR mutation analysis to determine whether an EGFR-TKI or chemotherapy is the appropriate first-line treatment for advanced NSCLC. Gefitinib, erlotinib and afatinib are all approved by the European Medicine Agency (EMA) for use in the first-line setting for EGFR mutation positive advanced NSCLC patients. The most common adverse events (AEs) associated with the use of these drugs are GI (diarrhoea and stomatitis/mucositis) and cutaneous (rash, dry skin and paronychia). These AEs are usually mild, but if they become moderate or severe, they can have a negative impact on the patient's quality of life (QOL) and lead to dose modifications or drug discontinuation. Given that therapy is likely to continue for at least 10 months, appropriate management of AEs, including prophylactic measures, supportive medications, treatment delays and dose reductions, is essential. [fig_ref] Table 1: Incidence of drug reductions/modifications and discontinuations in patients with EGFR mutation positive... [/fig_ref] summarises the incidence of drug reductions/modifications and discontinuations in patients with EGFR mutation positive advanced NSCLC taking EGFR-TKIs first line in phase III randomised clinical trials [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref]. Supportive care, dose reductions and treatment interruptions are appropriate strategies to manage EGFR-TKIassociated AEs [bib_ref] Management of the adverse events of afatinib: a consensus of the recommendations..., Arriola [/bib_ref]. The management goals for these patients are to support them throughout their treatment so that they can derive the maximum benefit from the therapy while maintaining a good QOL, and to avoid premature discontinuation of these drugs because of the potential loss of clinical benefit [bib_ref] Management of the adverse events of afatinib: a consensus of the recommendations..., Arriola [/bib_ref] [bib_ref] Clinical efficacy and toxicity of anti-EGFR therapy in common cancers, Harandi [/bib_ref] [bib_ref] Mechanisms of cutaneous toxicities to EGFR inhibitors, Lacouture [/bib_ref]. For the appropriate management of AEs, it is important that patients are followed up closely (i.e. bi-weekly) during the first 6 weeks of treatment. After that, clinical reviews can take place on a monthly basis. In 2009, an expert consensus group published guidelines on the management of erlotinib-associated cutaneous toxicity in the UK [bib_ref] Expert consensus on the management of erlotinib-associated cutaneous toxicity in the, Thatcher [/bib_ref]. By 2014, three EGFR-TKIs were available in the UK and it was considered that a review of management strategies for all of the AEs associated with these drugs would be beneficial. A consensus meeting of a UK-based multidisciplinary panel composed of medical and clinical oncologists with a special interest in lung cancer, dermatologists, gastroenterologists, lung cancer nurse specialists and oncology pharmacists, was held to develop guidelines on prevention and management of cutaneous and GI AEs associated with the administration of EGFR-TKIs. These guidelines detail supportive treatment measures, treatment delays and dose reductions for EGFR-TKIs. Although the focus of the guidelines is to support healthcare professionals in UK clinical practice, it is anticipated that the management strategies proposed will also be applicable in non-UK settings. ## Cutaneous adverse events The EGFR has multiple effects on skin physiology, including stimulation of epidermal growth, inhibition of differentiation, and acceleration of wound healing [bib_ref] Mechanisms of cutaneous toxicities to EGFR inhibitors, Lacouture [/bib_ref] [bib_ref] Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical..., Lynch [/bib_ref]. Inhibition of EGFR activity leads to a cascade of cellular events that results in multiple cutaneous AEs including rash, dry skin, pruritus and inflammation of nail/periungual tissues [bib_ref] Mechanisms of cutaneous toxicities to EGFR inhibitors, Lacouture [/bib_ref] [bib_ref] Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical..., Lynch [/bib_ref]. In phase III clinical studies of EGFR-TKIs, 54-89 % of patients experienced any grade of skin AEs and 0-16.2 % experienced grade C3 skin AEs [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref]. The incidence of skin-related AEs in phase III studies of EGFR-TKIs is presented in. The prevention and management of EGFR-TKI-related cutaneous AEs is summarised in . ## Prevention To reduce the risk of cutaneous AEs, patients should be advised to moisturise the skin intensively and to protect the skin from excessive exposure to sunshine. [fig_ref] Table 3: Examples of emollients and soap substitutes that are suitable for patients taking... [/fig_ref] detail creams, gels, ointments and soap substitutes that are suitable for patients taking EGFR-TKIs [bib_ref] Expert consensus on the management of erlotinib-associated cutaneous toxicity in the, Thatcher [/bib_ref] [bib_ref] Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced..., Hirsh [/bib_ref] [bib_ref] Dermatologic adverse events associated with afatinib: an oral ErbB family blocker, Lacouture [/bib_ref] [bib_ref] Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion, Potthoff [/bib_ref]. Patients should use an emollient several times a day [fig_ref] Table 5: Guidance for amounts of emollients that patients taking EGFR-TKIs should use per... [/fig_ref]. Ointments are generally more effective for dry, irritable rashes because they have a hydrating effect by improving the skin's lipid barrier. By contrast, water-based creams can further dry the skin and very greasy emollients may increase the risk of folliculitis. Although there is limited evidence that EGFR-TKIs trigger a photosensitive reaction, encouraging patients to cover their skin and to wear SPF 30 UVA/UVB non-occlusive sunscreen, especially in strong sunshine, is a EGFR epidermal growth factor receptor, TKIs tyrosine kinase inhibitors, NSCLC non-small cell lung cancer, NS not stated, AE adverse event a IPASS and FIRST-SIGNAL STUDY also enrolled patients with EGFR wild type tumours Grade 2 toxicity: continue EGFR TKI at current dose unless rash is prolonged or intolerable or the re are other intolerable AEs (refer to SPC); continue to moisturise regularly and intensify emollient use (check compliance again and advise about appr opriate amount to use per week); apply short term topical ste roids; continue topical antibiotics during and after oral antibiotic course (tetracycline 2 weeks); antihistamines can be considered (usually given at night for their potential sedative effect but be aware of impact on driving/using machinery). Provide patient education about prevention and management of skin AEs before EGFR TKI treatment starts. Explain that rash is not acne. Grade 3 toxicity: discontinue EGFR TKI and only reinstate (at reduced dose) when skin AE has resolved to Grade 2 (refer to SPC); manage as for Grade 2; oral antibiotics and topical steroids as appropriate: refer patient to dermatologist who specialises in drug related cutaneous AEs; investigate for cause(s) of infection. Management of skin adverse events in patients taking EGFR-TKIs (UK practice) [bib_ref] Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced..., Hirsh [/bib_ref] [bib_ref] Dermatologic adverse events associated with afatinib: an oral ErbB family blocker, Lacouture [/bib_ref]. EGFR epidermal growth factor receptor, TKis tyrosine kinase inhibitors, AEs adverse events, SPF sun protection factor, UVA ultra-violet A, UVB ultra-violet B, SPC summary of product characteristics pragmatic approach [bib_ref] Expert consensus on the management of erlotinib-associated cutaneous toxicity in the, Thatcher [/bib_ref] [bib_ref] Dermatologic adverse events associated with afatinib: an oral ErbB family blocker, Lacouture [/bib_ref] [bib_ref] Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion, Potthoff [/bib_ref]. For personal hygiene, aqueous emollients and soap substitutes are less dehydrating for the skin than normal soaps; shampoos that reduce the risk of scalp folliculitis, e.g. ketoconazole, betadine and ceanel, should be recommended. ## Management of rash Patients with grade 1 rash should continue their EGFR-TKI therapy and apply an emollient regularly . If there are signs of superadded infection, the EGFR epidermal growth factor receptor, TKIs tyrosine kinase inhibitors application of topical antibiotics in alcohol-free formulations, as recommended in local guidelines, should be considered for at least 14 days. If the rash has progressed to grade 2, the EGFR-TKI can be continued at the current dose as the rash improves within 2 weeks in the majority of cases . Dose reduction or interruption of the EGFR-TKI might be appropriate if grade 2 rash is prolonged or intolerable. Physicians should refer to the current EGFR-TKI summary of product characteristics (SPC) for prescribing advice. If a chronic grade 2 rash develops, a dermatologist should be consulted as the rash can have a deleterious effect on the patient's QOL. Moisturising should be intensified and topical steroids (e.g. 1-2.5 % hydrocortisone or eumovate ointment to the face; betnovate, elocon or dermovate ointment to the body) can be applied on a short-term basis (i.e. for 2-3 weeks), and then the patient's condition should be reviewed. Topical antibiotics (as alcohol-free formulations), in accordance with local guidelines, and/or a course of oral antibiotics (e.g. tetracycline C2 weeks) may be indicated. Oral antihistamines are sometimes prescribed for patients with grade 2 itchy rash, but only a limited proportion of the patients derive symptomatic benefit. Patients should be advised about the possible sedative effects of antihistamines on their ability to drive or operate machinery. In case of grade 3 rash, EGFR-TKI therapy should be temporarily interrupted and the treating physician should refer to the current SPC for each EGFR-TKI for prescribing advice . We recommend restarting EGFR-TKI therapy only when the rash has improved to grade B2. Dose reductions are recommended in the SPCs for erlotinib and afatinib, but not for gefitinib [bib_ref] Cancer statistics, Siegel [/bib_ref]. It is not uncommon in clinical practice to restart gefitinib on alternate days but this is not recommended in the SPC. The rash should be managed as recommended for grade 2 rash, with oral antibiotics and topical corticosteroids as appropriate and referral to a dermatologist who specialises in drug-related cutaneous AEs. Any potential infection associated with the rash should be identified and appropriately treated, as recommended in local guidelines. ## Paronychia Paronychia is a disorder characterised by an inflammatory process involving the soft tissues around the nail. It is a relatively common AE in EGFR-TKI-treated patients because EGFR-TKIs prevent normal EGFR signalling and this leads to alterations in, and inflammation of, the periungual tissues [bib_ref] Mechanisms of cutaneous toxicities to EGFR inhibitors, Lacouture [/bib_ref]. In phase III studies, between 4 and 56.8 % of patients experienced any grade of paronychia and 0-11.4 % experienced grade C3 paronychia [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref]. Paronychia can severely impact on a patient's QOL and ability to carry out his/her activities of daily living. It usually emerges 1-6 months after the initiation of EGFR-TKI therapy [bib_ref] Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical..., Lynch [/bib_ref] [bib_ref] Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion, Potthoff [/bib_ref]. Prevention and management of EGFR-TKI-related paronychia is summarised in [fig_ref] Figure 2: Management of paronychia in patients taking EGFR-TKIs [/fig_ref]. ## Prevention Educating patients about the risk of paronychia during EGFR-TKI therapy and how to prevent it is essential [fig_ref] Figure 2: Management of paronychia in patients taking EGFR-TKIs [/fig_ref] [bib_ref] Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion, Potthoff [/bib_ref]. Careful hand protection (as for hand dermatitis) is advisable. Patients should keep their hands and feet as dry as possible and not soak them in soapy water for prolonged periods of time without adequate protection, e.g. ## Management The prescribed dose of the EGFR-TKI can usually be maintained in the presence of grade 1 paronychia, but dose reductions and/or interruptions should be considered if toxicity becomes grade C2 (consult the summary of product characteristics (SPC) for each EGFR-TKI). At the first signs of nail problems, patients should inform their medical team as grade 1 paronychia can escalate to grade 2 very quickly. For grade 1 toxicity, some patients find warm water or white vinegar soaks beneficial [bib_ref] Acute and chronic paronychia, Rockwell [/bib_ref]. The affected area should be soaked in warm water for approximately 15 min 3-4 times per day. White vinegar soaks (1:1 white vinegar:water) can be used for 15 min every day. Prevention: Keep feet and hands as dry as possible; do not soak hands and feet in soapy water for a prolonged period of time without adequate protection; avoid nail trauma/injury; moisturise hands and feet regularly; dry feet carefully before putting on shoes; take care when cutting nails; wear cotton gloves underneath washing up gloves to protect hands. Shoes should protect nails but not be restrictive. Avoid skin irritants. Provide patient education about paronychia before EGFR TKI treatment starts; stress the need to alert healthcare professional (HCP) at first signs of paronychia. Usually emerges 1-6 months after EGFR TKI treatment initiation and reduces patient's quality of life. Grade 3 toxicity: discontinue EGFR TKI and only reinstate when AE has resolved to Grade 2 (check SPC). Refer for specialist support. Continue to apply topical very potent steroid, antifungals, antibiotics and/or antiseptics (preferably as combination preparations). Apply silver nitrate if over-granulation present. Swab any pus for culture and prescribe appropriate antibiotics. Consider surgical intervention. Consult a dermatologist for further assessment and management, such as potassium permanganate soaks. For grade 1-2 paronychia, topical very potent corticosteroids and antimicrobials (antifungals and antibiotics), preferably as combination preparations and as recommended in local guidelines, should be applied as necessary [fig_ref] Table 4: Examples of topical corticosteroid, corticosteroid/antimicrobial and other corticosteroid combination preparations that are... [/fig_ref]. For grade 2 toxicity, supportive treatment, including oral antibiotics, should be started and silver nitrate should be applied by a healthcare professional if over-granulation has developed. Consulting a podiatrist may be useful if the patient experiences feet-related symptoms. For grade 3 toxicity, the EGFR-TKI should be discontinued and only reinstated when toxicity has improved to grade B2 (consult SPC for details). The patient should be referred for specialist support (a dermatologist or podiatrist as appropriate). Continued application of topical very potent combinations of steroids, antifungals, antibiotics and/or antiseptics, as recommended in local guidelines, and of silver nitrate, if over-granulation is present, is advised. Any pus should be swabbed for culture and antibiotics prescribed accordingly. Surgical intervention, with or without intravenous antibiotics, should be considered if toxicity does not improve. ## Gastrointestinal adverse events ## Diarrhoea Diarrhoea is the most common AE experienced by patients treated with an EGFR-TKI. The underlying mechanism for this AE is poorly understood, but it is believed that EGFR-TKI-associated diarrhoea is due to excessive chloride secretion, which leads to a secretory form of diarrhoea [bib_ref] Clinical efficacy and toxicity of anti-EGFR therapy in common cancers, Harandi [/bib_ref] [bib_ref] Diarrhea associated with afatinib: an oral ErbB family blocker, Yang [/bib_ref]. In phase III studies, between 25 and 95 % of patients experienced any grade of GI AEs and 1-14 % experienced grade C3 GI AEs . Prevention and management of EGFR-TKI-related diarrhoea is summarised in [fig_ref] Figure 3: Management of diarrhoea in patients taking EGFR-TKIs [/fig_ref]. ## Prevention Prior to initiating EGFR-TKI therapy, the patient's baseline bowel history should be obtained [bib_ref] Diarrhea associated with afatinib: an oral ErbB family blocker, Yang [/bib_ref]. Although there is no validated questionnaire for this patient group, obtaining information about the patient's bowel habits for the 6-week period prior to starting EGFR-TKI treatment will provide a baseline against which any EGFR-TKI-induced GI changes can be assessed [fig_ref] Figure 3: Management of diarrhoea in patients taking EGFR-TKIs [/fig_ref]. Information on the patient's concomitant medications and other clinical conditions should be collected at baseline and assessed for their potential impact on the GI tract by checking the prescribing information for each drug. Drug:drug interactions that might lead to GI AEs should also be evaluated. The evidence base for interventions (e.g. special diets) to prevent EGFR-TKI-associated GI AEs is very limited [bib_ref] Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced..., Hirsh [/bib_ref]. Following a low-fat, low-fibre diet and minimising intake of fruit, red meat, alcohol, spicy food and caffeine may be a sensible approach for patients experiencing diarrhoea during EGFR-TKI treatment. If feasible, referral to a dietician will provide patients with the most up-to-date information about reducing the risk of diarrhoea and/or managing GI AEs. However, the physician must always be aware that dietary restrictions might have a negative impact on the patient's QOL and promote weight loss in a patient population where maintaining body weight can already be difficult. ## Management If diarrhoea occurs during EGFR-TKI therapy, it is important to determine whether this is drug-related or infective [bib_ref] Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced..., Hirsh [/bib_ref]. If there is evidence of a GI infection, the patient should be treated appropriately. The aim of EGFR epidermal growth factor receptor, TKIs tyrosine kinase inhibitors, NSCLC non-small cell lung cancer, NS not stated a IPASS and FIRST-SIGNAL STUDY also enrolled patients with EGFR wild type tumours managing GI AEs is to return the patient to his/her baseline state or to grade B1. If grade 1 or grade 2 (for less than 48 h) diarrhoea occurs, patients should be advised to take loperamide at a dose of 4 mg, followed by 2 mg after each episode of diarrhoea, up to a maximum of 16 mg/day (up to 20 mg/day in some countries outside the UK). Drinking 1-1.5 l per day of isotonic, oral rehydration salts (ORS) is recommended; patients should be advised not to drink more than 0.5 l of hypotonic fluids (e.g. water, tea, fruit juice) as this can make the diarrhoea worse [bib_ref] Diarrhea associated with afatinib: an oral ErbB family blocker, Yang [/bib_ref]. Most cases of grade 1 or short duration grade 2 diarrhoea resolve quickly and can be managed via telephone consultation. Patients should be advised to inform the medical team if they develop grade 1 or 2 diarrhoea that does not resolve within 48 h, or if they develop diarrhoea with fever. If the diarrhoea persists for [48 h, despite administration of the maximum daily dose of loperamide, or is grade 3-4, the patient's condition should be reviewed and EGFR-TKI should be discontinued [bib_ref] Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced..., Hirsh [/bib_ref]. Patients should be advised to phone their clinical nurse specialist if diarrhoea persists for [48 h or is grade 3-4. Adding codeine (starting with 30 mg/day which can be increased up to 60 mg four times a day) to the patient's regimen, on a short-term basis, may be beneficial [bib_ref] The medical management of intestinal failure: methods to reduce the severity, Nightingale [/bib_ref]. If codeine has been added to loperamide, it should be discontinued when the EGFR-TKI is stopped. Stool cultures should be performed and patients should be hospitalised and rehydrated with oral and intravenous fluids if necessary [bib_ref] Diarrhea associated with afatinib: an oral ErbB family blocker, Yang [/bib_ref]. They should be referred to a gastroenterologist if the diarrhoea does not improve despite discontinuing EGFR-TKI therapy. The EGFR-TKI should only be restarted when the patient has returned to baseline bowel habits or grade B1 toxicity [bib_ref] Diarrhea associated with afatinib: an oral ErbB family blocker, Yang [/bib_ref]. Dose reductions to improve treatment tolerability are recommended in the SPC for erlotinib and afatinib, but not for gefitinib. ## Stomatitis and mucositis In phase III studies, between 13 and 72.1 % of patients experienced any grade of stomatitis/mucositis and up to 8.7 % experienced grade C3 toxicity [fig_ref] Table 8: Provide patient education about stomatitis/mucositis before EGFR TKI treatment starts and throughout... [/fig_ref] [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref]. Prevention and management of EGFR-TKI-related stomatitis and mucositis is summarised in [fig_ref] Figure 4: Management of stomatitis/mucositis in patients taking EGFR-TKIs [/fig_ref]. A summary of healthcare products that are suitable for use in patients with mucositis is shown in [fig_ref] Table 9: Summary of healthcare products suitable for use in patients with mucositis [36-45]... [/fig_ref]. ## Prevention Patient education about the risk and causes of stomatitis/mucositis is essential before starting therapy [fig_ref] Figure 4: Management of stomatitis/mucositis in patients taking EGFR-TKIs [/fig_ref] ; [fig_ref] Table 9: Summary of healthcare products suitable for use in patients with mucositis [36-45]... [/fig_ref] [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref]. Patients must be aware of the need to alert a healthcare professional at the first signs of stomatitis/mucositis. Maintaining good oral hygiene is essential; non-alcoholic mouthwashes are recommended. It may be necessary to evaluate the use of dental appliances (braces, dentures, retainers, etc.) before therapy begins, as they can aggravate oral mucositis. Patients should be advised to eat food that will not cause oral lesions, i.e. soft, moist, nonirritating food that is easy to chew and swallow. Patients should drink plenty of water and lip balms can help to reduce mouth dryness. ## Management Patients with grade 1 stomatitis/mucositis (erythema of the mucosa) can usually continue the EGFR-TKI at the current dose [fig_ref] Figure 4: Management of stomatitis/mucositis in patients taking EGFR-TKIs [/fig_ref]. Oral rinses (0.9 % saline or sodium bicarbonate) can soothe the mouth [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref] and only nonalcoholic mouthwashes should be used. Prophylaxis against fungal, viral and/or bacterial infections can be considered; infections must be treated as appropriate with topical or systemic antimicrobials, as recommended in local guidelines. For grade 2 stomatitis/mucositis, it may be necessary to stop the treatment or, if the SPC recommends it, reduce the dose. In the UK, it is common practice to reduce the dose of gefitinib with administration of a tablet every other day, although this is not advised in the SPC 2 and there are no data to support this dosing schedule. EGFR-TKI should be restarted when the stomatitis/mucositis has improved to grade B1. Topical anaesthetics, mucosal coating agents and/or benzydamine HCl may be administered as needed for pain relief [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref]. Infections should be treated with topical or systemic antimicrobials. Obtaining specialist advice should be considered. In the case of a grade 3 stomatitis/mucositis, treatment with an EGFR-TKI should be discontinued and the patient is usually hospitalised to receive supportive care. Appropriate pain relief and antimicrobials should be administered [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref]. The EGFR-TKI can be restarted, at a lower dose as per the SPC, once the toxicity has resolved to grade B1. If grade 4 stomatitis/mucositis develops, a specialist dermatology assessment should be sought, especially if Stevens-Johnson Syndrome is suspected [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref]. EGFR-TKI therapy should have already been discontinued, and restarting treatment at a reduced dose should only be attempted after complete resolution of toxicity and a careful assessment of the patient. [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref]. EGFR epidermal growth factor receptor, TKis tyrosine kinase inhibitors, SPC summary of product characteristics appropriately, possibly within a multi-specialty team, in order to minimise the impact of these AEs and preserve the patient's QOL, trying to avoid unnecessary dose reductions or early discontinuation of these effective therapies. ## Compliance with ethical standards Funding Boehringer Ingelheim provided financial support for medical writing, authorship meetings and submission costs. Boehringer Ingelheim also completed a factual review with respect to afatinib data within the article. Boehringer Ingelheim had no editorial input into the content. Nocte at night, mane in the morning, QDS four times daily, TDS three times daily, BD twice daily, OTC over the counter [fig] Figure 2: Management of paronychia in patients taking EGFR-TKIs (UK practice). EGFR epidermal growth factor receptor, TKis tyrosine kinase inhibitors, AEs adverse events, SPC summary of product characteristics [/fig] [fig] Figure 3: Management of diarrhoea in patients taking EGFR-TKIs (UK practice)[32]. EGFR epidermal growth factor receptor, BID twice daily, TKis tyrosine kinase inhibitors, SPC summary of product characteristics [/fig] [fig] Figure 4: Management of stomatitis/mucositis in patients taking EGFR-TKIs (UK practice) [/fig] [table] Table 1: Incidence of drug reductions/modifications and discontinuations in patients with EGFR mutation positive a advanced NSCLC taking EGFR-TKIs first line in phase III randomised clinical trials [/table] [table] Table 3: Examples of emollients and soap substitutes that are suitable for patients taking EGFR-TKIs [/table] [table] Table 4: Examples of topical corticosteroid, corticosteroid/antimicrobial and other corticosteroid combination preparations that are suitable for patients taking EGFR-TKIs [/table] [table] Table 5: Guidance for amounts of emollients that patients taking EGFR-TKIs should use per 2 weeks [/table] [table] Table 9: Summary of healthcare products suitable for use in patients with mucositis [36-45] Prevention of mucositis Treatment of oral mucositis Treatment of anorectal mucositis Review drug history Suitable antacid therapy-see local formulary Prednisolone 20 mg/100 ml retention enema, nocte Dental review (pre-treatment) Saline mouth wash 10 ml QDS (mix 1 teaspoon of table salt into 500 ml water) 10 ml QDS (mix 1 teaspoon of table salt and threequarter teaspoon of bicarbonate of soda [baking soda] into 500 ml water) Mesalazine 1 g/100 ml retention enema, nocte Soft bristle tooth brush Saline-peroxide MW 10 ml QDS Hydrogen peroxide mouthwash BP-can be prescribed, 15 ml (diluted in 250 ml water) BD-TDS Peroxyl mouthwash is available OTC 10 mL QDS Maintain adequate oral fluid intake (1.5 l/day) Benzydamine 0.15 % mouthwash 15 ml QDS Ice cubes/ice chips/ice lollies (including for secondary prophylaxis) Limit consumption of tobacco, alcohol, acidic food, spicy food and hot foods/beverages Antacid and oxcetacaine 15 ml mouthwash QDS (before food) (Unlicensed Special, Rosemont Pharmaceuticals Ltd.) Avoid alcohol-based mouthwashes Caphosol mixed as directed 15 ml mouthwash 4-10 times daily as required (where available) Primary prophylaxis: Caphosol (mixed as directed) 15 ml mouthwash 4-10 times daily as required (where available) Sucralfate 1 g QDS (before meals) Secondary prophylaxis: Gelclair 15 ml mouthwash TDS If oral candida: nystatin suspension 1 ml QDS for 7 days (oral local formulary alternative-caution: check potential interactions with EGFR-TKI) Systemic antifungal as required Systemic antibacterial as required According to local formulary. Caution: check potential interactions with EGFR-TKI [/table]	None	https://link.springer.com/content/pdf/10.1007/s40265-015-0434-6.pdf	None
86ef1cd9675a88b5099b62608bfbb409fdeba9ca	pubmed	SEOM clinical guideline for treatment of cancer pain (2017)	SEOM clinical guideline for treatment of cancer pain (2017) Pain is a highly prevalent symptom in patients with cancer. Despite therapeutic advances and well-accepted treatment guidelines, a percentage of patients with pain are under-treated. Currently, it has been recognized that several barriers in pain management still exist and, in addition, there are new challenges surrounding complex subtypes of pain, such as breakthrough and neuropathic pain, requiring further reviews and recommendations. This is an update of the guide our society previously published and represents the continued commitment of SEOM to move forward and improve supportive care of cancer patients. # Introduction Pain is one of the most common symptoms related with cancer and its treatment [bib_ref] Professional survey on knowledge and clinical patterns of pain management in Spanish..., Escobar Á Lvarez [/bib_ref]. Prevalence ranges from 39% in patients following curative treatment up to 66-80% in advanced or terminal phases [bib_ref] Update on prevalence of pain in patients with cancer: systematic review and..., Van Den Beuken-Van Everdingen [/bib_ref]. Several epidemiological studies carried out in Spain have shown that approximately 55% of cancer patients suffer from pain [bib_ref] Have we improved pain control in cancer patients. A multicenter study of..., Porta-Sales [/bib_ref]. Of these, 20-33% display neuropathic pain [bib_ref] Prevalence of pain and relative diagnostic performance of screening tools for neuropathic..., Pérez [/bib_ref] , and breakthrough cancer pain is present in 41% [bib_ref] Breakthrough cancer pain: prevalence and characteristics in patients in Catalonia, Gómez-Batiste [/bib_ref]. Specific cancer types such as pancreatic, primary bone, lung and head and neck cancer associate particularly high prevalence rates of neuropathic pain, while bone metastasis is the most common cause of cancer-related pain [bib_ref] Association of performance status and pain in metastatic bone pain management in..., Dómine [/bib_ref]. Moreover, it changes over time along the course of disease and is most frequent in late phases of the oncologic process. Despite the tremendous progress in the knowledge about cancer-related pain and its treatment, recent studies have shown that pain is not adequately controlled in up to 31% of cases [bib_ref] Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes, Breivik [/bib_ref]. Several barriers to adequate pain management in patients with cancer have been acknowledged: lack of knowledge among health professionals regarding cancer pain assessment and management; fear of the adverse effects of opioids; patients struggle with misconceptions about analgesic use, and concerns surrounding pain communication [bib_ref] Barriers to effective cancer pain management: a review of the literature, Pargeon [/bib_ref]. We must overcome obstacles and develop and implement interventions to manage pain optimally in patients with cancer. Medication should not be the sole approach; educational interventions for patients and professionals can contribute to successfully managing pain [bib_ref] Educational interventions to improve cancer pain control: a systematic review, Allard [/bib_ref]. Regular, adequate, self-report assessments of pain intensity with the help of validated multidimensional assessment tools are needed for effective treatment. We must work towards a pain assessment approach that can both accurately diagnose and monitor a patient's specific pain, while still being simple enough to be used in routine clinical practice [bib_ref] The challenges of cancer pain assessment, Stewart [/bib_ref]. Whenever possible, patients should be encouraged to be active participants in the management of their own pain. Their caregivers should also be given and taught to use a pain diary to monitor all pain concerns. The use of technological advances may improve the accuracy of patient-reported outcomes. The purpose of this document was to establish recommendations that can be applied by professionals in their clinical practice to optimize cancer pain management. # Guideline methods Under the auspices of the Spanish Society of Medical Oncology (SEOM), a number of experts in the field, together with two coordinators, were designated to draft these evidence-based, clinical practice guidelines. The recommendations and evidence have been graded, based on the guideline development recommendations [bib_ref] Developing clinical guidelines, Shekelle [/bib_ref]. ## First and second step Mild pain (first WHO analgesic step) Non-opioids, such as paracetamol and NSAIDs, must be considered for management of cancer pain in this setting. They are useful in mild or mild/moderate pain and there is no evidence to claim that some NSAIDs are more effective or safer than others [bib_ref] Oral nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer pain in adults, Derry [/bib_ref]. At therapeutic doses, all of them present anti-inflammatory, analgesic, and antipyretic properties to a greater or lesser extent. Paracetamol and NSAIDs are effective drugs at any step of the WHO analgesic ladder, regardless of their intensity and provided that their use is not contraindicated (level of evidence I, degree of recommendation A). Some studies have reported that the combination of paracetamol with stronger opioids improves pain management and increases the sense of wellbeing [bib_ref] Acetaminophen (paracetamol) improves pain and wellbeing in people with advanced cancer already..., Stocker [/bib_ref]. Adverse effects of NSAIDs include gastrointestinal, renal, hematologic, and pulmonary effects. It is recommended that a limited number of drugs be used, depending on the clinician's expertise and keeping patient's references/tolerance in mind. Combining two NSAIDs does not improve analgesia and increases toxicity. NSAIDs and paracetamol do not cause tolerance but do have a therapeutic ceiling and used above the maximum recommended dose, do not increase the analgesic effect; however, they do increase toxicity. Moderate pain (second WHO analgesic step (VAS 3-6/10) After assessing the individual, analgesic treatment is selected according to their VAS score [bib_ref] on behalf of the ESMO Guidelines Working Group. Management of cancer pain:..., Ripamonti [/bib_ref]. Mild opioids are the basis of treatment (in combination or not with drugs described in the first step). Step 2 includes: codeine, dihydrocodeine, and tramadol. All of these compounds are available in controlled-release forms. Low doses of transdermal fentanyl and buprenorphine can also be considered [bib_ref] on behalf of the ESMO Guidelines Working Group. Management of cancer pain:..., Ripamonti [/bib_ref]. Some studies have shown that effectiveness at the second step of the WHO ladder lasts for about 1 month for most patients, due to insufficient analgesia. Since weak opioids have therapeutic ceiling, some authors have proposed abandoning up their use in moderate pain in favor of early initiation of the third step with low doses of strong opioids [bib_ref] on behalf of the ESMO Guidelines Working Group. Management of cancer pain:..., Ripamonti [/bib_ref]. Mild opioids could be prescribed in combination with non-opioid analgesics (level of evidence III, degree of recommendation C). However, in a meta-analysis of randomized clinical trials, no significant difference was found between 1st step analgesics alone and combining them with a mild opioid [bib_ref] on behalf of the ESMO Guidelines Working Group. Management of cancer pain:..., Ripamonti [/bib_ref]. Their effectiveness is limited with time (40 days) and due to their dose ceiling effect, above which there is no additional analgesic effect, but an increase in side effects (level of evidence I, degree of recommendation B) [bib_ref] Long-term efficacy and safety of oxycodone-naloxone prolonged-release formulation (up to 180/90 mg..., Dupoiron [/bib_ref]. Low doses of strong opioids together with non-opioid drugs can be weighed as an alternative to mild opioids (level of evidence III, degree of recommendation C). Severe pain (third WHO analgesic step (VAS > 6/10) Neuropeptides such as enkephalins, dynorphins, and endorphins interact at opioid receptors (MOP; DOP; KOP; NOP) located in the CNS, pituitary, and GI tract [bib_ref] Basic opioid pharmacology: an update, Pathan [/bib_ref]. Opioid agonists lock onto receptors, blocking neurotransmitters release. Opioid agonists lock onto receptors, blocking the release of neurotransmitters. Opioids differ in affinity, pharmacokinetics, physicochemical properties, side-effect profiles, administration routes, tolerance, and immunomodulation propensity. Opioid antagonists bind to opioid receptors but produce no analgesia. Strong opioids are the cornerstone of analgesia in this setting. Morphine, methadone, oxycodone, hydromorphone, fentanyl, and buprenorphine are the most widely used in Europe. Opioids undergo metabolism in the liver: phase I-via CYP450; phase II-glucuronidation via UGT [bib_ref] Opioid metabolism and clinical aspects, Mercadante [/bib_ref]. Age, genetics, comorbidities, kidney or liver function, and concomitant drugs can affect their metabolism; consequently, the choice of one over another must factor in these factors. The available evidence suggests that oral morphine, hydromorphone, oxycodone, and methadone provide similar efficacy (level of evidence I, degree of recommendation A). The choice should take into account efficacy, safety, and flexibility (level of evidence II, degree of recommendation B). Morphine is the gold standard, given its versatility (oral, rectal, s.c., i.v., i.m., intrathecal routes), safety, and price [fig_ref] Table 1: WHO 3rd step Adapted from Ripamonti C [/fig_ref]. The first choice is oral morphine (level of evidence IV, degree of recommendation D) [bib_ref] European Oncology Nursing Society guidelines. Breakthrough cancer pain, Wengström [/bib_ref]. When urgent relief is required, titrate with parenteral opioids; likewise, they may also be used in patients for whom oral opioids are not suitable and analgesic requirements are unstable. The equianalgesic ratio between oral and parenteral routes is 2:1 or 3:1 (level of evidence II, degree of recommendation A). Transdermal (TTS) opioids (fentanyl, buprenorphine) are valid alternatives when oral opioids are not suitable and analgesic requirements are stable (level of evidence II, degree of recommendation A). TTS fentanyl displays good patient compliance (level of evidence I, degree of recommendation B). There is insufficient evidence as yet to support the use of combination opioid therapy. Strong opioids can be combined with continued use of a nonopioid analgesic (level of evidence II, degree of recommendation B). In renal impairment opioids should be used with caution; in this setting, buprenorphine is the safest (level of evidence IV, degree of recommendation C). Titration is the process by which a tailored dose is found that provides pain relief with lowest possible degree of toxicity. Normal release opioids are indicated for titration and treating breakthrough pain episodes. All patients should receive round-the-clock dosing and a 'breakthrough dose' (usually 10-15% of the total daily dose) to manage breakthrough pain (level of evidence IV, degree of recommendation C). Once the appropriate dose has been determined by means of titration, slow-release opioids are indicated (level of evidence IV, degree of recommendation C). Other recommendations: respect patients' preferences whenever feasible; correct myths and misconceptions; ensure the patient has accurate information so as to improve compliance [bib_ref] European Oncology Nursing Society guidelines. Breakthrough cancer pain, Wengström [/bib_ref]. ## Management of side effects The main toxicities associated with opioids consist of: GI (constipation, nausea, vomiting), CNS (cognitive impairment, hyperalgesia, allodynia, and myoclonia), respiratory depression, and others (pruritus, dry mouth, urinary retention, hypogonadism, and immune depression) [bib_ref] Management of chronic pain in survivors of adult cancers, Paice [/bib_ref]. Management includes the following: (1) patient information and prophylactic measures; (2) reduction in opioid dose through the use of a co-adjuvant and/or first step drug; (3) pharmacological strategies, such as antiemetics for nausea, laxatives for constipation, tranquillizers for confusion, psychostimulants for drowsiness, and (4) switching to another opioid or route. For persistent constipation, consider PAMORAs (peripherally acting mu-opioid receptor antagonists) with demonstrated benefit in nononcological settings. Naloxegol per os was approved by the EMA for opioid-induced constipation in adult cancer patients. Naloxone is an antagonist capable of reverting symptoms of severe opioid overdose. ## New opioids New opioids have been developed in recent decades with different metabolic pathways, delivery systems, or receptor activities [bib_ref] New drugs for pain management in advanced cancer patients, Mercadante [/bib_ref]. Several systematic reviews support the use of oral morphine, oxycodone, or hydromorphone for cancer pain. No differences between analgesic efficacy and tolerability were found between these opioids. Consequently, oral formulations of any of these drugs can be chosen to begin step 3 for moderate to severe cancer pain (level of evidence I, degree of recommendation A). The choice of an opioid should be informed by the individual's condition and clinical need. Oxycodone is a semisynthetic derivative of thebaine and, therefore, does not undergo the same metabolic changes as morphine. This makes it especially useful in the elderly, as well as patients presenting impaired hepatic/ renal function or comorbidities. Both long-acting and short-acting presentations are available. Naloxone is a competitive antagonist of opioid receptors and acts on bowel transit via different mechanisms, avoiding opioidinduced constipation. The combination of oxycodone and naloxone up to a dose of 160/80 mg per day is effective and generally well tolerated (level of evidence I, degree of recommendation B) [bib_ref] The use of opioids for treatment of cancer pain, Mercadante [/bib_ref]. Hydrocodone has been marketed with acetaminophen presentations which precludes the use of higher doses. It is metabolized at the liver involving cytochrome P450. Drug inhibiting CYP3A4 activity may result in increase plasma concentration of the drug. Hydromorphone is the active metabolite of hydrocodone; is more potent and has a higher affinity for l-opioid receptor, and is eliminated by the kidneys. It has a short half-life; consequently, it can be used to titrate doses. Its long-acting presentation has the advantage of being taken once daily. The latest review involved 604 patients from four trials that compared hydromorphone to oxycodone or morphine. Similar analgesic efficacy was demonstrated between groups with both comparisons (level of evidence II, degree of recommendation A) [bib_ref] Hydromorphone for cancer pain, Bao [/bib_ref]. Tapentadol is a centrally acting oral analgesic that possesses a combined mechanism of action: it is a l-receptor agonist and norepinephrine reuptake inhibitor. Morphine milligram equivalents are based on the degree of l-receptor agonist activity, although it has yet to be elucidated whether this drug is associated with overdose in the same dose-dependent manner as observed with medications that are solely opiate-l-receptor agonists. Tapentadol's antihyperalgesic effects could be potentially helpful in states of hyperexcitation, such as those observed in patients who have undergone multiple unsuccessful trials of opioids [bib_ref] Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations..., Caraceni [/bib_ref]. In contrast, a recent review in cancer patients failed to clearly demonstrate tapentadol's superiority with respect to earlier generation opioids. Likewise, there is an absence of non-inferiority trials comparing tapentadol to fentanyl or oxycodone-naloxone [bib_ref] Tapentadol for cancer pain management: a narrative review, Carmona-Bayonas [/bib_ref]. As a result, tapentadol is an effective, well-tolerated alternative for moderate or severe cancer pain (level of evidence II, degree of recommendation A). Transdermal fentanyl and buprenorphine are alternatives to morphine and may even be the preferred step III opioid for some patients (level of evidence II, degree of recommendation A). For individuals who are unable to swallow, they comprise an effective, non-invasive means of opioid delivery. Methadone is a synthetic opioid that poses certain challenges as regards dose titration and is proven to cause potentially fatal arrhythmias in some patients. Its major disadvantage is that it has a long, unpredictable, half-life with interindividual variability as to its half-life, potency, and duration, making it more difficult to manage. It is recommended that it be initiated only by experienced practitioners (level of evidence I, degree of recommendation B). Given that it is lipophilic, it crosses the bloodbrain barrier. In a recent update review, somnolence was found to be more common with methadone versus morphine in patients with cancer (level of evidence II, degree of recommendation A) [bib_ref] Methadone for cancer pain, Nicholson [/bib_ref]. ## Opioid rotation Patients with cancer who experience pain often require changes in opioid therapy during the course of disease because of disease progression, pain characteristics, and prolonged use of opioids. Opioid rotation is defined as the substitution of a potent, previously prescribed opioid for a potent alternative opioid with the specific objective of obtaining a better analgesia and /or reducing unacceptable toxicity. The practice of opioid rotation is often successful [fig_ref] Figure 1: Flowchart impact on patients' quality of life [/fig_ref] although the scientific evidence remains poor because of a lack of controlled studies (level of evidence II, degree of recommendation A). The goal of equianalgesic rotation is to obtain the amount of opioid in the new prescription that equals the amount administered in the previous form of administration, to avoid over-or under-dosing. Some of the most important precautions in calculating morphine milligram equivalent doses (MME) are as follows: [bib_ref] CDC guideline for prescribing opioids for chronic pain-United States, Dowell [/bib_ref]. - Equianalgesic dose conversions do not take individual variability into account. - When calculating a new opioid, it should be dosed at a lower dose than the calculated MME to prevent overdose due to incomplete cross-tolerance and individual variability in opioid pharmacokinetics. - The conversion factor with methadone increases at higher doses. - Care must be exercised when converting to fentanyl or vice versa as it is dosed in lg/h. Opioid rotation should be avoided if experience is not available or patient follow-up cannot be adequately monitored [bib_ref] Opioid switching in cancer pain: From the beginning to nowadays, Mercadante [/bib_ref]. Finally, all potent opioids may have the same side effects, some of which are serious, such as respiratory depression or delirium. Naloxone (sc/iv) is reserved for the former, while delirium, myoclonus, or agitation is treated with benzodiazepines and/or neuroleptics. (Morphine milligram equivalent doses (MME) MME and some clinical situations are summarized in [fig_ref] Table 2: Morphine miligram equivalent doses [/fig_ref]. ## Adjuvant therapy Adjuvant therapy consists of drugs that are not primarily used as analgesics, but that possess analgesic or additive properties to opioid analgesia. Therefore, they reduce opiate doses, as well as their adverse effects, and can be used at any stage of the analgesic ladder (level of evidence IV, degree of recommendation C) [bib_ref] Nonopioid drugs in the treatment of cancer pain, Vardy [/bib_ref]. [fig_ref] Table 3: Adjuvant therapies and clinical uses [/fig_ref] shows the most used as well as their main indications in pain management [bib_ref] Nonopioid drugs in the treatment of cancer pain, Vardy [/bib_ref] [bib_ref] A user's guide to cannabinoid therapies in oncology, Maida [/bib_ref]. ## Breakthrough cancer pain (btcp): evaluation and management Although there is no universally accepted definition of BTCP, most authors have defined it as a transient exacerbation of pain that occurs either spontaneously or in relation to a predictable or unpredictable trigger, despite stable, controlled background pain [bib_ref] Science Committee of the Association for Palliative Medicine of Great Britain and..., Davies [/bib_ref]. BTCP is different from background pain; hence, its treatment is also different. Other terms such as 'episodic' or 'transient' pain have been used to describe BTCP, but these must not be incorrectly used for episodes of pain in a patient without adequate control of background pain, or pain just prior to their next dose ('end-of-dose failure') [bib_ref] Breakthrough cancer pain-still a challenge, Margarit [/bib_ref]. The clinical features of BTCP vary from one individual to the next, from one episode to the next, and within the same individual over time. Generally speaking, an episode of BTCP is characterized by: Location: typically the same as background pain, Severity: usually more severe than the background pain, Rapid onset: maximum severity within 3-5 min, Short duration: 15-30 min or shorter, and Number of episodes: 3-4 per day. Prevalence rates vary widely (35-95%), depending on the definition used and the populations studied (hospitalized or ambulatory patients, end-of-life care). BTCP can be caused by the neoplasm (70-80%), anticancer treatment (10-20%), or be unrelated to the tumor or its management (\ 10%). In only one half of all episodes of pain is it possible to identify triggering factors. Diagnosis is based on medical history, physical examination, and performance of complementary tests. Davies algorithm [bib_ref] Science Committee of the Association for Palliative Medicine of Great Britain and..., Davies [/bib_ref] is useful to establish diagnosis of BTCP and to discriminate it from uncontrolled background pain. A validated tool for BTCP has not yet been developed for clinical use, although there is a minimum of information that should be included in the medical history (level of evidence IV, degree of recommendation D) [bib_ref] Assessment and management of breakthrough pain in cancer patients: current approaches and..., Hagen [/bib_ref] - Number of episodes; - features of the pain: onset, duration, intensity, frequency, site, quality, and radiation; - exacerbation and/or relief factors; - response to analgesics or to other interventions; - associated symptoms, and - interference with activities of daily living. The aim of BTCP management is to minimize the intensity and severity of each pain episode, as well as to An interdisciplinary approach should be considered to improve BTCP progression: Lifestyle changes Reduce activities that precipitate BTCP; use special aids for daily activities or specific exercises can improve BTCP. Management of reversible causes Minimize mobilization in the case of bone metastases; antitussives if cough, or laxatives if constipation. Modification of disease processes Treat the underlying cause of the pain; options include surgery, radiotherapy, chemotherapy, hormone therapy, targeted therapy, and immunotherapy. Pharmacological management [bib_ref] Treatment of cancer pain: Spanish Society of Medical Oncology (SEOM) recommendations for..., Virizuela [/bib_ref] It is important to optimize background analgesia (adjuvant drugs, opioid titration, opioid switching) and supplement with rescue medication. Opioids are the drug rescue of choice for BTCP and the ideal medication should meet the following: High potency analgesia, rapid onset of action, short duration of action, minimal side effects, and easy administration (self-administration). Traditionally, immediate-release morphine has been used to treat BTCP, but its mechanism is not suited for this purpose. Rapid-onset opioids (ROOs) have been developed for this purpose; in particular, transmucosal and intranasal fentanyl (level of evidence IV, degree of recommendation C). [fig_ref] Table 4: Characteristic of ROOs Adapted from Virizuela et al[41] [/fig_ref] displays the ROOs available in Spain and their characteristics. Fentanyl should be titrated to establish the appropriate dose for each individual. Response should be monitored and side effects treated. Some patients fail to achieve adequate analgesia despite correct assessment and may benefit from interventional ## Neuropathic cancer pain (ncp) NCP results from injury to the peripheral or central nervous system as a consequence of compression by or infiltration of the tumor or from treatment toxicity. Neuropathic pain is usually described as burning, numbing, or electrical, and can present with additional neurological manifestations, such as sensory changes, muscle weakness, or autonomic dysfunction. The overall prevalence of NCP varies from 5 to 40% depending on the specific patient population or if mixed pain is included [bib_ref] Prevalence of neuropathic pain in cancer patients: pooled estimates from a systematic..., Roberto [/bib_ref]. Proper NCP management is complex, given the heterogeneity of etiologies, variability of symptoms, and the underlying neurogenic pathophysiology. Treatment must be tailored to each individual, initiating one medication at a time and slowly titrating to match response and tolerability [bib_ref] Pharmacological treatment of neuropathic cancer pain: a comprehensive review of the current..., Vadalouca [/bib_ref]. NCP can be relieved by multimodal treatment following WHO guidelines. It must be remembered that most cancer patients suffer multiple types of pain [bib_ref] Assessment and treatment of neuropathic cancer pain following WHO guidelines, Grond [/bib_ref] ; nevertheless, adjuvant analgesics are proposed as first choice in purely NCP. ## Opioids for ncp Opioids are first-line treatment for moderate to severe NCP (level of evidence II, degree of recommendation B). No proved difference between various opioids exists, though higher doses are usually required. A combination of adjuvant analgesics is recommended for patients displaying incomplete response. Transdermal fentanyl should not be used as first line when pain can be stabilized with other opioids (level of evidence II, degree of recommendation B). Tapentadol does not offer any benefit over other opioids (level of evidence III, degree of recommendation C) [bib_ref] Is tapentadol different from classical opioids? A review of the evidence, Langford [/bib_ref]. ## Adjuvants analgesics for ncp In this setting, a variety of medications with analgesic properties can be used in some painful conditions, including anticonvulsants (e.g., gabapentin, pregabalin), antidepressants (e.g., SSRIs, SNRIs-duloxetine, venlafaxine, tricyclic antidepressants), NMDA antagonist (ketamine), corticosteroids, and local anesthetics/topical agents (e.g., topical lidocaine patch) [fig_ref] Table 5: Most used adjuvant in NCP LOE/GOR level of evidence/grade of recommendation CIPN... [/fig_ref] (level of evidence III, degree of recommendation C) [bib_ref] Pharmacological treatment of pain in cancer patients: the role of adjuvant analgesics,..., Van Den Beuken-Van Everdingen [/bib_ref] Gabapentin appears to have a mild to moderate benefit, but no definitive conclusion can be drawn due to the tremendous variability of study design [bib_ref] Beyond neuropathic pain: gabapentin use in cancer pain and perioperative pain, Yan [/bib_ref]. A systematic review was unable to draw definitive conclusions regarding pregabalin's effect in NCP (level of evidence III, degree of recommendation C) [bib_ref] Pregabalin for the management of neuropathic pain in adults with cancer: a..., Bennett [/bib_ref]. Two phase-3 trials of venlafaxine [bib_ref] Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity:..., Durad [/bib_ref] and duloxetine [bib_ref] Effect of duloxetine on pain, function, and quality of life among patients..., Smith [/bib_ref] , demonstrated decreased pain intensity in patients with NCP, although this corresponded only to a reduction of just over 1 on a 0-10 Likert pain scale (level of evidence III, degree of recommendation C). ## Other treatments to control cancer pain interventional therapies Despite management pain according the WHO ladder, between 10 and 20% of patients may have poorly controlled pain or may not tolerate analgesics [bib_ref] A validation study of the WHO method for cancer pain relief, Ventafridda [/bib_ref]. Interventional techniques make it possible to control pain and decrease systemic analgesic [bib_ref] Interventional techniques for pain management in palliative care, Simpson [/bib_ref]. These therapies typically involve modifying nerve conduction and may be non-destructive (reversible agent by injection or catheter placement) or destructive (chemical or physical methods). Patient prognosis should be considered. The main indications are failure to achieve adequate analgesia or intolerable adverse effects and pain likely to be relieved with nerve block. Following successful treatment, patients should be closely monitored with scheduled opioid reduction to avoid opiaterelated side effects. Some patients with refractory pain or who are intolerant to opioids can benefit from interventional therapies, such as celiac plexus neurolysis (level of evidence II, degree of recommendation B) [bib_ref] Celiac plexus neurolysis in the management of unresectable pancreatic cancer: when and..., Wyse [/bib_ref]. ## Peripheral nerve blocks Peripheral nerve blocks are performed to denervate specific areas and can be helpful for perioperative or acute cancer pain (pathological rib fracture or vascular occlusion). They include paravertebral or intercostal blocks, brachial plexus block, or Gassesian ganglion block (for intractable facial pain). ## Autonomic nerve bocks In the sympathetic nervous system, afferent nerve fibers carry pain from the viscera; blocking these nerve fibers can reduce pain. Celiac plexus neurolysis improves pain relief from pancreatic cancer [bib_ref] Neurolytic celiac plexus block for pain control in unresectable pancreatic cancer, Yan [/bib_ref] and is commonly recommended after failure of opioid therapy; nevertheless, when distant Data taken from summary of product characteristics disease is evident, success rates decrease [bib_ref] Opioid pharmacotherapy in the management of cancer pain: a survey of strategies..., Cherny [/bib_ref]. Superior hypogastric plexus neurolysis and ganglion impar block may relief visceral pelvic and perineal pain, respectively. ## Neuroaxial infusion Infusion of drugs into the epidural/intrathecal space leads to decrease opioid consumption (approximately 1% of opioid oral dose for intrathecal infusion) and should be considered for patients who are refractory/intolerant to systemic treatment (level of evidence II, degree of recommendation B). Opioid, local anesthetic, clonidine (for neuropatic pain) or ziconotide are common used as percutaneous lines or fully implanted pumps. ## Vertebroplasty/kyphoplasty Ostelytic involvement of the spine may cause pain due to pathologically vertebral fracture and percutaneous injection of bone cement can stabilize the fractured vertebrae and relief persistent or refractory pain (level of evidence III, degree of recommendation B) [bib_ref] Metastatic bone tumors of the pelvis and lower extremity, Buggay [/bib_ref]. The main specific contraindications are epidural involvement, retropulsion of bone fragments into the spinal cord or neurological damage. ## Radiation therapy (rt) All patients with painful bone metastases should be evaluated for RT since it provides excellent and often rapid pain relief (level of evidence I, degree of recommendation A) [bib_ref] Effect of radiotherapy on painful bone metastases: a secondary analysis of the..., Mcdonald [/bib_ref]. Although different regimens can be used (10 9 300 cGy, 6 9 400 cGy, 5 9 400 cGy), pain relief is equivalence and ASTRO support treatment with single 8 Gy fraction based on better convenience, cost-effective and no increase toxicity (level of evidence I, degree of recommendation A) [bib_ref] Palliative radiation therapy for bone metastases: update of an ASTRO evidence-based guideline, Lutz [/bib_ref]. Reirradiation may be necessary when pain relapses, but may not be feasible due to the limited tolerance of tissues [bib_ref] Effectiveness of reirradiation for painful bone metastases: a systematic review and meta-analysis, Huisman [/bib_ref]. ## Radiofrequency ablation for bone lesions Nonsurgical ablation of painful skeletal metastases is possible when moderate/severe pain persists after RT. This pain is generally from osteolytic metastases that must be separable from critical structures [bib_ref] Neuroanatomic considerations in percutaneous tumor ablation, Kurup [/bib_ref]. Radiofrequency ablation relies upon a needle electrode to deliver a current that results in frictional heating (coagulative necrosis). Cryoablation provides immediate cooling that results in a visible ice ball. Focused ultrasound is a non-invasive, MRI-guided, ablative method in which energy is directed at the focal point, raising the temperature and producing thermal tissue destruction (level of evidence III, degree of recommendation C) [bib_ref] Bone metastases: approaches to management, Janjan [/bib_ref]. ## Tanezumab Tanezumab is a monoclonal antibody that inhibits neurotrophin nerve growth factor and has been shown to reduce osteoarthritis and chronic low back pain [bib_ref] Efficacy and safety of tanezumab added on to diclofenac sustained release in..., Balanescu [/bib_ref]. In cancer pain, two phase-2 studies have assessed tanezumab in painful bone metastases [bib_ref] Efficacy and safety of tanezumab in the treatment of pain from bone..., Sopata [/bib_ref]. Although the primary endpoint was not achieved, the data suggest improved analgesia and a phase-3 trial is currently on-going (NCT02609828) (level of evidence III, degree of recommendation C). ## Psychological approaches to cancer pain Psychological aspects such as emotional stress, anxiety, depression, uncertainty, and hopelessness influence the perception of pain and hinder its control [bib_ref] Psychological and behavioral approaches to cancer pain management, Syrjala [/bib_ref]. Inversely, pain can cause or worsen psychological problems. This vicious circle must be broken by actions directed both at pain relief and patients' psychological needs. Furthermore, we should treat the symptoms that often accompany pain: fatigue, sleep disorders, anorexia, etc., that impair patients' quality of life and concern them. Several meta-analyses and randomized clinical trials have shown that pain intensity can be reduced through psychological interventions (level of evidence I, degree of recommendation A). Cognitive-behavioral and mind-body therapies (relaxation, imagery, hypnosis, and biofeedback) can be extremely useful (level of evidence II, degree of recommendation B) [bib_ref] Metaanalysis of psychosocial interventions to reduce pain in patients with cancer, Sheinfeld Gorin [/bib_ref]. Music, exercise, and yoga can help patients during cancer treatment, as well as cancer survivors [bib_ref] Music interventions for improving psychological and physical outcomes in cancer patients, Bradt [/bib_ref]. Multidisciplinary care is essential and should include oncologists, psychologists, social workers, rehabilitators, etc. Equally necessary is good communication between the team caring for the patient and the patient's family. ## Pain in cancer survivors Up to 40% of cancer survivors present pain and in 5-10% it is both chronic and severe [bib_ref] Chronic pain in cancer survivors: a growing issue, Van Den Beuken-Van [/bib_ref]. Strong opioids may be indicated but, since 40% of cancer survivors live longer than 10 years, there is a growing concern about the long-term side effects of opioids, opiate use to treat anxiety, overdose, and abuse in ''non-patients''. Therefore, greater emphasis should be placed on non-opioid analgesics and non-pharmacological therapies. ## Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Ethical approval This article does not contain any studies with human participants performed by any of the authors. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://crea tivecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. [fig] Figure 1: Flowchart impact on patients' quality of life. The strategy for dealing with BTCP should be individualized, depending on a variety of pain-related (etiology, physiopathology, clinical features) and patient-related factors (performance status, disease stage, personal preferences). [/fig] [table] Table 1: WHO 3rd step Adapted from Ripamonti C. ESMO Guideline[16] [/table] [table] Table 2: Morphine miligram equivalent doses (MME) and recommendations in some clinical situations Adapted from Gonzalez-Barboteo[34] [/table] [table] Table 3: Adjuvant therapies and clinical uses [/table] [table] Table 4: Characteristic of ROOs Adapted from Virizuela et al[41] [/table] [table] Table 5: Most used adjuvant in NCP LOE/GOR level of evidence/grade of recommendation CIPN chemotherapy-induced peripheral neuropathy [/table]	None	https://link.springer.com/content/pdf/10.1007/s12094-017-1791-2.pdf	None
40b248b9f9cb77b0aace3196a36c66b1a49a6218	pubmed	Standards for the diagnosis and management of complex regional pain syndrome: Results of a European Pain Federation task force	Standards for the diagnosis and management of complex regional pain syndrome: Results of a European Pain Federation task force Background: Complex regional pain syndrome is a painful and disabling post-traumatic primary pain disorder. Acute and chronic complex regional pain syndrome (CRPS) are major clinical challenges. In Europe, progress is hampered by significant heterogeneity in clinical practice. We sought to establish standards for the diagnosis and management of CRPS. Methods: The European Pain Federation established a pan-European task force of experts in CRPS who followed a four-stage consensus challenge process to produceThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. # \| introduction Complex regional pain syndrome (CRPS) is a painful and disabling post-traumatic primary pain disorder affecting, usually, distal limbs [bib_ref] Complex regional pain syndrome -phenotypic characteristics and potential biomarkers, Birklein [/bib_ref] [bib_ref] Clinical features and pathophysiology of complex regional pain syndrome, Marinus [/bib_ref]. Signs and symptoms are normally restricted to the affected limb but can spread [bib_ref] Spreading of complex regional pain syndrome: Not a random process, Van Rijn [/bib_ref]. The incidence of CRPS may vary between populations (Sandroni, [bib_ref] Complex regional pain syndrome type I: Incidence and prevalence in Olmsted county,..., Perez [/bib_ref]. In a population-based European study, the incidence was 20-26/100,000 in the Netherlands . The clinical presentations of CRPS vary enormously between patients . For example, the affected limb may appear hot and red, or cold and blue; these symptoms and signs can also fluctuate in any single patient over time. Patients often also report disordered spatial awareness, and bodily and limb agency distortions [bib_ref] Body perception disturbance: A contribution to pain in complex regional pain syndrome..., Lewis [/bib_ref]. The aetiology of CRPS is likely multifactorial . It is thought to be pathological not psychopathological in origin [bib_ref] Demographic and medical parameters in the development of complex regional pain syndrome..., Beerthuizen [/bib_ref]. Most patients will improve over time [bib_ref] Outcome of the complex regional pain syndrome, De Mos [/bib_ref] , although appropriate management very likely hastens recovery [bib_ref] Can we reduce the incidence of complex regional pain syndrome type I..., Gillespie [/bib_ref]. However, full recovery is less common, and many patients will be left with varying degrees of persistent pain and functional impairment [bib_ref] Extent of recovery in the first 12 months of complex regional pain..., Bean [/bib_ref]. For some people, CRPS may become a long-lasting, highly disabling and distressing chronic pain condition. The costs of CRPS are significant, at a personal, familial and societal level [bib_ref] Economic evaluation of spinal cord stimulation for chronic reflex sympathetic dystrophy, Kemler [/bib_ref]. In 2016, the European Pain Federation convened a CRPS Task Force to support the development of best care for these patients through Europe. The Task Force members were CRPS experts with geographical and professional representation within Europe and a patient representative. As its first objective, the Task Force was asked to develop standards that could guide minimally acceptable levels of CRPS care applicable across a diversity of healthcare structures and economies within Europe. Some European countries have developed their own guidelines for CRPS care [bib_ref] Complex regional pain syndrome type I: Incidence and prevalence in Olmsted county,..., Perez [/bib_ref] ; however, any adoption within additional countries is often impeded by differences in healthcare economics and structures. The application of standards can go some way to establish a primary common position. We recognize that terms such as "standards," "guidelines," "policy" and "procedure" are often used interchangeably, and currently, there is no internationally agreed definition for the term "standards" as applied to health care. For our purposes, we considered the UK Faculty of Pain Medicine interpretation of standards, as applied to pain: "Standards must be followed. Standards aim to represent current best practice in pain management as published in relevant literature and/or agreed by a body of experts" . Notably, standards can change over time . Standards can act as a benchmark, but can also be utilized as a tool for healthcare professionals, commissioners and policymakers in the identification and appropriate allocation of resources. # \| methods Our development process followed that outlined by the UK National Institute of Clinical Excellence (NICE, see Supporting Information Appendix S1). A patient-member (IT) provided service user perspectives. The CRPS standards mandatory quality standards worded as grammatically imperative (must-do) statements. Results: We developed 17 standards in 8 areas of care. There are 2 standards in diagnosis, 1 in multidisciplinary care, 1 in assessment, 3 for care pathways, 1 in information and education, 4 in pain management, 3 in physical rehabilitation and 2 on distress management. The standards are presented and summarized, and their generation and consequences were discussed. Also presented are domains of practice for which no agreement on a standard could be reached. Areas of research needed to improve the validity and uptake of these standards are discussed. Conclusion: The European Pain Federation task force present 17 standards of the diagnosis and management of CRPS for use in Europe. These are considered achievable for most countries and aspirational for a minority of countries depending on their healthcare resource and structures. Significance: This position statement summarizes expert opinion on acceptable standards for CRPS care in Europe. ## \| 643 GOEBEL Et aL. were derived through discussion and a process of consolidation and challenge which had four stages: First, we took account of the evidence from recently published systematic reviews [bib_ref] Treatment of complex regional pain syndrome: An updated systematic review and narrative..., Duong [/bib_ref] [bib_ref] Interventions for treating pain and disability in adults with complex regional pain..., O'connell [/bib_ref]. Second, a draft document outlining the domains of practice and the likely areas of difference was produced and discussed in e-mail and telephone discussions from November 2016 to May 2017. Third, we convened a one-day face-to-face meeting in June 2017. The focus of the meeting was to seek agreement among the members of the Task Force on the areas of practice. A "challenge" process was developed in which we drafted the standards as grammatically imperative (must-do) statements. This presentation of each standard of care as mandatory was useful because it forced members to think about exceptional cases or alternatives. Finally, a draft document of standards was then drafted. Each member of the group had one more opportunity to veto any highly contentious area and suggest further changes. No veto was enacted. The resulting standards were considered achievable for most countries and aspirational for a minority of countries depending on their healthcare resource and structures. # \| results We developed 17 standards, highlighted in italics, in 8 areas of care. There are 2 standards in diagnosis, 1 in multidisciplinarity, 1 in assessment, 3 in care pathways, 1 in information and education, 4 in pain management, 3 in physical rehabilitation and 2 in distress management. ## F i g u r e 1 budapest diagnostic criteria for crps. notes: (1) If the patient has a lower number of signs or symptoms, or no signs, but signs and/or symptoms cannot be explained by another diagnosis, "CRPS-NOS" (not otherwise specified) can be diagnosed. This includes patients who had documented CRPS signs/symptoms in the past. (2) If A, B, C and D above are all ticked, please diagnose CRPS. If in doubt, or for confirmation, please refer to your local specialist. (3) Psychological findings, such as anxiety, depression or psychosis, do not preclude the diagnosis of CRPS (3) Distinction between CRPS type 1 (no nerve injury) and CRPS type 2 (major nerve injury) is possible, but has little relevance for treatment. Explanation of terms: "Hyperalgesia" is when a normally painful sensation (e.g., from a pinprick) is more painful than normal; "allodynia" is when a normally not painful sensation (e.g., from touching the skin) is now painful; and "hyperaesthesia" is when the skin is more sensitive to a sensation than normal. A special feature in CRPS: In category 4, the decreased range of motion/weakness is not always due to pain. It is also not necessarily due to nerve damage or a joint or skin problem. Some patients' experience of an inability to move their limb may be due to yet poorly understood, disturbed motor coordination which can be reversible. A helpful question to assess this feature is: "If I had a magic wand to take your pain away, could you then move your… (e.g., fingers)?" Many patients will answer with "no" to that question. Unusual CRPS: Around 5% of patients cannot recall a specific trauma or may report that their CRPS developed with an everyday activity such as walking or typewriting. In very few people, CRPS can have a bilateral onset. In some patients, CRPS can spread to involve other limbs. Around 15% of CRPS cases do not improve after 2 years. It is appropriate to make the diagnosis of CRPS in these unusual cases 3.1 \| The diagnosis of complex regional pain syndrome Complex regional pain syndrome is diagnosed according to the "New IASP Criteria" (sensitivity: 0.99; specificity: 0.68 for the "clinical" criteria) [bib_ref] Diagnostic criteria: The statistical derivation of the four criterion factors, Harden [/bib_ref] [bib_ref] Validation of proposed diagnostic criteria (the "Budapest Criteria") for complex regional pain..., Harden [/bib_ref] which are sometimes also referred to as the "Budapest criteria" . The use of these criteria requires some degree of prior belief that the condition is likely to be CRPS, that is, the patient has a regional affection distally in extremities, not corresponding to a nerve innervation territory. As an exception, the rare subtype of CRPS II after nerve injury can sometimes correspond to the injured nerve's innervation territory. These criteria stipulate that CRPS is a diagnosis of exclusion, and alternative ("differential") diagnoses are provided in Box 1. Uncertainty about the diagnosis can be distressing to patients and may lead to inappropriate treatment. European countries differ in their current standards about the timely manner of diagnosing CRPS; however, each country is better than the worst situation: where patients are never being diagnosed . Improvements in diagnostic standards are possible and desirable through information and training of healthcare professionals and patients. For example, in Switzerland an information leaflet about CRPS was sent to all practising medical doctors in the country, and there is consensus that awareness has improved (SUVA, 2013). While there are "perfect" diagnostic standards, it is important to establish realistic, country-related next goals and consequently identify which steps that aim to improve current standards will help to achieve these goals (see -this process can later be repeated as appropriate. The use of a diagnostic checklist is helpful, as shown in . The European Pain Federation task force members recognize the challenges about the future development of the CRPS Budapest criteria ; these challenges include, among others, the diagnostic approach to a small number of patients diagnosed according to Budapest criteria, who over time lose some of their CRPS signs such as swelling, but have unchanged pain. These patients are currently labelled as "CRPS-not otherwise specified" (CRPS-NOS, , which has sometimes led to challenges with the reimbursement of therapies, or in the context of insurance-and medico-legal proceedings, and a better solution may be required. Standard 1: "Budapest" diagnostic criteria for CRPS must be used, as they provide acceptable sensitivity and specificity. Standard 2: Diagnosing CRPS does not require diagnostic tests, except to exclude other diagnoses. It is worth noting that different opinions existed within the Task Force regarding the usefulness of three-phase bone scintigraphy or magnetic resonance imaging for the diagnosis of CRPS, with some members considering these techniques useful, and the majority not. There was agreement that existing tests do not reflect pathognomonic parameters. ## \| the management and referral of patients with crps Standard 3: The management of mild (mild pain and mild disability) CRPS may not require a multiprofessional team; however, the degree of severity and complexity of CRPS must dictate the need for appropriately matched multi-professional care (for details, see section care structure and . ## Standard 4: Patients diagnosed with CRPS must be appropriately assessed; this assessment must establish any triggering cause of their CRPS, their pain intensity and the interference their pain causes on their function, their activities of daily living, participation in other activities, quality of life, sleep and mood. Most patients have short-lasting CRPS which may improve within a few months, even without treatment , so that these patients are best treated in non-specialized care, provided by healthcare professionals who have had standard training within their discipline (e.g., physiotherapist and general practitioner-see ; early treatment is highly likely to shorten the time of suffering for many patients [bib_ref] Can we reduce the incidence of complex regional pain syndrome type I..., Gillespie [/bib_ref]. ## Standard 5: Referral to specialized care must be initiated for those patients who do not have clearly reducing pain and improving function, within 2 months of commencing treatment for their CRPS, despite good patient engagement in rehabilitation. There is consensus that the best exact time may vary somewhat between patients, but that 2 months is a reasonable guide. ## Standard 6: Referral to super-specialized care must be initiated for the small number of patients with complications such as CRPS spread, fixed dystonia, myoclonus, skin ulcerations or infections or malignant oedema in the affected limb, and those with extreme psychological distress. Referral to super-specialized care may also be appropriate for patients which are not improving in specialized services: (a) for additional expertise in treating this rare patient group and (b) for consideration of interventions not available in specialized care . There was no consensus about the best names for these three types of services, although most Task Force members considered the current wording in standard 6 to be acceptable. There is agreement that other wordings may be substituted as is nationally or locally appropriate. Treating healthcare professionals should be aware of appropriate specialized care services and any services with specific expertise and interest in the management of CRPS nationally ("super-specialized" care facilities), Standard 7: Specialized care facilities must provide advanced treatments for CRPS including multidisciplinary psychologically informed rehabilitative pain management programmes (PMP). If they do not provide these treatments, then they must refer for these treatments, if needed, to other specialized care facilities, or to super-specialized care facilities . We propose that specialized care facilities , who wish to establish quality indicators about their regional CRPS pathway, should in the first instance establish an internal registry of CRPS cases seen. Since the incidence of CRPS in Europe (20-26/100,000) is known, such a registry may support BOX 1 Possible differential diagnoses 1. Local pathology: Distortion, fracture, pseudoarthrosis, arthrosis, inflammation (cellulitis, myositis, vasculitis, arthritis, osteomyelitis and fasciitis), compartment syndrome and immobilization-induced symptoms. Persistent defects after limb injury: osteoarthritis developing after joint fractures; myofascial pain due to changed (protective) movement patterns 2. Affection of arteries, veins or lymphatics, for example traumatic vasospasm, vasculitis, arterial insufficiency, thrombosis, Raynaud's syndrome, thromboangiitis obliterans (Buerger's syndrome), lymphedema and secondary erythromelalgia. 3. Connective tissue disorder 4. Central lesion, for example spinal tumour 5. Peripheral nervous system lesion (nerve compression, cervico-brachial or lumbo-sacral plexus affection, acute sensory polyneuropathy, (poly-)neuritis, autoimmune (e.g., posttraumatic vasculitis) and infectious (e.g., borreliosis)) 6. Malignancy (Pancoast tumour/paraneoplastic syndrome/occult malignancy) 7. Factitious disorder Particular awareness about differential diagnosis is advised in spontaneously developing CRPS (no trauma, about 5% of cases), when the involvement is a proximal part of the limb, such as the shoulder, or when there is primary involvement of more than one limb. professionals to estimate whether those patients in their region who are in need of their service do in fact reach them. The registry, once established, can also serve as a basis for additional quality improvement efforts. Each Chapter of the European Pain Federation should institute an appropriate treatment guideline for CRPS that is valid for the circumstances in that country, even if this is adapted from existing guidelines in other countries. Production of lay audience-appropriate versions should be considered. ## \| prevention Early, appropriate rehabilitation treatment post-trauma may prevent the development of CRPS; however, more data are needed to fully understand its impact [bib_ref] Can we reduce the incidence of complex regional pain syndrome type I..., Gillespie [/bib_ref]. A high pain score one week after trauma may indicate a "fracture at risk" [bib_ref] Intense pain soon after wrist fracture strongly predicts who will develop complex..., Moseley [/bib_ref] and thus identify patients who benefit most from preventative early rehabilitation. There is conflicting evidence about the value of using vitamin C after distal radius fracture to prevent the development of CRPS. There is also very preliminary evidence about the value of steroids to prevent a prolonged course of CRPS after very early CRPS has been diagnosed. More studies are needed before recommendations can be given. The Task Force decided that there is insufficient evidence for or against any methods of prevention to allow for a standard to be written. ## \| patient information and education Standard 8: Patients, and where appropriate their relatives and carers must receive adequate information soon after diagnosis on (a) CRPS, (b) its causation (including the limits of current scientific knowledge), (c) its natural course, (d) signs and symptoms, including body perception abnormalities, (e) typical outcomes and (f) treatment options. Provision of information is by all therapeutic disciplines and must be repeated as appropriate. Emphasis should be put on the goals of treatment and on the patient's active involvement in the treatment plan. The typically benign prognosis should be emphasized. ## F i g u r e 3 services and competencies. pmp = multidisciplinary pain management programme integrating psychological care and functional rehabilitation; & additionally "Hand Therapists" in some European Countries, note, some pain clinics and rehabilitation facilities do not provide group-based PMP, whereas others additionally provide "super-specialized" services; *neuromodulation is listed to highlight the care structure within which it is delivered; some centres will not provide this service Information is available from various sources (e.g., [bib_ref] The incidence of complex regional pain syndrome: A population-based study, Crpsvereniging [/bib_ref] [bib_ref] Complex regional pain syndrome type I: Incidence and prevalence in Olmsted county,..., Perez [/bib_ref]. ## \| pain managementmedication and procedures Standard 9: Patients must have access to pharmacological treatments that are believed to be effective in CRPS. Appropriate pain medication treatments are considered broadly similar with those for neuropathic pains, although high-quality studies in CRPS are not available [bib_ref] Treatment of complex regional pain syndrome: An updated systematic review and narrative..., Duong [/bib_ref]. All patients with CRPS must receive a pain treatment plan consistent with any geographically relevant guidelines. Treatment with bisphosphonates and/or steroids has also been considered. However, the Task Force members did not reach agreement about the evidence for or against their efficacy and safety. Standard 10: Efforts to achieve pain control must be accompanied by a tailored rehabilitation plan Standard 11: Medications aimed at pain relief may not be effective in CRPS, while causing important adverse effects; therefore, stopping rules should be established and a medication reduction plan must be in place if on balance continuation is not warranted. Standard 12: CRPS assessment (see above) must be repeated as appropriate, because both the natural development of the disease and of treatment may change the clinical picture over time. Some patients who have not responded to other treatments may be considered for invasive neuromodulation and should be referred for assessment. ## \| physical and vocational rehabilitation In partnership with the patient, appropriate, generally gentle, graded exercises in the presence of pain should be advised upon by a trained healthcare professional; this is essential as to give the best chance of a good outcome and minimize distress. Immobilization of the CRPS limb should be avoided wherever possible. [bib_ref] Can we reduce the incidence of complex regional pain syndrome type I..., Gillespie [/bib_ref]. Standard 13: Patient's limb function, overall function and activity participation, including in the home and at work or school, must be assessed early and repeatedly as appropriate. Patients should have access to vocational rehabilitation (as relevant). ## Standard 14: Patients with CRPS must have access to rehabilitation treatment, delivered by physiotherapists and/or occupational therapists, as early as possible in their treatment pathway. This may shorten the early disease course and preserve limb function. In some European countries, these treatments are guided by medical doctors, including rehabilitation specialists, general practitioners or others. ## Standard 15: Physiotherapists and occupational therapists must have access to training in basic methods of pain rehabilitation and CRPS rehabilitation ## \| identifying and treating distress Standard 16: Patients must be screened for distress including depression, anxiety, posttraumatic stress, pain-related fear and avoidance. This must be repeated where appropriate [bib_ref] Do psychological factors influence recovery from complex regional pain syndrome type 1?..., Bean [/bib_ref]. ## Standard 17: Where required, patients must have access to evidence-based psychological treatment ## \| long-term care Some patients will continue to experience impediments to their quality of life even after appropriate treatment has been completed. These impediments either are due to ongoing consequences of CRPS even though the condition has improved (about 40% of all patients), or are caused by unresolved CRPS (about 15%-20%; de [bib_ref] Outcome of the complex regional pain syndrome, De Mos [/bib_ref]. Particularly, the latter group may benefit from the offer of a long-term management plan, mainly aiming to maximize support for self-management. Long-term management is ideally initiated through specialized or super-specialized services and may include referral back to these services if CRPS-specific symptoms change ; an example is described here . T A B L E 1 European Pain Federation standards for the diagnosis and management of complex regional pain syndrome ## Diagnosis Standard 1 "Budapest" diagnostic criteria for CRPS must be used, as they provide acceptable sensitivity and specificity. Standard 2 Diagnosing CRPS does not require diagnostic tests, except to exclude other diagnoses. ## Management and referral Standard 3 The management of mild (mild pain and mild disability) CRPS may not require a multi-professional team; however, the degree of severity and complexity of CRPS must dictate the need for appropriately matched multi-professional care (for details, see section care structure and . ## Standard 4 Patients diagnosed with CRPS must be appropriately assessed; this assessment must establish any triggering cause of their CRPS, their pain intensity and the interference their pain causes on their function, their activities of daily living, participation in other activities, quality of life, sleep and mood. Standard 5 Referral to specialized care must be initiated for those patients who do not have clearly reducing pain and improving function within 2 months of commencing treatment for their CRPS despite good patient engagement in rehabilitation. ## Standard 6 Referral to super-specialized care must be initiated for the small number of patients with complications such as CRPS spread, fixed dystonia, myoclonus, skin ulcerations or infections or malignant oedema in the affected limb, and those with extreme psychological distress. Standard 7 Specialized care facilities must provide advanced treatments for CRPS including multidisciplinary psychologically informed rehabilitative pain management programmes (PMP). If they do not provide these treatments, then they must refer for these treatments, if needed, to other specialized care facilities, or to super-specialized care facilities . ## Prevention None No Standards were considered as having sufficient support to recommend as mandatory. ## Information and education Standard 8 Patients and where appropriate their relatives and carers must receive adequate information soon after diagnosis on (a) CRPS, (b) its causation (including the limits of current scientific knowledge), (c) its natural course, (d) signs and symptoms, including body perception abnormalities, (e) typical outcomes and (f) treatment options. Provision of information is by all therapeutic disciplines and must be repeated as appropriate. Pain Management Standard 9 Patients must have access to pharmacological treatments that are believed to be effective in CRPS. Appropriate pain medication treatments are considered broadly similar with those for neuropathic pains, although high-quality studies in CRPS are not available [bib_ref] Treatment of complex regional pain syndrome: An updated systematic review and narrative..., Duong [/bib_ref]. All patients with CRPS must receive a pain treatment plan consistent with any geographically relevant guidelines. Standard 10 Efforts to achieve pain control must be accompanied by a tailored rehabilitation plan. ## Standard 11 Medications aiming at pain relief may not be effective in CRPS, while causing important side effects; therefore, stopping rules should be established and a medication reduction plan must be in place if on balance continuation is not warranted. Standard 12 CRPS assessment (see above) must be repeated as appropriate, because both the natural development of the disease and of the treatment may change the clinical picture over time. ## Physical and vocational rehabilitation Standard 13 Patient's limb function, overall function and activity participation, including in the home and at work or school, must be assessed early and repeatedly as appropriate. Patients should have access to vocational rehabilitation (as relevant). ## Standard 14 Patients with CRPS must have access to rehabilitation treatment, delivered by physiotherapists and/or occupational therapists, as early as possible in their treatment pathway. ## Standard 15 Physiotherapists and occupational therapists must have access to training in basic methods of pain rehabilitation and CRPS rehabilitation. ## Identifying and treating distress Standard 16 Patients must be screened for distress including depression, anxiety, post-traumatic stress, pain-related fear and avoidance. This must be repeated where appropriate. ## Standard 16 Where required, patients must have access to evidence-based psychological treatment. Long-term Care None No standards were considered as having sufficient support to recommend as mandatory. Version January 2019 \| 649 GOEBEL Et aL. # \| discussion We here present 17 standards for the diagnosis and management of CRPS for consideration of adoption in Europe. They are summarized in . These standards can be considered best practice in CRPS as supported by expert and patient agreement. We followed a method that focused on evidence review but which prioritized the production of a series of mandatory statements of optimal clinical practice that could be followed in the majority of the 37 countries who are members of the European Pain Federation. We deliberately avoided statements of optional, desirable or aspirational practice, focusing on what was considered achievable by most. There are a number of limitations to our approach that should be taken into account. First, we did not canvas all clinicians working in this field across all of the 37 countries, or managers, politicians or other non-healthcare stakeholders. We focused instead on an expert group supported by a patient representative. It is possible that different experts would have produced different standards. This was a deliberate decision on our behalf as we needed to set a first list of expert-driven standards from which to build. Second, we did not produce a series of evidence syntheses (e.g., meta-analytic review of efficacy or review of assessment tools). We judged that such an effort would be resource-heavy and unlikely to yield any clarity due to the well-documented absence of primary research into this orphan disease. Instead, we relied on the extant literature which is well known to the group. Third, our decision to craft standards as mandatory meant that the heterogeneity of different views and nuanced opinions was not reported. Presented only is the result. The standards and their production have clinical, research and policy implications. ## 1. Clinical implications: the next step is to share the standards with Federation members, which has a number of challenges. First, language translation of the standards is necessary. Second, we need to survey clinicians for current practice as it relates to the standards to establish a baseline of common clinical practice. 2. Research implications: there is no standard that could not benefit from further study. And there are two areas where we were unable to set standards of care. The group considered that a priority for research was to better understand the heterogeneity of presentation within the current broad category of CRPS. For example, there is a need to differentiate between an early and late presentation. There is a need to look at sex and age differences. And, there is a need to look at CRPS in the context of comorbidities. There are also challenges to the Budapest criteria which, summarized in , need urgent attention. 3. Policy implications: these standards are the first step in a process. Standards are essentially a tool to improve practice, but practice only improves if they are used. We next need to understand the barriers to their implementation, whether they are resource, educational, legislative or organizational. We propose that a CRPS pain champion be appointed by each of the 37 national pain chapters, who can guide development and be a point of contact for this work. Finally, we recognize that these standards are open to change and should be reviewed regularly. In particular, we need to take account of national standards, practice reviews, guidance and guidelines, either from individual pain societies or those in rehabilitation, neurology or other therapy areas. We need also to be mindful of non-European work that could influence these standards, including any new and emerging evidence. We have therefore agreed with the European Pain Federation to review these standards five years from their date of publication. T A B L E 2 Challenges for the future development of CRPS Budapest criteria that arise from the 17 Standards Challenge 1 How should we deal with "CRPS-like conditions" fulfilling only some diagnostic criteria (from the start-never fulfilled Budapest diagnosis)? Challenge 2 How shall we term those cases of CRPS which initially clearly conformed with Budapest criteria, but which have now very few signs not conforming with Budapest criteria, but ongoing pain. This includes cases, where that pain is as strong as initially, and (more often) other cases, where the pain is improved, but stable and still problematic to the patient's quality of life. We recognize that these cases are rare, since sensory and motor signs providing the basis for the Budapest diagnosis are almost always present. Where the diagnosis of CRPS was correctly made, and documented in the past, might these cases be termed, for example, "partially recovered," or "sequelae"? Challenge 3 How can we better clarify the specificity of the Budapest diagnosis outside neuropathic pain settings? [fig] F: I G U R E 2The European Task orce dynamic diagnostic standard quality framework for CRPS. HP: [/fig]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ejp.1362	Complex regional pain syndrome is a painful and disabling post‐traumatic primary pain disorder. Acute and chronic complex regional pain syndrome (CRPS) are major clinical challenges. In Europe, progress is hampered by significant heterogeneity in clinical practice. We sought to establish standards for the diagnosis and management of CRPS.
55b681f8b275860bd67b0b7ebdefb6e7f0a98b1f	pubmed	The unvirtuous cycle of discrimination affecting people with hepatitis B: a multi-country qualitative assessment of key-informant perspectives	The unvirtuous cycle of discrimination affecting people with hepatitis B: a multi-country qualitative assessment of key-informant perspectives Background: An estimated 296 million individuals live with chronic hepatitis B worldwide, most have not been diagnosed and remain at risk of liver disease and cancer. People with hepatitis B often face discrimination that denies them employment or education opportunities, results in unfair treatment at work or in school, limits their ability to emigrate to certain countries, and in some cases prohibits them from serving in the military. Discrimination specific to hepatitis B has not been widely documented within the literature. This study aims to investigate and describe hepatitis B related discrimination, document discrimination occurring around the globe, and provide initial recommendations for addressing discrimination using key informant interviews.Methods:Purposive and snowball sampling were used to identify potential key informants for qualitative interview. Key informants identified as community health leaders, public health scientists, doctors, and researchers, many of whom were also living with hepatitis B. Using a semi-structured guide, participants were asked to describe their experience and any challenges for people living with hepatitis B including marginalization and its' consequences. A codebook was used to guide the organization of data for analysis, and all transcripts N = 17 were double coded.Results:The overarching themes identified from interviews demonstrate explicit experiences with discrimination of those directly affected, the psychological responses, and the negative health outcomes associated with the unvirtuous cycle of discrimination. All key informants reported on the substantial quality of life implications and often poorer health outcomes resulting from hepatitis B discrimination. Participants also identified the significant impact of hepatitis B discrimination occurring within a range of education-based services across several countries as well as military exclusion or removal if individuals are found to have hepatitis B.Conclusion:Our data demonstrate that hepatitis B discrimination has a significant impact. Discrimination can occur at various points in life from education, to seeking employment, to marriage, to restrictions on entry, travel and stay in other countries. This study demonstrates the impact of discrimination and the need for future research that can lead to policy change and protections for people living with and impacted by hepatitis B. 820,000 deaths worldwide attributed to chronic hepatitis B, mostly from cirrhosis and hepatocellular carcinoma (HCC, primary liver cancer). An estimated 296 million individuals live with chronic hepatitis B worldwide, most of whom have not been diagnosed and remain at risk of liver disease, including cancer [bib_ref] Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016:..., Observatory Collaborators [/bib_ref]. Clinical management, including regular monitoring and pharmaceutical treatment effectively reduces the risk of mortality resulting from the infection [bib_ref] Chronic hepatitis B: Update, Lok [/bib_ref]. While most people are unaware of their hepatitis B infection, those that have been diagnosed often face significant social marginalization from stigma and discrimination as a result of their hepatitis B infection [bib_ref] Social determinants of stigma and discrimination in vietnamese patients with chronic hepatitis..., Van Le [/bib_ref] [bib_ref] More than a virus: A qualitative study of the social implications of..., Wallace [/bib_ref] [bib_ref] The lived experience of chronic hepatitis B: A broader view of its..., Tu [/bib_ref]. People with hepatitis B often experience disease-related stigma [bib_ref] The lived experience of chronic hepatitis B: A broader view of its..., Tu [/bib_ref]. Stigma has been defined as a social process, experienced or anticipated, and which is characterized by exclusion, rejection, blame or devaluation resulting from experience, perception or reasonable anticipation of an adverse social judgement about a person or a group [bib_ref] Health-related stigma, Scambler [/bib_ref]. Stigma resulting from hepatitis B infection has contributed to discrimination, a reduction in quality of life, and difficulty accessing employment, education and immigration. Within academic literature, limited research is available specifically describing hepatitis B related stigmaand the consequences of stigma, including discrimination. People with hepatitis B often face discrimination that denies them employment or education opportunities, results in unfair treatment at work or in school, limits their ability to emigrate to certain countries, and in some cases prohibits them from serving in the military. Most research about discrimination has been conducted in China, or with people of Chinese ethnicity living in other countries. In 2010, China outlawed a requirement for hepatitis B testing for school admissions and employment applications [bib_ref] Discrimination against hepatitis B carriers in China, Yang [/bib_ref] [bib_ref] The experience of discrimination of individuals living with chronic hepatitis B in..., Han [/bib_ref]. Despite this, the U.S. State Department's 2015 human rights report noted that testing for hepatitis B remains common practice in employment screening in China. It has been documented that people who test positive for hepatitis B are not hired and provided a reason other than their positive status [bib_ref] Discrimination against people with hepatitis B in China, Kan [/bib_ref]. There appears to be limited awareness of the anti-discrimination laws and workers' rights in China as well as limited laws available to respond to hepatitis B specific discrimination [bib_ref] The experience of discrimination of individuals living with chronic hepatitis B in..., Han [/bib_ref]. Despite legal prohibitions in place in China, a survey done in Beijing, China in 2015 showed that 40% of participants with hepatitis B were required to undergo pre-employment testing, with 29% believing they lost employment opportunities due to their infection [bib_ref] Survey of hepatitis B knowledge and stigma among chronically infected patients and..., Huang [/bib_ref]. In the U.S., discrimination is experienced by healthcare students, causing denial of school admission or enrollment, restriction of clinical training or dismissal from an academic program [bib_ref] Protecting the Rights of Health Care Students Living With Hepatitis B Under..., Moraras [/bib_ref]. While hepatitis B discrimination has largely been reported anecdotally within a global context, this study aims to investigate and describe hepatitis B related discrimination, document discrimination occurring around the globe, and provide initial recommendations for addressing discrimination using key informant interviews. For the purposes of this study, discrimination is described by modifying the HIV-specific discrimination definitions within the United Nations, and where discrimination specific to hepatitis B is defined as the unjust, unfair, or prejudicial treatment of a person on the grounds of their hepatitis B status. In other words, being treated differently from others in the community because of being infected with hepatitis B. # Methods ## Data collection Purposive and snowball sampling were used to identify potential key informants to interview. First, individuals were classified as key informants by investigators as being community health leaders, public health scientists (N = 3), doctors (N = 3), researchers (N = 1) and patient advocates (N = 17), many of whom were also living with hepatitis B (N = 8) and actively work in hepatitis B in their respective communities (N = 16). All were over 18 years old. All key informants could speak to hepatitis B-specific challenges related to discrimination from their professional research, personal, or community-based organization experiences most participants had lived experience related to hepatitis B and are known within the viral hepatitis community as champions and key leaders. Several participants started their own community-based organizations to help others after experiencing a personal diagnosis with hepatitis B (N = 8) and actively work on addressing community health needs in their respective communities (N = 17). Participants were approached via email by study staff (CF and LM), informed of the study goals and were requested an interview using the zoom platform. In total, 34 people were emailed with an interview request, some individuals did not agree to participate due to not having enough information to contribute (N = 3), their role being clinically focused (N = 2), while some were unreachable (N = 12). Once an interview was scheduled by study staff (LM) the interviews were conducted by two trained facilitators (CF and LM) using a structured interview guide and using the Zoom platform. The structured interview guide was designed using literature on discrimination from other disease states, followed by expert review (Appendix). Participants were first asked to describe their work or experience as it relates to hepatitis B, describe challenges for people living with hepatitis B including marginalization in the communities the participant serves, if, why and how people with hepatitis B are marginalized, its' consequences, and recommendations to addressing this marginalization. At the end of each interview, participants were asked if there were other people we should speak to who had working knowledge of hepatitis B-specific discrimination or could speak to personal experiences with discrimination. Interviews took place between January 2021 to May 2021 and lasted 25 to 70 min in length. Each interview was conducted in the English language, electronically recorded and transcribed verbatim. Interviews were performed by study staff until saturation was reached and no new details were emerging from interviews related to hepatitis B discrimination. # Data analysis A directed content analysis approach was used to create the codebook and guide the organization of data. Codes were developed by review of the literature (a priori) and through line-by-line reading of a subsample of queries [bib_ref] Three approaches to qualitative content analysis, Hsieh [/bib_ref]. Each code was given a specific definition to ensure coding accuracy and to improve intercoder reliability. The codebook is provided as [fig_ref] Figure 1: The cycle of discrimination experienced by those living with hepatitis B and... [/fig_ref] and includes the themes and their frequencies of reference throughout the data analysis and coding process. All data transcripts (N = 17) were independently double coded by two members of the research team (LM, VW) to ensure coding accuracy. Inter-coder reliability (ICR) was assessed to identify coding discrepancies, and the analysis team met throughout the coding process to discuss and resolve discrepancies in coding. A kappa score of 0.80 or greater was considered good coding agreement. After coding was complete, the team reviewed the coding and organized findings into thematic categories. Data analysis used Nvivo version 12 (QRS International, Doncaster, Australia), a software program that facilitates organization of qualitative data. This study was approved by the Heartland Institutional Review Board with verbal consent obtained and recorded by all study participants prior to each interview. This study was performed in accordance with the ethical standards in the 1964 Declaration of Helsinki and its later amendments and comparable ethical standards. # Results Most study participants lived in hepatitis B endemic regions including Ethiopia, Nigeria (N = 2), Ghana, Uganda, Tanzania, Philippines (N = 2), Kiribati, China (N = 2), Mongolia, India, Turkey, and non-endemic regions including Australia, and the United States. Several overarching themes emerged related to experiences associated with discrimination and are depicted in [fig_ref] Figure 1: The cycle of discrimination experienced by those living with hepatitis B and... [/fig_ref]. The themes demonstrate specific experiences with discrimination, the psychological response, and the health outcomes associated with an unvirtuous cycle that impacts people's lives in various ways at various points in their life. Below we describe each element of the discrimination cycle: the causes or influences of discrimination, the experience and context of discrimination, and the outcomes of discrimination represented by quotes from all key informants. Strategies for addressing discrimination from the perspective of key informants is also included as recommendations towards addressing discrimination. ## Exposure to discrimination: psychological impact All key informants reported on the substantial quality of life implications and often poorer health outcomes resulting from hepatitis B discrimination. For some, these This study found psychological responses to discrimination including trauma, suicide, mental health challenges, depression, economic instability, and social isolation. One participant shared the broader impact of hepatitis B discrimination stating, "[they] find out that they have hepatitis, so the problem now is since for example, you studied up to college and you are now to go to work and help your family then suddenly you are being denied not even once but twice or thrice so it really demoralizing. " Another participant explained challenges for women in relation to childbearing. In most countries it is recommended that women are mandatorily tested for hepatitis B during pregnancy to reduce hepatitis B mother to child transmission during delivery. The psychological and practical impact of this diagnosis on women can be substantial in a context where clinical guidelines are not followed: "You hear people being forced to abort child, because during their pregnancy, there were found to be positive…these women and sometimes even by their own families they're disowned. " Hepatitis B-related discrimination was identified to affect people with hepatitis B from a very young age: "Even parents don't like to send their children to school because again they believe the child is infected and that they might not even live long. " The impact of the social marginalization of people with hepatitis B was seen to cause significant mental health challenges, with one participant describing that, "Because people are discriminating against them so some people can even kill, or suicide", while another noted that people with hepatitis B "definitely feel very lonely because they got disease and they get rejected by their beloved, and their friends, and colleagues. " ## Exposure to discrimination: individual impact stigma Stigma, both self-stigma or stigma internalized by people as a result of external or public stigma, and public or external social stigma [bib_ref] On the self-stigma of mental illness: stages, disclosure, and strategies for change, Corrigan [/bib_ref] were described as key factors contributing to discrimination. Many of the informants, particularly those with hepatitis B described some of the social contexts that affected them daily. One key informant noted, "One battle is inside the body that we are facing every day that effect[s] mental health or physical health and in society, we face discrimination, and you know disrespectful manners, we face stigma about the disease. For a hepatitis B positive patient, it's very difficult to survive in this world. " Another person with hepatitis B noted that people with hepatitis B were deeply affected by concerns related to transmission "people feel so much guilt about potentially transmitting the virus to your loved ones. " It was described how misunderstandings about the infection affect people's lives in many ways, including their intimate, romantic and familial relationships. One informant shared, '[people think] hepatitis is always a terminal illness, you will not live long so that is a barrier to most couples even getting married. They just feel people should not get involved with people like that. " Other's report being stigmatized because of their hepatitis B, one individual explained, "when I go for a lecture in the community to educate about hepatitis B, most of the time I faced discrimination that people fear to touch and they hesitate to again, like [to have] lunch together or they hesitate to handshake. " Overall, a variety of factors including common misconceptions, lack of knowledge about transmission and low awareness specific to hepatitis B contribute to stigma that in turn can progress towards discrimination. ## Lack of awareness Overall lack of awareness of hepatitis B among the public is a significant contributor to discrimination according to several key informants. One participant shared, "For me, I think the reason why hepatitis B patients are discriminated is because those who discriminate them in the first place, are not informed about hepatitis B. " Alternatively, one participant noted that increased knowledge would prevent discrimination within the workforce: "if people knew employers knew it needs blood contact to get hepatitis, they would not discriminate against people …but they say it is contagious, that it is airborne and it so …infectious so that's why they discriminated against people even in jobs. " The impact of the lack of awareness about hepatitis B had a significant impact on the development of community based responses to the infection with one informant describing the fundraising challenges result from lack of community awareness and the unvirtuous cycle this produces: "We have been trying as an organization to do (raise) awareness, but you as you might be aware, most of our funding is donor driven, and we don't have so many donors for hepatitis. " ## Misinformation Overall participants overwhelmingly described how the significant level of misinformation specific to hepatitis B transmission, vaccination, and treatment was a primary cause of discrimination. Several participants noted the impact of misinformation in relation to transmission and vaccination: Within healthcare schools (i.e. medical school, nursing school), limits on education for people with hepatitis B were described. One participant shared, "I received a[n] email that a girl got a rejection in medical college just because she was a hepatitis B positive. ", while another described, "I've heard students who had to meet with their [advisor], they were told they couldn't rotate through certain rotations like surgery. " In the Philippines, one participant reported, "We had a student who is a I think she was studying as a nurse, she was forced to drop out and transfer to another curriculum. " Another participant described how, "two students lost their medical acceptances just a couple weeks before matriculating: when they submitted their health forms and the letters written by the schools were just so mean they said, you are a threat to you yourself and others and you can't matriculate. " ## Employment based discrimination Employment based discrimination affecting people with hepatitis B was reported as occurring by all participants except those from Mongolia. Interviewees explained that people with hepatitis B were denied access to employment as a result of their hepatitis B status. One key stakeholder from India reported, "In India, every day we hear about the denied employment, just because of the hepatitis B positive. " Some participants also reported employers conducting random and unnecessary workplace-based hepatitis B screening. In Ghana for example, an interviewee explained, "I know about three guys that wrote me they work in a bank, and they did this random testing, and they were positive, and the result came out and the banks told them, they don't need their services anymore. Because of their hepatitis B status. " One informant from the Philippines noted consequences of pre-employment screening for hepatitis B. Key informants noted that in order to gain employment in many jobs, whether government or military, and even within some private industries screening for hepatitis B can take place and if someone tests positive for hepatitis B, they are denied employment despite their qualifications. This means that any regulation or law affecting employees cannot be used for redress. One individual described, "Most of the cases is pre-employment. When it comes to pre-employment, since you're not still technically an employee it's very hard to complain. I mean you can go to the Department of Labor and complain, but some would say that because you're not an employee, management has the prerogative to decide whether to accept you, so you don't really have a choice. " The settings in which employment-based testing was broad with one participant noting restrictions occurring within the hospitality industry, "When it comes to food-like company, producing food, hotel job, … people doing anything food … before you can get employment, you go for medical checkup. After medical checkup, if you are qualified, they will just call you… if you have any hepatitis B, they will disqualify. " Other forms of employment-based discrimination come from policing or military services in many countries with informants from Africa particularly, although not exclusively, noting this issue. A participant reported from Ghana, "recruitment into the military when they do that test and they are positive, they will discriminate against them they don't get employed because of they are hep B positive. Another participant shared their experience in Uganda, "In the Uganda police force and Uganda people defense forces… when they are advertised for recruitment before you go for the training, they subject you to the tests. So, once they get you with hepatitis B that is enough to kick you out. " Similar instances were described within Nigeria, "Within Nigeria, we have people that are Another participant from Ghana talked of the challenges associated with religiously-mandated pre-marital screening, and the impact of this testing on people with hepatitis B within this context, "Mostly just because this is organized by religious organizations for intending couples to get the screenings. And then, some of them lack this knowledge to know that if one partner is positive, then the other could be vaccinated so for some as soon as the one partner is positive, it becomes like an end to the relationship. " ## Recommendations Participants were asked to recommend what needed to occur to address hepatitis B related discrimination. A variety of suggestions were made including the development of comprehensive public education to address hepatitis B misinformation and lack of knowledge within the community, and among health care workers. Others reported the need for the systematic documentation of discrimination, and support for people living with and affected by hepatitis B with one participant noting, "If we have more data to showcase and tell the world what is happening, I believe that will go a long way. " To improve awareness a participant shared, "For the patient you need a lot of support some of these community driven activities to drive to increase awareness, to get people tested. And then that will probably make change happen." Most informants noted the importance of national policies to protect individuals living with hepatitis B from discrimination with one noting, "First of all, we need a national policy. " Another informant noted the experience of government response to the HIV epidemic and its success in developing systematic responses limiting testing, "Policy, what we need is really like HIV, they have a very specific policy that pertains to testing, so the employer cannot force you to take a test like that, so what we want is similar to HIV. " Another participant described the importance of partnership between government and people living with hepatitis B to effectively develop policy against discriminatory practices and explained, "When we are proposing those policy changes, how would you expect their policies to change if you're not involving the people who are watching on the ground in the community. " # Discussion While hepatitis B is a chronic manageable health condition, our data demonstrate that hepatitis B discrimination has a significant impact on the lives of those affected. Discrimination can occur in a cyclic nature at various points in an individual's life from education, to seeking employment, to marriage, to restrictions on entry, travel and stay in other countries. Hepatitis B discrimination impacts mental and physical health of those experiencing it firsthand and limits overall wellbeing, quality of life, can lead to poor health outcomes and avoidance of testing and management. Within the context of HIV, and where discrimination related to HIV is well documented and has been for several years, hepatitis B related discrimination is occurring in health care settings, reducing access to health services or engaging in quality health care, and findings from this study demonstrate a parallel between the experience of HIV and hepatitis B within health care as key informants describe discrimination contributing to limiting access to health care services for clinical management, including diagnosis. Future research should continue to explore and document the impact of discrimination within the context of health care services and specifically hepatitis B. Findings from this study illustrate sources of discrimination as a combination of lack of information, misinformation, and poor hepatitis B knowledge, which is consistent with previous research. Literature documents low knowledge related to transmission as a key contributor of discrimination within China specifically [bib_ref] Discrimination against hepatitis B carriers in China, Yang [/bib_ref]. Within this study, key informants describe the limited understanding of hepatitis B transmission and prevention within populations specifically leading to stigma and discrimination [bib_ref] Barriers to hepatitis B screening and prevention for African immigrant populations in..., Freeland [/bib_ref] [bib_ref] Knowledge, attitudes and practices among people with chronic hepatitis B attending a..., Mohamed [/bib_ref]. Hepatitis B is primarily transmitted in countries with rigorous vaccination programs through unprotected sex or unsafe injecting and is understood and described within health systems as a sexually transmitted infection [bib_ref] Hepatitis B virus infection, Liaw [/bib_ref] [bib_ref] Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg..., Ott [/bib_ref]. This framing can lead to further discrimination and stigma which was described by key informants as a significant challenge. Our study identified many consequences of discrimination and the clear lack of knowledge associated with hepatitis B. An identified downstream impact is the promotion of false cures and treatments sought by people living with hepatitis B in many countries. Similar findings have been identified within literature, with a commentary on discrimination in China highlighting the impact of advertising of alleged cures and remedies that contribute to the deep antipathy towards people living with hepatitis B [bib_ref] Discrimination against hepatitis B carriers in China, Yang [/bib_ref]. While many studies have demonstrated a clear gap in knowledge related to hepatitis B, efforts at every level should continue to work towards increasing knowledge and awareness of hepatitis B transmission, prevention, and diagnosis working to normalize conversation around hepatitis B to work towards reducing stigma and discrimination. Within interviews, herbalists or traditional medicine was reported in several countries including Nigeria, Uganda, Ghana, and China and works to convince people living with hepatitis B that they can falsely be cured and remove the cause of their discrimination. Interviewees reported that in desperation, people living with hepatitis B are determined to try any means to remove the virus from their body. Key informants described that herbal or traditional medicine can provide a "promised solution" to remove hepatitis B, reduce their financial costs, provide access to a medication, and remove the thing that is causing their discrimination. That individuals are seeking false cures and traditional medicine highlights the lack of information and knowledge associated with the disease among those directly impacted by it. Additionally, the possible impact of herbal and traditional medicines in the context of hepatitis B discrimination needs further exploration. Overall, hepatitis B discrimination was reported to affect health outcomes, mental health, contribute to economic and family instability, social isolation, suicide, loss of employment, and trauma. The impact of discrimination directly affects not only the individual but their families and relationships as seen with the described pre-marital testing in this study. It is important to further explore the context of pre-marital testing as authors anticipate it taking place in more than the countries explored within this study and of the consequences of this testing on people diagnosed with hepatitis B. The educational and employment discrimination that people with hepatitis B face directly affects their economic contributions to their families and future opportunities. Unfortunately, in many reported instances, employment discrimination occurs through pre-employment or pre-admission screening when individuals have no authority to appeal or protest limiting their options and forcing individuals to accept what the employer or institution decides. Further, key informants describe many individuals in sub-Saharan Africa and the Western Pacific seek employment opportunities as domestic workers in the Middle East and parts of Asia. As people seek these opportunities, they are screened for hepatitis B and denied employment opportunities if positive hepatitis B test occurs. Denial of employment or education as a result of hepatitis B infection is unethical, and contradicts World Health Organization hepatitis B guidance. There is no reason that people with hepatitis B should not be provided with the equal opportunities for employment, travel, and education and anything otherwise considered a human rights violation. As noted previously, most literature describing hepatitis B related stigma and discrimination comes from China or is related to people with Chinese ethnicity. Given the increasing global role of China and its economic support of many developing countries in Africa, Asia and the Pacific Islands, the social marginalization resulting from hepatitis B infection is being carried over with this support. It is normal in China for people with hepatitis B to be socially marginalized, with these norms affecting African students, and one participant from Africa noted "For African nations to send young people to universities to study in China now part of that practice is screening them for HIV, syphilis and all major infectious diseases including hepatitis B and C. Those who are found to be positive, are essentially deported. " The same scenario commonly was reported to occur for health professionals across all countries with the denial of [bib_ref] The experience of discrimination of individuals living with chronic hepatitis B in..., Han [/bib_ref] [bib_ref] Protecting the Rights of Health Care Students Living With Hepatitis B Under..., Moraras [/bib_ref]. Even with protections and policy in place, refusal of admission within nursing and medical schools still is reported to occur [bib_ref] Protecting the Rights of Health Care Students Living With Hepatitis B Under..., Moraras [/bib_ref]. There is a need to systematically document discrimination at local, country, regional and global levels and which should include the location, the causes of discrimination, where and how it is occurring at a local level. This documentation could be used to inform policy that ensures people with hepatitis B are provided protection and equal opportunity for employment, education, travel and immigration. In some countries policies are in place to protect against discrimination specific to employment and individuals living with hepatitis B. In the United States, for example, individuals with hepatitis B fall under protections with the Americans with Disabilities Act and therefore have protections in place legally against discrimination [bib_ref] Protecting the Rights of Health Care Students Living With Hepatitis B Under..., Moraras [/bib_ref]. This is not the case with militaries however, and even in the United States Military service, people living with hepatitis B are barred from deployment and have their careers put at risk due to infection. Within most countries, no transparent policies exist regarding hepatitis B despite reported discrimination occurring. In contrast to hepatitis B, most countries have policies in place against HIV discrimination, however, there is a need to make this policy broader and include diseases like hepatitis B to ensure discrimination is not tolerated. Additionally, the Global Health Sector Strategy on Viral Hepatitis emphasizes the need to address stigma and discrimination, but it is not written into the action plans of many countries. Future efforts should ensure that each country with elimination strategies include hepatitis B discrimination protections and policies. In addition to implementing policy to prevent discrimination, there should be redress for individuals to address and report the discrimination that they experience. In China it has been documented despite a robust anti-discrimination policy, the discrimination is still widely occurring largely due to lack of knowledge of the existing policy at the local level [bib_ref] Discrimination against hepatitis B carriers in China, Yang [/bib_ref]. Efforts should be made to ensure antidiscrimination policies trickle down to local and employer levels to ensure robust implementation. Of the few published studies on hepatitis B discrimination within China, all recommended comprehensive informational campaigns to improve awareness regarding modes of hepatitis B transmission,and prevention through vaccination [bib_ref] Discrimination against hepatitis B carriers in China, Yang [/bib_ref] [bib_ref] The experience of discrimination of individuals living with chronic hepatitis B in..., Han [/bib_ref]. The recommendations provided by our key informants is in line with the need for improved awareness in the general population. Finally, those that have personal experiences related to discrimination should be at the forefront of the discussion and provided opportunities to share their lived experiences of how discrimination has directly impacted their lives and livelihood. To effectively address discrimination and stigma occurring related to hepatitis B those individuals who have firsthand knowledge of its consequences should be part of the solutions. Overall, discrimination specific to hepatitis B plays a considerable role in the lives of those directly affected and can occur at various points in an individual's life. There is a need for more research, advocacy, and policy at all levels to effectively address discrimination, bring awareness to this issue, and work towards reducing its unjust consequences for those living with hepatitis B globally. # Limitations While this study provides valuable insight into hepatitis B discrimination and the consequences of that discrimination, there are important limitations that should be noted. First, while qualitative data collection methods provide rich, in-depth, experiential data, the data are limited in external validity (generalizability) and not representative of all experiences related to discrimination. While much of the sample identified as living with hepatitis B and had spent extensive time working in hepatitis B sectors, the sample size was small, only represented a small number of countries where hepatitis B is endemic, and future work should be done to gather and document additional data on hepatitis B discrimination globally. While issues of discrimination were noted by all informants, this is not to imply that hepatitis B related discrimination is an issue in all countries. Additionally, all interviews were conducted in English, limiting the global representativeness of the sample itself. # Conclusion Findings from our analysis demonstrate that hepatitis B discrimination has a significant impact on the lives of those infected. Discrimination can occur in a cyclic nature at various points in life from education, to seeking employment, to marriage, to restrictions on immigration entry, travel and stay in other countries. Hepatitis B discrimination has a substantial impact and affects an individual's mental and physical health and limits overall wellbeing, quality of life, can lead to poor health outcomes and avoidance of testing and management. Future research should continue to examine the consequences of hepatitis B discrimination using systematic documentation of it happening on the ground at local, country, regional and global levels. Ultimately, policy change is needed to ensure people with hepatitis B are provided protection and equal opportunity for employment, education, travel, and immigration. CF, project lead on the questionnaire development, data collection and analysis and initial draft and interpretation of the study results. LM, assisted in the development of the questionnaire, conducting interviews, transcription, and analysis of study. CF and LM both completed training in qualitative data collection techniques, including completion of graduate level courses. VC, assisted in transcription and analysis of the study as well as review of the manuscript. JW, assisted in the conceptualization, analysis, identification of key informants, editing and review of the manuscript. CC, assisted in the conceptualization, analysis, and identification of key informants, editing and review of the manuscript. The author(s) read and approved the final manuscript. # Funding No funding was granted for the research conducted or the publication of this manuscript. ## Availability of data and materials Transcripts related to this study are available to corresponding author upon a reasonable request. Transcripts will not include any identifiable information if data is requested. # Declarations Ethics approval and consent to participate This study was approved by the Heartland Institutional Review Board with verbal consent obtained and recorded by all study participants prior to each interview. This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments and comparable ethical standards. ## Consent for publication Not applicable. Overcoming Discrimination Use when individual describes current methods of overcoming stigma or discrimination or suggests strategies to overcome discrimination or stigma associated with hepatitis B ## 247 Pre-marital testing Use when the individual describes getting tested for hepatitis as part of the process before marriage Reason for Discrimination Use when the individual describes their experience or understanding related to why individuals are being discriminated against (Examples (from interviews so far) include lack of knowledge related to hepatitis B prevention and transmission) ## 147 Stigma Use when the person describes or mentions being treated differently due to their hepatitis B status 13 [fig] Figure 1: The cycle of discrimination experienced by those living with hepatitis B and outcomes as a result of this discrimination [/fig] [table] Table 1: Hepatitis B discrimination qualitative interview codebook Alternative Medicine Anytime a person is denied preventive care and resorts to using alternative medicine (ex: traditional medicine, herbalists, etc.) Cost Associated w Discrimination Use when/if an individual describes economic loss or gain that is effected by discrimination 8 55 Descriptive Information Use when an individual is referencing specific communities/countries/regions served. Or demographic information 15 44 Diagnosis Use if the individual describes how they were diagnosed with hepatitis B and how it impacted their life related to discrimination. (This code might not be applicable to all participants, but many have described their diagnosis which led to them personally being discriminated against) Education-Based Discrimination Use when an individual describes challenges attending any form of schooling due to their hepatitis B status. Could mean withdrawn from an institution due to their hepatitis B status 10 28 Employment Based Discrimination Use when individual describes discrimination that occurs within the setting of employment/ occupation. This can include screening requirements pre or post-employment 13 109 Immigration Discrimination Use when individual describes challenges associated with travel, visa access, or employment abroad in the context of living with hepatitis B Impact of Discrimination Use when individual describes the consequences, or effects that discrimination has on those living with hepatitis B or larger society as a whole. This can be either positive or negative impacts associated with discrimination. (Examples: mental health, suicide, isolation, job loss, other challenges) 14 181 Military Based Discrimination Use when individual refers to discrimination in the context of the military 5 14 Other forms of Discrimination Use when individual describes other forms of discrimination (Do not use if it relates to education, employment, immigration or military based discrimination) [/table]	None	https://equityhealthj.biomedcentral.com/track/pdf/10.1186/s12939-022-01677-6	None
5a106b6e223078410f60944f9307d98836829d41	pubmed	7th Brazilian Guideline of Arterial Hypertension: Chapter 8 - Hypertension and Associated Clinical Conditions	7th Brazilian Guideline of Arterial Hypertension: Chapter 8 - Hypertension and Associated Clinical Conditions ## Diabetes mellitus The association of AH and DM doubles the CV risk and has increased the AH prevalence, which is related to the elevation in overweight and obesity rates, as well as the increase in the elderly population. The incidence of AH in type 1 diabetic patients increases from 5%, at the age of 10 years, to 33%, at the age of 20 years, and to 70%, at the age of 40 years. 2 There is a strict relationship between the development of AH and the presence of albuminuria in that population. 3 That increase in the AH incidence can reach 75-80% in patients with diabetic kidney disease. Approximately 40% of patients with a recent diagnosis of DM have AH. In approximately 50% of type 2 diabetic patients, AH occurs before the development of albuminuria. All diabetic hypertensives are at high CV risk. In addition to all complementary tests recommended for hypertensives, diabetic patients require the search for urine albumin excretion, fundoscopic eye exam and assessment of probable postural hypotension, which can characterize the presence of autonomic nervous system dysfunction. The BP targets to be achieved are still controversial. However, there is recent consensus on a BP target < 130/80 mm Hg. (GR: IIb; LE: B). For the NPT of AH in diabetic individuals, all recommendations expressed in Chapter 6 apply. The therapeutic choice should be based on drug efficacy and tolerability. Considering that all diabetic patients are at high CV risk, the initial treatment includes the association of at least two drugs of different classes. In diabetic hypertensives without nephropathy, all antihypertensive drugs can be used. In the presence of diabetic nephropathy, however, RAAS inhibitors are preferred. 8 (GR: I; LE: A). Simultaneous use of ACEI and ARB should be avoided because of the risk of complications. 9,10 Although worsening insulin resistance, BB are useful for BP control in diabetic patients, especially when used in combinations to treat hypertensives with CAD or HF. 11 ## Metabolic syndrome Metabolic syndrome (MS) is characterized by the coexistence of CVRFs (low HDL-C, high triglycerides, AH and dysglycemia) either associated or not with central obesity (identified by the AC measure). The definitions of MS differ according to different entities. In 2009, those entities convened a task force to conciliate the different definitions of MS. 12 The criteria are described in Chapter 4 about CV risk stratification. The presence of AH in MS increases global CV risk. The initial treatment is based on lifestyle changes in association or not with the use of drugs. Because nonpharmacological measures isolated do not control BP, pharmacological treatment is required whenever BP ≥ 140/90 mm Hg. 13 There is no evidence of benefit in the use of antihypertensive agents for MS with normal BP levels. When dysglycemia is present, the preferred drugs to begin AH treatment in MS are RAAS blockers and CCB. Coronary artery disease The treatment of AH associated with CAD, which includes patients after myocardial infarction, with chest angina and myocardial revascularization, should preferably comprise BBs, ACEIs and ARBs, in addition to statins and acetylsalicylic acid. Beta-blockers have proven highly beneficial after AMI, especially within 2 years from the acute event. Similarly, ACEIs tested on that condition have also proven beneficial. In patients with chronic CAD and multiple RFs, such as AH, ACEIs have shown a favorable effect to reduce relevant clinical outcomes. 23 (GR: I; LE: A). Regarding BP target, it is worth considering the likelihood of the J curve effect, demonstrated in different studies, 24-27 in which the excessive BP reduction, mainly in DBP, can precipitate CV events in patients with obstructive CAD. Additional drugs to meet target BP (BP < 130/80 mm Hg) are CCBs and thiazide DIUs. 28 (GR: IIa; LE: B). ## Stroke Stroke is the most common manifestation of the vascular damage caused by AH. In transient ischemic attack (TIA), the neurologic deficit is solved in 24 hours, with no clinically detectable sequelae. ## Pharmacological treatment of ah in the patient with previous stroke Chronically, the effective antihypertensive therapy, maintaining BP < 130/80 mm Hg, has played a decisive role in the secondary prevention of all types of stroke and TIA. 29-35 (GR: IIa; LE: B). As long as BP is reduced, any antihypertensive drug can be used. 20,36,37 There is no clinical evidence allowing a definitive conclusion about the preferential use of ARBs as compared to other antihypertensive drugs for the secondary prevention of stroke. There is currently no evidence showing the effectiveness of beginning antihypertensive therapy for SBP < 140 mm Hg for patients with a previous stroke. (GR: III; LE: B). ## Chronic kidney disease For patients with that disease, BP reduction is the most effective measure to reduce CV risk and to slow kidney damage progression, regardless of the antihypertensive drug used. 38,39 (GR: I; LE: A). Special attention should be paid to patients with high albuminuria, which determines the unfavorable course of kidney disease 40 and increases CV risk. 41 (GR: IIa; LE: A). Elderly patients with renovascular disease, CAD and risk for postural hypotension often require customization of the antihypertensive treatment. 40 (GR: IIa; LE: C). Usually, BP levels < 130/80 mm Hg are recommended, especially for those with albuminuria > 30 mg/g of creatinine and diabetic patients. In such patients, maintaining BP < 130/80 mm Hg reduces albuminuria and the risk for stroke, but there is no evidence that it decreases CV events and mortality. 44,45 (GR: IIa; LE: A). However, it is controversial whether BP reduction to those levels is associated with better CKD course and with a reduction in mortality. 7,46,47 (GE: IIb; LE: B). The present guideline suggests the adoption of BP targets shown in Chart 1. The risk of hyperpotassemia should be considered, especially with the latter. The double RAAS block is controversial. The combination of ACEI with ARB 59,60 or of a renin inhibitor with ACEI or ARB 10 has resulted in more acute kidney damage and hyperpotassemia, leading to a ban on that strategy from nephrological practice. (GR: I; LE: A). However, in a recent study on adult polycystic kidney diseaseand a meta-analysis on diabetic patients with CKD, [bib_ref] Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes..., Palmer [/bib_ref] the association of IECA and ARB has delayed the course of nephropathy without causing severe hyperpotassemia and acute kidney damage. (GR: IIb; LE: B). However, the double RAAS block remains contraindicated. (GR: I; LE: A). The CCBs are effective, especially for combined use with ACEI or ARB, being associated with a reduction in CV events. [bib_ref] Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril..., Dahlof [/bib_ref] Other options include BBs, adrenergic inhibitors of central action, and, occasionally, direct acting vasodilators, such as minoxidil and hydralazine. ## Approach to stage 5 chronic kidney disease on kidney replacement therapy Most studies on AH in patients with CKD undergoing dialysis is based on measuring pre-dialysis BP levels. However, BP obtained in that way is known to have large variability, in addition to being usually overestimated, as it is underestimated when obtained after dialysis. [bib_ref] Pre-and postdialysis blood pressures are imprecise estimates of interdialytic ambulatory blood pressure, Agarwal [/bib_ref] [bib_ref] Age-related blood pressure patterns and blood pressure variability among hemodialysis patients, Rohrscheib [/bib_ref] In those patients, BP should be preferably measured outside the dialysis centers, in the interdialytic intervals. 67 (GR: IIa; LE: B). Home BP measures are more reproducible than those obtained before and after dialysis, have a fair association with both 44-hour ABPM and CV prognosis in patients undergoing dialysis. 68-70 (GR: IIa; LE: B). In addition, a randomized study has shown that therapeutic decisions based on HBPM associate with better interdialytic BP control assessed with 24-hour ABPM as compared to predialysis BP measurement.Regarding ABPM, it is worth noting that, although the 44-hour long exam is considered gold-standard for assessment of hemodialysis patients, its technical difficulties favor the use of 24-hour ABPM and home BP measurements. The association between BP and mortality in patients with CKD undergoing dialysis has a "U" distribution for SBP and DBP, thus, both elevated and reduced levels relate to bad prognosis. 70 (GR: IIa; LE: B). There are not enough studies to support with satisfactory level of evidence the diagnosis of AH in patients undergoing dialysis; however, the most accepted pre-and post-hemodialysis BP levels for that purpose are ≥ 140/90 mm Hg and ≥ 130/80 mm Hg, respectively. 70,71 (GR: IIa; LE: C). A study with 326 hemodialysis patients has associated better prognosis with mean SBP levels between 120 and 130 mm Hg, in HBPM, and between 110 and 120 mm Hg, in ABPM. [bib_ref] Blood pressure and risk of all-cause mortality in advanced chronic kidney disease..., Bansal [/bib_ref] Because, in that population, hypervolemia plays a major role in AH etiology, the therapeutic management should consider that variable, focusing the treatment on gradual control of "dry weight", via salt and water restriction, in addition to promoting adequate ultrafiltration during hemodialysis sessions. [bib_ref] Blood pressure in chronic kidney disease stage 5D -report from a Kidney..., Levin [/bib_ref] [bib_ref] DOQI clinical practice guidelines for cardiovascular disease in dialysis patients, K/Doqi Workgroup [/bib_ref] [bib_ref] Dialysis: normovolemia is a therapeutic target for hypertension, Horl [/bib_ref] [bib_ref] Dry-weight reduction in hypertensive hemodialysis patients (DRIP): a randomized, controlled trial, Agarwal [/bib_ref] (GR: IIa, LE: B). The choice of antihypertensive drugs should be individualized and based on characteristics, such as comorbidities, and drug's cardioprotective effect, intra-and interdialytic pharmacokinetic characteristics, and side effects. 71,72 (GR: IIa; LE: C). In kidney-transplanted patients, CCBs are a good option for AH treatment, because they are effective antihypertensive agents that antagonize arteriolar vasoconstriction caused by cyclosporine. [bib_ref] Calcium blockers inhibit cyclosporine A-induced hyperreactivity of vascular smooth muscle cells, Grześk [/bib_ref] The RAAS blockers can improve the transplant outcome in patients with increased urine albumin excretion. Diuretics, BBs, central action sympatholytic drugs and vasodilators can be used based on clinical judgement. [bib_ref] Antihypertensives for kidney transplant recipients: systematic review and meta-analysis of randomized controlled..., Cross [/bib_ref] [table] , 78: Chart 1 -Blood pressure targets for patients on conservative treatment, according to kidney disease etiology and albuminuria22. Gustafsson F, Kober L, Torp-Pedersen C, Hildebrandt P, Ottesen MM, Sonne B, et al. Long-term prognosis after acute myocardial infarction in patients with a history of arterial hypertension. TRACE study group. Eur Heart J. 42. Sarnak MJ, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease study. Ann Intern Med. 2005;142(5):342-51. 43. Appel LJ, Wright JT Jr, Greene T, Agodoa LY, Astor BC, Bakris GL, Cleveland WH, et al; AASK Collaborative Research Group. Intensive blood pressure control in hypertensive chronic kidney disease. N Engl J Med. 2010;363(10):918-29. 44. Bangalore S, Kumar S, Lobach I, Messerli FH. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and Bayesian random-effects meta-analyses of randomized trials. Circulation. 2011;123(24):2799-810. 45. Reboldi G, Gentile G, Angeli F, Ambrosio G, Mancia G, Verdecchia P. Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73,913 patients. J Hypertens. 2011;29(7):1253-69. 46. Upadhyay A, Earley A, ShaHaynes SM, Uhlig K. Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier. Ann Intern Med. 2011;154(8):541-8. 47. McBrien K, Rabi DM, Campbell N, Barnieh L, Clement F, Hemmelgarn BR, et al. Intensive and standard blood pressure targets in patients with type 2 diabetes mellitus systematic review and meta-analysis. Arch Intern Med. 2012;172(17):1296-303. 48. Verbeke F, Lindley E, Van Bortel L, Vanholder R, London G, Cochat P, et al. A European Renal Best Practice (ERBP) position statement on the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Blood Pressure in Non-dialysis-dependent Chronic Kidney Disease. Nephrol Dial Transplant. 2014;29(3):490-6. 49. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial 2008 (ALLHAT). JAMA. 2002;288(23):2981-97. Erratum in: JAMA. 2004;291(18):2196. 50. Rahman M, Ford CE, Cutler JA, Davis BR, Piller LB, Whelton PK, et al; ALLHAT Collaborative Research Group. Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR. Clin J Am Soc Nephrol. 2012;7(6):989-1002. 51. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829-40. 52. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355(9200):253-9. 53. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al; RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-9. 54. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870-8. 55. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069):1857-63. 56. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358(23):2433-46. [/table]	None	None	The association of AH and DM doubles the CV risk and has increased the AH prevalence, which is related to the elevation in overweight and obesity rates, as well as the increase in the elderly population.1 The incidence of AH in type 1 diabetic patients increases from 5%, at the age of 10 years, to 33%, at the age of 20 years, and to 70%, at the age of 40 years.2 There is a strict relationship between the development of AH and the presence of albuminuria in that population.3 That increase in the AH incidence can reach 75-80% in patients with diabetic kidney disease.4 Approximately 40% of patients with a recent diagnosis of DM have AH.5 In approximately 50% of type 2 diabetic patients, AH occurs before the development of albuminuria. All diabetic hypertensives are at high CV risk. In addition to all complementary tests recommended for hypertensives, diabetic patients require the search for urine albumin excretion, fundoscopic eye exam and assessment of probable postural hypotension, which can characterize the presence of autonomic nervous system dysfunction.6
c6fe67aee47c2d9a7dcf9deb0fdd615035f0870f	pubmed	European guidance for the diagnosis and management of osteoporosis in postmenopausal women	European guidance for the diagnosis and management of osteoporosis in postmenopausal women Guidance is provided in a European setting on the assessment and treatment of postmenopausal women at risk from fractures due to osteoporosis. 1. The operational definition of osteoporosis is based on the T-score for BMD assessed by DXA at the femoral neck or spine and is defined as a value for BMD 2.5 SD or more below the young female adult mean. 2. For clinical purposes, other sites and techniques can be used for diagnosis. 3. Low bone mass (osteopenia) should not be considered a disease category but is intended solely for purpose of epidemiological description. Risk factors for fragility fractures 1. Several factors contribute significantly to fracture risk over and above that provided by bone mineral density measurements. These include age, sex, low body mass index, ## 1. Recommendations should include a daily calcium intake of between 800 and 1200 mg and sufficient dietary protein, ideally achieved through dairy products. 2. A daily dose of 800 IU cholecalciferol should be advised for postmenopausal women at increased risk of fracture. ## Calcium supplementation is appropriate if the dietary in- take is below 800 mg/day, and vitamin D supplementation considered in patients at risk of, or showing evidence of, vitamin D insufficiency. 4. Regular weight-bearing exercise should be advised, tailored to the needs and abilities of the individual patient. ## A history of falls should be obtained in individuals at increased risk of fracture with further assessment and appropriate measures undertaken in those at increased risk. Pharmacological intervention in postmenopausal women 1. The oral bisphosphonates (alendronate, risedronate and ibandronate) may be used as initial treatments in the majority of cases. In women intolerant to oral bisphosphonates (or in those for whom they are contraindicated), intravenous bisphosphonates or denosumab provide the most appropriate alternatives, with raloxifene, or menopause hormone therapy as additional options. Teriparatide is preferentially recommended for patients at high risk of fracture. 2. Treatments should be reviewed after 3-5 years treatment with bisphosphonate. Fracture risk should be reassessed after a new fracture, regardless of when it occurs. The risk of new clinical and vertebral fractures increases in patients who stop treatment. 3. Withdrawal of denosumab therapy is associated with a rebound in vertebral fracture rate. Bisphosphonate therapy can be considered after discontinuation of denosumab. 4. There is little evidence to guide decision-making beyond 10 years of treatment and management options in such patients should be considered on an individual basis. Intervention thresholds for pharmacological intervention 1. The thresholds recommended for decision-making are based on probabilities of major osteoporotic and hip fracture derived from FRAX. These vary in different healthcare systems with variation in 'willingness to pay'. 2. Women aged over 65 years with a prior fragility fracture can be considered for treatment without the need for further assessment; BMD measurement may be felt more appropriate in younger postmenopausal women. 3. Age-dependent intervention thresholds provide clinically appropriate and equitable access to treatment and have been shown to be cost-effective. # Introduction In 1997 The European Foundation for Osteoporosis and Bone Disease (subsequently the International Osteoporosis Foundation; IOF) published guidelines for the diagnosis and management of osteoporosis [bib_ref] Guidelines for diagnosis and management of osteoporosis. The European Foundation for Osteoporosis..., Kanis [/bib_ref] , subsequently updated in 2008 [bib_ref] European guidance for the diagnosis and management of osteoporosis in postmenopausal women, Kanis [/bib_ref] and 2013 [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] by the IOF and European Society for Clinical and Economic Evaluation of Osteoporosis and Osteoarthritis (ESCEO). The scope of the present guideline is to review and update the assessment and diagnosis of osteoporosis, the therapeutic interventions available and the manner in which these can be used to develop management strategies for the prevention of fragility fracture in postmenopausal women. The guideline is intended for all healthcare professionals involved in the management of osteoporosis. Where available, systematic reviews, meta-analyses and randomised controlled trials have been used to provide the evidence base. The evidence base was updated using PubMed to identify systematic reviews and meta-analyses from January 2008 to December 2017. The recommendations in this guideline were endorsed by the Scientific Advisory Board of ESCEO and the Committee of Scientific Advisors and the Committee of National Societies of the IOF. The high societal and personal costs of osteoporosis pose challenges to public health and physicians, particularly since most patients with osteoporosis remain untreated. There is a large gap between the number of women who are treated compared to the proportion of the population that could be considered eligible for treatment based on their fracture risk. In the European Union (EU), it is estimated that there are and 18.44 million women who have a fracture probability that equals or exceeds that of a woman with a prior fragility as assessed by FRAX® (i.e. individuals at or above a 'fracture threshold'). On the conservative assumption that treatments are only given to patients at high risk, prescription data suggest that more than 57% of women at high risk do not receive bone-specific treatment [bib_ref] Osteoporosis in the European Union: medical management, epidemiology and economic burden. A..., Hernlund [/bib_ref]. Moreover, uptake of treatments for osteoporosis, particularly the bisphosphonates, has declined in recent years [bib_ref] The osteoporosis treatment gap, Kanis [/bib_ref] [bib_ref] Impact of the U.S. Food and Drug Administration's safety-related announcements on the..., Kim [/bib_ref]. In patients with fragility fractures, less than 20% of patients with a fragility fracture receive therapy to reduce future fracture within the year following fracture [bib_ref] Practice patterns in the diagnosis and treatment of osteoporosis after a fragility..., Elliot-Gibson [/bib_ref] [bib_ref] Fragility fractures and the osteoporosis care gap: an international phenomenon, Giangregorio [/bib_ref] [bib_ref] Closing the osteoporosis care gap: increased osteoporosis awareness among geriatrics and rehabilitation..., Haaland [/bib_ref]. Against this sobering background, the aim of this guidance is to stimulate a cohesive approach to the management of osteoporosis in Europe. The term guidance rather than guidelines is used, to avoid any prescriptive connotations since country-or regionspecific guidelines are now widely available in many European countries and continue to evolve. Rather, the guidance can inform the development of new guidelines or the revision of existing guidelines. Whilst focussed on a European perspective and on postmenopausal women, the principles may be of some assistance in other regions of the world and in men. ## Osteoporosis in europe Osteoporosis is defined as a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Although the diagnosis of the disease relies on the quantitative assessment of bone mineral density, which is a major determinant of bone strength, the clinical significance of osteoporosis lies in the fractures that arise. Because a variety of non-skeletal factors contribute to fracture risk [bib_ref] Prediction of osteoporotic fractures by postural instability and bone density, Nguyen [/bib_ref] , the diagnosis of osteoporosis by the use of BMD measurements is at the same time an assessment of a risk factor for the clinical outcome of fracture. For these reasons, there is a distinction to be made between the use of BMD for diagnosis and for risk assessment. Common sites for osteoporotic fracture are the spine, hip, distal forearm and proximal humerus. The remaining lifetime probability in women at the menopause of a fracture at any one of these sites exceeds that of breast cancer (approximately 12%), and the likelihood of a fracture at any of these sites is 40% or more in Western Europe [bib_ref] Long-term risk of osteoporotic fracture in Malmo, Kanis [/bib_ref] , a figure close to the probability of coronary heart disease. Fragility fractures are a major cause of morbidity in the population. Hip fractures cause acute pain and loss of function, and nearly always lead to hospitalisation. Recovery is slow, and rehabilitation is often incomplete, with many patients permanently institutionalised in nursing homes. Vertebral fractures may cause acute pain and loss of function but may also occur without serious symptoms. Vertebral fractures often recur, however, and the consequent disability increases with the number of fractures. Distal radial fractures also lead to acute pain and loss of function, but functional recovery is usually good or excellent. In 2010, it was estimated that 22 million women and 5.5 million men in the EU had osteoporosis using the diagnostic criterion of the WHO [bib_ref] Osteoporosis in the European Union: medical management, epidemiology and economic burden. A..., Hernlund [/bib_ref]. The number of new fractures in 2010 in the EU was estimated at 3.5 million, comprising approximately 610,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures (i.e. pelvis, rib, humerus, tibia, fibula, clavicle, scapula, sternum and other femoral fractures). Two thirds of all incident fractures occurred in women. Among people age 50 years or more who were still alive in 2010, 3.3 million individuals had sustained a hip fracture (prevalence of prior hip fracture). The corresponding number of men and women with prior clinical vertebral fractures was estimated at 3.5 million. Due to changes in population demography, the annual number of fragility fractures will rise from 3.5 million in 2010 to 4.5 million in 2025, corresponding to an increase of 28%. Remaining lifetime probability of a major osteoporotic fracture at the age of 50 and 80 years in men and women from Sweden [bib_ref] Long-term risk of osteoporotic fracture in Malmo, Kanis [/bib_ref] It is widely recognised that osteoporosis and the consequent fractures are associated with increased mortality, with the exception of forearm fractures [bib_ref] Population-based study of survival after osteoporotic fractures, Cooper [/bib_ref]. In the case of hip fracture, most deaths occur in the first 3-6 months following the event, of which 20-30% is causally related to the fracture event itself [bib_ref] The components of excess mortality after hip fracture, Kanis [/bib_ref]. In Sweden, the number of deaths that are causally related to hip fracture account for more than 1% of all deaths, somewhat higher than the deaths attributed to pancreatic cancer and somewhat lower than the deaths attributed to breast cancer [bib_ref] The components of excess mortality after hip fracture, Kanis [/bib_ref]. In 2010, the number of deaths in the EU that were causally related to fractures was estimated at 43,000. Approximately 50% of fracture-related deaths in women were due to hip fractures, 28% to clinical vertebral and 22% to other fractures. Corresponding proportions for men were 47, 39 and 14%, respectively [bib_ref] Osteoporosis in the European Union: medical management, epidemiology and economic burden. A..., Hernlund [/bib_ref]. The total health burden, measured in terms of lost qualityadjusted life years (QALYs), was estimated at 1,180,000 QALYs for the EU. Twice as many QALYs were lost in women compared to men. The majority of the QALYs lost were a consequence of prior fractures. In Europe, osteoporosis accounted for more disability and life years lost (DALYs) than rheumatoid arthritis, but less than osteoarthritis. With regard to neoplastic diseases, the burden of osteoporosis was greater than for all sites of cancer, with the exception of lung cancers [bib_ref] An estimate of the worldwide prevalence and disability associated with osteoporotic fractures, Johnell [/bib_ref]. The cost of osteoporosis, including pharmacological intervention in the EU in 2010, was estimated at €37 billion. Costs of treating incident fractures represented 66% of these costs, pharmacological prevention 5% and long-term fracture care 29%. Excluding cost of pharmacological prevention, hip fractures represented 54% of the costs, 'other fractures' represented 39% and vertebral and forearm fractures represented 5 and 1%, respectively [bib_ref] Osteoporosis in the European Union: medical management, epidemiology and economic burden. A..., Hernlund [/bib_ref]. Assigning a QALY the value of 2xGDP, the total value of QALYs lost in 2010 was estimated at €61.4 billion. ## Bone mineral measurements The objectives of bone mineral measurements are to provide diagnostic criteria, prognostic information on the probability of future fractures, and a baseline on which to monitor the natural history of the treated or untreated patient. Bone mineral density (BMD) is the amount of bone mass per unit volume (volumetric density), or per unit area (areal density), and both can be measured in vivo by densitometric techniques. A wide variety of techniques is available to assess bone mineral that are reviewed elsewhere . The most widely used are based on X-ray absorptiometry in bone, particularly dual energy X-ray absorptiometry (DXA). Other techniques include quantitative ultrasound (QUS), quantitative computed tomography (QCT) applied both to the appendicular skeleton and to the spine, peripheral DXA, digital X-ray radiogrammetry, radiographic absorptiometry and other radiographic techniques. Other important determinants of bone strength for both cortical and trabecular bone include macroand microarchitecture (e.g. cross-sectional moment of inertia, hip axis length, cortical thickness, finite element analysis, trabecular bone score, cortical porosity) . DXA is the most widely used bone densitometric technique. It is versatile in the sense that it can be used to assess bone mineral density/bone mineral content of the whole skeleton as well as specific sites, including those most vulnerable to fracture. Areal density (g/cm 2 ) rather than a true volumetric density (g/cm 3 ) is measured since the scan is two dimensional. Areal BMD accounts for about two thirds of the variance of bone strength as determined in vitro on isolated bones, such as the vertebral body or proximal femur. DXA can also be used to visualise lateral images of the spine from T4 to L4 to detect fractures of the vertebral bodies . Vertebral fracture assessment (VFA) may improve fracture risk evaluation, since many patients with vertebral fracture may not have a BMD T-score classified as osteoporosis. This procedure involves less radiation and is less expensive than a conventional X-ray examination but performs comparably to traditional radiographs . Whereas whole body bone, fat and lean mass can also be measured using DXA, these measurements are useful for research, but they do not assist in the routine diagnosis or assessment of osteoporosis. The performance characteristics of many measurement techniques have been well documented . For the purpose of risk assessment and for diagnosis, a characteristic of major importance is the ability of a technique to predict fractures. This is traditionally expressed as the increase in the relative risk of fracture per standard deviation unit decrease in bone mineral measurement-termed the gradient of risk. # Limitations of bmd There are a number of technical limitations in the general application of DXA for diagnosis, which should be recognised [bib_ref] Fundamentals and pitfalls of bone densitometry using dual-energy X-ray absorptiometry (DXA), Watts [/bib_ref]. The presence of osteomalacia, a complication of poor nutrition in the elderly, will underestimate total bone matrix because of decreased mineralisation of bone. Osteoarthrosis or osteoarthritis at the spine or hip are common in the elderly, and contribute to the density measurement, but not necessarily to skeletal strength. Heterogeneity of density due to osteoarthrosis, previous fracture or scoliosis can often be detected on the scan and in some cases excluded from the analysis. Some of these problems can be overcome with adequately trained staff and rigorous quality control. The T-score describes the number of SDs by which the BMD in an individual differs from the mean value expected in young healthy individuals. The operational definition of osteoporosis is based on the T-score for BMD assessed at the femoral neck and is defined as a value for BMD 2.5 SD or more below the young female adult mean (T-score less than or equal to − 2.5 SD) [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] [bib_ref] Updated data on proximal femur bone mineral levels of US adults, Looker [/bib_ref] [bib_ref] A reference standard for the description of osteoporosis, Kanis [/bib_ref]. The Z-score describes the number of SDs by which the BMD in an individual differs from the mean value expected for age and sex. It is mostly used in children and adolescents [bib_ref] Osteoporosis in young adults: pathophysiology, diagnosis, and management, Ferrari [/bib_ref]. The reference range recommended by the IOF, ESCEO, ISCD, WHO and NOF for calculating the T-score [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] [bib_ref] Updated data on proximal femur bone mineral levels of US adults, Looker [/bib_ref] [bib_ref] A reference standard for the description of osteoporosis, Kanis [/bib_ref] [bib_ref] An update on the diagnosis and assessment of osteoporosis with densitometry. Committee..., Kanis [/bib_ref] is the NHANES III reference database for femoral neck measurements in women aged 20-29 years [bib_ref] Updated data on proximal femur bone mineral levels of US adults, Looker [/bib_ref]. Note that the diagnostic criteria for men use the same female reference range as that for women. This arises fortuitously because for any age and BMD at the femoral neck, the risk of hip fracture or a major osteoporotic fracture is approximately the same in men and women [bib_ref] Hip fracture prediction in elderly men and women: validation in the Rotterdam..., Laet [/bib_ref] [bib_ref] Predictive value of BMD for hip and other fractures, Johnell [/bib_ref] [bib_ref] Towards a diagnostic and therapeutic consensus in male osteoporosis, Kanis [/bib_ref]. On GE Healthcare bone densitometers, there is an option for T-scores for men to be given relative to either the male or female reference range in DXA readouts. However, the T-score cannot be used interchangeably with different techniques and at different sites, since the prevalence of osteoporosis and proportion of individuals allocated to any diagnostic category would vary, as does the risk of fracture [bib_ref] An update on the diagnosis and assessment of osteoporosis with densitometry. Committee..., Kanis [/bib_ref]. These considerations have led to the adoption of the femoral neck as the reference site [bib_ref] An update on the diagnosis and assessment of osteoporosis with densitometry. Committee..., Kanis [/bib_ref] , but do not preclude the use of other sites and technologies in clinical practice, though it should be recognised that the information derived from the T-score will differ from that provided by BMD at the femoral neck. ## Measurement of multiple skeletal sites A number of guidelines favour the concurrent use of BMD at the proximal femur and at the lumbar spine for patient assessment. Patients are defined as having osteoporosis on the basis of the lower of two T-scores [bib_ref] Official positions of the international society for clinical densitometry, Lewiecki [/bib_ref]. The prediction of fracture is, however, not improved overall using multiple sites [bib_ref] Does the combination of two BMD measurements improve fracture discrimination?, Blake [/bib_ref] [bib_ref] The use of multiple sites for the diagnosis of osteoporosis, Kanis [/bib_ref] [bib_ref] Single-site vs multisite bone density measurement for fracture prediction, Leslie [/bib_ref]. Selection of patients on the basis of a minimum value from two or more tests will, however, increase the number of patients selected. The same result can be achieved by less stringent criteria for the definition of osteoporosis, by defining osteoporosis, for example, as a T-score of < − 2.0 SD rather than < − 2.5 SD. Notwithstanding, the measurement of more than one site can aid in the assessment of individuals (discussed below). ## Low bone mass (osteopenia) It is recommended that diagnostic criteria be reserved for osteoporosis and that low bone mass (osteopenia) should not be considered a disease category. ## Prevalence of osteoporosis Because the distribution of BMD in the young healthy population is normally distributed and bone loss occurs with advancing age, the prevalence of osteoporosis increases with age and thus depends on the demography of the population. The prevalence of osteoporosis in the 27 countries of the EU in men and women is shown in [bib_ref] Osteoporosis in the European Union: medical management, epidemiology and economic burden. A..., Hernlund [/bib_ref]. Approximately 21% of women aged 50-84 years are classified as having osteoporosis accounting for more than 22 million women in these countries. These data assume that the distribution of femoral neck BMD is the same in these index countries. There may be small differences in the age-and sex-specific BMD in different European countries as well as within countries. If so, these differences in BMD are relatively small [bib_ref] Assessing the impact of osteoporosis on the burden of hip fractures, Odén [/bib_ref] and insufficient to account for the observed differences in fracture rates (see below). ## Risk factors for fracture BMD Assessment of BMD has provided a pivotal determinant of fracture risk and many guidelines have used BMD thresholds to determine whether treatments should be recommended. Intervention thresholds have ranged from Tscores of − 3 SD to − 1.5 SD depending on the clinical context, the country or on health economic factors. The use of bone mass measurements for prognosis depends upon accuracy. Accuracy in this context is the ability of the measurement to predict fracture. In general, all densitometric techniques have high specificity but low sensitivity, which varies with the cutoff chosen to designate high risk. At the age of 50 years, for example, the proportion of women with osteoporosis who will fracture their hip, spine or forearm or proximal humerus in the next 10 years (i.e. positive predictive value) is approximately 45%. Despite this, the overall detection rate for these fractures (sensitivity) is low and 96% of fractures at the spine, hip, forearm or proximal humerus will occur in women without osteoporosis [bib_ref] Ten-year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds, Kanis [/bib_ref]. The low sensitivity is one of the reasons why widespread population-based screening with BMD is not widely recommended in women at the time of the menopause. Many cross-sectional and prospective population studies indicate that the risk for fracture increases by a factor of 1.5 to 3.0 for each standard deviation decrease in bone mineral density . There are, however, significant differences in the performance of different techniques at different skeletal sites. In addition, the performance depends on the type of fracture that one wishes to predict [bib_ref] Bone density at various sites for prediction of hip fractures. The Study..., Cummings [/bib_ref]. For example, BMD assessments by DXA to predict hip fracture are more predictive when measurements are made at the hip rather than at the spine or forearm . For the prediction of hip fracture, the gradient of risk provided by hip BMD in a meta-analysis is 2. . In other words, the fracture risk increases 2.6-fold for each SD decrease in hip BMD. Thus, an individual with a Z-score of − 3 SD at the hip would have a 2.6 3 or greater than 15-fold higher risk than an individual of the same age with a Z-score of 0. Where the intention is to predict any osteoporotic fracture, the commonly used techniques are comparable: The risk of fracture increases approximately 1.5-fold for each standard deviation decrease in the measurement so that an individual with a measurement of 3 standard deviations below the average value for age would have a 1.5 3 or greater than 3fold higher risk than an individual with an average BMD. Note that the risk of fracture in individuals with an average BMD is lower than the average fracture risk, since fracture risk is a convex function of BMD. The performance characteristics of quantitative ultrasound are similar. Most studies suggest that measurements of broadband ultrasound attenuation or speed of sound at the heel are associated with a 1.5-to 2-fold increase in risk for each standard deviation decrease in the measured variable [bib_ref] Quantitative ultrasound of the heel and fracture risk assessment: an updated meta-analysis, Moayyeri [/bib_ref]. Comparative studies indicate that these gradients of risk are very similar to those provided by peripheral assessment of bone mineral density at appendicular sites by absorptiometric techniques to predict any osteoporotic fracture . Unlike DXA, however, the long-term predictive value wanes with time. Note also that the WHO criteria for the diagnosis of osteoporosis cannot be applied to ultrasound results. ## Clinical risk factors A large number of risk factors for fracture have been identified [bib_ref] Risk factors for hip fracture in white women. Study of Osteoporotic Fractures..., Cummings [/bib_ref] [bib_ref] Assessment of the risk of post-menopausal osteoporosis using clinical factors, Ribot [/bib_ref] [bib_ref] Predictors of hip fractures in elderly men, Poor [/bib_ref]. For the purposes of improving risk assessment, interest lies in those factors that contribute significantly to fracture risk over and above that provided by bone mineral density measurements or age [bib_ref] Diagnosis of osteoporosis and assessment of fracture risk, Kanis [/bib_ref]. A good example is age. For any BMD, fracture risk is much higher in the elderly than in the young [bib_ref] Age and bone mass as predictors of fracture in a prospective study, Hui [/bib_ref]. This is because age contributes to risk independently of BMD. At the threshold for osteoporosis (T-score = − 2.5 SD), the 10-year probability of hip fracture ranges 5-fold in women from Sweden depending on age [bib_ref] Ten-year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds, Kanis [/bib_ref]. Thus, the consideration of age and BMD together increases the range of risk that can be identified. Over the past few years, a series of meta-analyses have been undertaken to identify additional clinical risk factors that could be used in case-finding strategies, with or without the use of BMD. There are a number of factors to be considered in the selection of risk factors for case finding. Of particular importance in the setting of primary care is the ease with which they might be used. For a globally applicable tool, the chosen risk factors should also be valid in an international setting and their predictive value documented over time. A further and critical consideration is the reversibility of risk, i.e. is there evidence that the risk identified by a risk factor is amenable to therapeutic intervention (reversibility of risk-not reversible risk). Age is an example of an irreversible risk factor, but the risk of fracture identified by age has reversibility. The risk factors that are used for clinical assessment with FRAX are summarised in [fig_ref] Table 4: Clinical risk factors used for the assessment of fracture probability [12] Centre... [/fig_ref] [bib_ref] Predictive value of BMD for hip and other fractures, Johnell [/bib_ref] [bib_ref] A family history of fracture and fracture risk: a meta-analysis, Kanis [/bib_ref] [bib_ref] A meta-analysis of prior corticosteroid use and fracture risk, Kanis [/bib_ref] [bib_ref] Alcohol intake as a risk factor for fracture, Kanis [/bib_ref] [bib_ref] Smoking and fracture risk: a meta-analysis, Kanis [/bib_ref] [bib_ref] Body mass index as a predictor of fracture risk: a meta-analysis, Laet [/bib_ref] [bib_ref] Patients with prior fractures have an increased risk of future fractures: a..., Klotzbuecher [/bib_ref] [bib_ref] A meta-analysis of previous fracture and subsequent fracture risk, Kanis [/bib_ref]. Each of these risk factors has been shown to identify reversibility of risk [bib_ref] FRAXwith and without bone mineral density, Kanis [/bib_ref]. In the case of causes of secondary osteoporosis, the increase in fracture risk is presumed to be mediated by low BMD. The exceptions are glucocorticoid exposure and rheumatoid arthritis for which risks have been identified that are independent of BMD. A further candidate is type 2 diabetes mellitus since recent evidence suggests an important independent risk [bib_ref] Association of BMD and FRAX score with risk of fracture in older..., Schwartz [/bib_ref] [bib_ref] FRAX underestimates fracture risk in patients with diabetes, Giangregorio [/bib_ref] [bib_ref] Perspective: diabetes and bone, Leslie [/bib_ref]. It should be noted that falls risk is not included in [fig_ref] Table 4: Clinical risk factors used for the assessment of fracture probability [12] Centre... [/fig_ref] , though it has been used in some risk engines [bib_ref] Development of prognostic nomograms for individualizing 5-year and 10-year fracture risks, Nguyen [/bib_ref] [bib_ref] Predicting risk of osteoporotic fracture in men and women in England and..., Hippisley-Cox [/bib_ref] , since the risk of fracture that is identified may not be associated with reversibility of risk. For example, patients selected on the basis of risk factors for falling may respond less to agents that preserve bone mass than those selected on the basis of low BMD [bib_ref] Effect of risedronate on the risk of hip fracture in elderly women...., Mcclung [/bib_ref]. Biochemical assessment of fracture risk Bone markers are increased after the menopause, and in several studies the rate of bone loss varies according to the marker value [bib_ref] The use of biochemical markers of bone turnover in osteoporosis. Committee of..., Delmas [/bib_ref]. Thus, a potential clinical application of biochemical indices of skeletal metabolism is in assessing fracture risk. The IOF and International Federation of clinical Chemistry and Laboratory Medicine (IFCC) have proposed two of several markers as reference analytes in the prediction of fracture risk; serum procollagen type I N propeptide (s-PINP) and serum Cterminal cross-linking telopeptide of type I collagen (s-CTX) as markers of bone formation and bone resorption, respectively [bib_ref] Markers of bone turnover for the prediction of fracture risk and monitoring..., Vasikaran [/bib_ref]. A meta-analysis of prospective studies showed a significant association between s-PINP and the risk of fracture. The hazard ratio per SD increase in s-PINP (gradient of risk; GR) was 1.23 (95% CI 1.09-1.39) for men and women combined unadjusted for bone mineral density. There was also a significant association between s-CTX and risk of fracture GR = 1.18 (95% CI 1.05-1.34) unadjusted for bone mineral density. For the outcome of hip fracture, the association between s-CTX and risk of fracture was slightly higher, 1.23 (95% CI 1.04-1.47) [bib_ref] A meta-analysis of reference markers of bone turnover for prediction of fracture, Johansson [/bib_ref]. Thus, there is a modest but significant association between these markers and the future risk of fractures. Currently, there are efforts by IFCC and IOF to harmonise markers of bone turnover, which, if successful, may promote markers of bone turnover for fracture risk prediction [bib_ref] Clinical usefulness of bone turnover marker concentrations in osteoporosis, Morris [/bib_ref]. ## Trabecular bone score Trabecular bone score (TBS) is a recently developed analytical tool that performs novel grey-level texture measurements on lumbar spine DXA images, and thereby captures information relating to trabecular microarchitecture. Low TBS is consistently associated with an increase in both prevalent and incident fractures that is partly independent of both clinical risk factors and areal BMD at the lumbar spine and proximal femur [bib_ref] Trabecular bone score (TBS) as a new complementary approach for osteoporosis evaluation..., Harvey [/bib_ref]. It can thus be used as an adjunct to BMD measurements and is a software option for densitometers. Studies including a metaanalysis have shown an incremental improvement in fracture prediction when lumbar spine TBS is used in combination with FRAX variables [bib_ref] A metaanalysis of trabecular bone score in fracture risk prediction and its..., Mccloskey [/bib_ref] [bib_ref] Clinical utility of using lumbar spine trabecular bone score to adjust fracture..., Martineau [/bib_ref] [bib_ref] Spine bone texture assessed by trabecular bone score (TBS) predicts osteoporotic fractures..., Leslie [/bib_ref] [bib_ref] Adjusting fracture probability by trabecular bone score, Mccloskey [/bib_ref] [bib_ref] Lumbar spine texture enhances 10-year fracture probability assessment, Leslie [/bib_ref]. In the meta-analysis, when additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (Gradient of risk = 1.32, 95% CI 1.24-1.41) [bib_ref] A metaanalysis of trabecular bone score in fracture risk prediction and its..., Mccloskey [/bib_ref]. The Ten-year probability of hip fracture in women from Sweden according to age and T-score for femoral neck BMD [bib_ref] Ten-year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds, Kanis [/bib_ref] , with kind permission from Springer Science and Business Media adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX® hip fracture probability GR 2.25 vs. 2.22). Thus, TBS is a predictor of fracture risk independently of FRAX and supports the use of TBS to adjust for FRAX probability. Adjustment of FRAX probabilities [bib_ref] A metaanalysis of trabecular bone score in fracture risk prediction and its..., Mccloskey [/bib_ref] is available from a dedicated web site (https://www.sheffield.ac.uk/TBS/ CalculationTool.aspx) or via the FRAX web site (see [fig_ref] Figure 2: Screen page for input of data and format of results in the... [/fig_ref]. TBS may also have a role in the assessment of fracture risk in some causes of secondary osteoporosis (e.g. diabetes, hyperparathyroidism and glucocorticoid-induced osteoporosis). ## Vertebral fracture assessment The majority of vertebral fractures do not come to medical attention and thus remain undiagnosed [bib_ref] What proportion of incident radiographic vertebral deformities is clinically diagnosed and vice..., Fink [/bib_ref]. Moderate or severe vertebral fractures, even when asymptomatic, are strong risk factors for subsequent fracture at the spine and other skeletal sites [bib_ref] Vertebral fractures predict subsequent fractures, Melton Lj 3rd [/bib_ref] [bib_ref] Mild morphometric vertebral fractures predict vertebral fractures but not non-vertebral fractures, Johansson [/bib_ref]. Vertebral fracture assessment should therefore be considered in high-risk individuals, using either lateral lumbar and thoracic spine radiographs or lateral spine DXA imaging. Vertebral fracture assessment should be considered in postmenopausal women if there is a history of ≥ 4 cm height loss, kyphosis, recent or current long-term oral glucocorticoid therapy, or a BMD T-score ≤ − 2.5. It should also be considered in individuals with a history of non-vertebral fracture. ## Assessment of fracture risk Whereas assessment guidelines have traditionally been based on BMD, its limitations have stimulated the development of risk engines that integrate several risk factors for fracture [bib_ref] Overview of fracture prediction tools, Kanis [/bib_ref]. These include the Garvan fracture risk calculator [bib_ref] Development of prognostic nomograms for individualizing 5-year and 10-year fracture risks, Nguyen [/bib_ref] , QFracture® [bib_ref] Predicting risk of osteoporotic fracture in men and women in England and..., Hippisley-Cox [/bib_ref] and FRAX® [bib_ref] FRAX and the assessment of fracture probability in men and women from..., Kanis [/bib_ref]. Of these, FRAX has been the most extensively used. Since its release in 2008, models have been made available for 64 countries in 34 languages, covering 80% of the world population. The website (http://www.shef.ac.uk/FRAX) receives approximately 6 million visits annually and in 2012-2013 calculations arose from 173 countries [bib_ref] Worldwide uptake of FRAX, Kanis [/bib_ref]. This underestimates considerably the uptake of FRAX because the website is not the sole portal for the calculation of fracture probabilities. For example, FRAX is available in BMD equipment, on smartphones, and, in some countries, through hand-held calculators. FRAX has been incorporated into more than 80 guidelines worldwide [bib_ref] A systematic review of intervention thresholds based on FRAX, Kanis [/bib_ref]. # Introduction to frax FRAX® is a computer-based algorithm that calculates the 10year probability of a major fracture (hip, clinical spine, humerus or wrist fracture) and the 10-year probability of hip fracture. Fracture risk is calculated from age, body mass index and dichotomized risk factors comprising prior fragility fracture, parental history of hip fracture, current tobacco smoking, ever use of long-term oral glucocorticoids, rheumatoid arthritis, other causes of secondary osteoporosis and alcohol consumption [fig_ref] Figure 2: Screen page for input of data and format of results in the... [/fig_ref]. Femoral neck BMD can be optionally input to enhance fracture risk prediction [bib_ref] The use of clinical risk factors enhances the performance of BMD in..., Kanis [/bib_ref]. Fracture probability is computed taking both the risk of fracture and the risk of death into account. The use of clinical risk factors in conjunction with BMD and age improves sensitivity of fracture prediction without adverse effects on specificity [bib_ref] The use of clinical risk factors enhances the performance of BMD in..., Kanis [/bib_ref]. Fracture probability differs markedly in different regions of the world [bib_ref] International variations in hip fracture probabilities: implications for risk assessment, Kanis [/bib_ref]. The heterogeneity in Europe is shown in . For this reason, FRAX is calibrated to those countries where the epidemiology of fracture and death is known (currently 64 countries). # Limitations of frax The limitations of FRAX have been reviewed recently [bib_ref] A systematic review of intervention thresholds based on FRAX, Kanis [/bib_ref]. The FRAX assessment takes no account of dose-responses for several risk factors. For example, two prior fractures carry a much higher risk than a single prior fracture [bib_ref] Interpretation and use of FRAX in clinical practice, Kanis [/bib_ref]. Doseresponses are also evident for glucocorticoid exposure [bib_ref] Use of oral corticosteroids and risk of fractures, Van Staa [/bib_ref] , cigarette smoking [bib_ref] Smoking and fracture risk: a meta-analysis, Kanis [/bib_ref] and alcohol intake [bib_ref] Alcohol intake as a risk factor for fracture, Kanis [/bib_ref]. Since it is not possible to accommodate all such scenarios with the FRAX algorithm, these limitations should temper clinical judgement. A history of falls is a significant risk factor for fracture but is not incorporated into the FRAX model. Moreover, a significant risk of fracture remains after adjusting for FRAX [bib_ref] Falls predict fractures independently of FRAX probability: a meta-analysis of the Osteoporotic..., Harvey [/bib_ref]. However, the incorporation of falls into FRAX is problematic for several reasons. First, at the time of the release of FRAX, existing falls data were not of adequate quality, including the heterogeneous construct of questions on falls. Second, falls risk is inherently taken into account in the algorithm, though not as an input variable [bib_ref] FRAX predicts incident falls in elderly men. Findings from MrOs Sweden, Harvey [/bib_ref]. Thus, the fracture probability given for any combination of risk factors assumes that the falls risk is that observed (but not documented) in the cohorts used to construct FRAX. Third, the interrelationship of falls risk with the other FRAX variables has been inadequately explored on an international basis. Fourth, the relationship between the risk variable and mortality needs to be accounted for, but there are no data available. These technical problems aside, risk assessment tools are intended to identify a risk that is amenable to a therapeutic intervention. However, falls as a risk variable do not consistently pass the test of reversibility of risk [bib_ref] Effect of risedronate on the risk of hip fracture in elderly women...., Mcclung [/bib_ref] [bib_ref] Strategies to prevent falls and fractures in hospitals and care homes and..., Oliver [/bib_ref] [bib_ref] Can fall risk be incorporated into fracture risk assessment algorithms: a pilot..., Kayan [/bib_ref] [bib_ref] Interventions for preventing falls in older people living in the community, Gillespie [/bib_ref] , a necessary feature of any risk variable used in tools to direct interventions [bib_ref] FRAXwith and without bone mineral density, Kanis [/bib_ref] [bib_ref] Primary care-relevant interventions to prevent falling in older adults: a systematic evidence..., Michael [/bib_ref]. To address some of these and other limitations, relatively simple arithmetic adjustments have been proposed, which can be applied to conventional FRAX estimates of probabilities of hip fracture and a major fracture to adjust the probability assessment with knowledge of: Ten-year probability (%) of a major osteoporotic fracture in women from different European countries. BMI set to 25 kg/m 2 . Data from http://www.shef.ac.uk/ FRAX high, moderate, and low exposure to glucocorticoids [bib_ref] Guidance for the adjustment of FRAX according to the dose of glucocorticoids, Kanis [/bib_ref] -see below concurrent data on lumbar spine BMD [bib_ref] Spine-hip discordance and fracture risk assessment: a physician-friendly FRAX enhancement, Leslie [/bib_ref] [bib_ref] Impact of femoral neck and lumbar spine BMD discordances on FRAX probabilities..., Johansson [/bib_ref] -see below trabecular bone score [bib_ref] A metaanalysis of trabecular bone score in fracture risk prediction and its..., Mccloskey [/bib_ref] [bib_ref] Adjusting fracture probability by trabecular bone score, Mccloskey [/bib_ref] [bib_ref] Lumbar spine texture enhances 10-year fracture probability assessment, Leslie [/bib_ref] [bib_ref] Risk-equivalent T-score adjustment using lumbar spine trabecular bone score (TBS): the Manitoba..., Leslie [/bib_ref] hip axis length [bib_ref] Adjusting hip fracture probability in men and women using hip axis length:..., Leslie [/bib_ref] falls history [bib_ref] on behalf of the FRAX Position Conference members (2011) Can falls and..., Masud [/bib_ref] immigration status [bib_ref] Is the Swedish FRAX model appropriate for immigrants to Sweden?, Johansson [/bib_ref] type 2 diabetes [bib_ref] Perspective: diabetes and bone, Leslie [/bib_ref] [bib_ref] Comparison of methods for improving fracture risk assessment in diabetes: the Manitoba..., Leslie [/bib_ref] With regard to glucocorticoids,summarises the manner in which FRAX estimates of probabilities of hip fracture and a major osteoporotic fracture can be adjusted with knowledge of the dose of glucocorticoids [bib_ref] Guidance for the adjustment of FRAX according to the dose of glucocorticoids, Kanis [/bib_ref]. For example, a woman aged 60 years from the UK taking glucocorticoids for rheumatoid arthritis (no other risk factors and BMI of 24 kg/m 2 ) has a 10year probability for a major fracture of 13%. If she is on a higher than average dose of prednisolone (> 7.5 mg daily), then the revised probability should be 15% (13 × 1.15). Lumbar spine BMD is frequently measured by DXA and indeed is incorporated into several clinical guidelines. It is the site favoured for monitoring treatment and there is thus much interest in the implications for FRAX of measurements at the lumbar spine, since there are situations where there is a large discordance in the T-score at different skeletal sites in individuals for whom the use of this information will enhance the accuracy for the characterisation of risk, particularly if they lie close to an intervention threshold. The impact of spine/ femoral neck T-score discordance has been explored in a large BMD-referral population from Manitoba, Canada. There was approximately a 10% change in fracture risk for each unit of Tscore discordance [bib_ref] Spine-hip discordance and fracture risk assessment: a physician-friendly FRAX enhancement, Leslie [/bib_ref]. On this basis, the clinician may increase/decrease FRAX estimate for a major fracture by one-tenth for each rounded T-score difference between the lumbar spine and femoral neck. Additionally, FRAX values have been shown to be largely unaffected by socioeconomic status [bib_ref] FRAX provides robust fracture prediction regardless of socioeconomic status, Brennan [/bib_ref] , variation in body composition [bib_ref] Estimated lean mass and fat mass differentially affect femoral bone density and..., Leslie [/bib_ref] and a concern that treatment might invalidate the interpretation of FRAX appears misplaced [bib_ref] Does osteoporosis therapy invalidate FRAX for fracture prediction?, Leslie [/bib_ref]. ## Assessment of risk At present there is no universally accepted policy for population screening in Europe to identify patients with osteoporosis or those at high risk of fracture. With the increasing development of effective agents and price reductions, this view may change, particularly for elderly people [bib_ref] A randomized controlled trial of screening in the community to reduce fractures..., Shepstone [/bib_ref] [bib_ref] Management of patients with high baseline hip fracture risk by FRAX reduces..., Mccloskey [/bib_ref]. In the absence of a screening policy, patients are identified opportunistically using a case-finding strategy on the finding of a previous fragility fracture or the presence of significant risk factors. The risk factors that are used for clinical assessment, summarised in [fig_ref] Table 4: Clinical risk factors used for the assessment of fracture probability [12] Centre... [/fig_ref] , may be used but in principle any risk factor that alerts the physician to the possibility of osteoporosis is a candidate. Examples are height loss (> 4 cm) [bib_ref] Number and type of vertebral deformities: epidemiological characteristics and relation to back..., Ismail [/bib_ref] , thoracic kyphosis and the many other less well-characterised causes of secondary osteoporosis. A general approach to risk assessment is shown in 4 [bib_ref] Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds..., Kanis [/bib_ref]. The process begins with the assessment of fracture probability and the categorisation of fracture risk on the basis of age, sex, BMI and the clinical risk factors. On this information alone, some patients at high risk may be considered for treatment without recourse to BMD testing. For example, many guidelines in Europe [bib_ref] Guidelines for diagnosis and management of osteoporosis. The European Foundation for Osteoporosis..., Kanis [/bib_ref] [bib_ref] A systematic review of intervention thresholds based on FRAX, Kanis [/bib_ref] [bib_ref] Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds..., Kanis [/bib_ref] recommend treatment in the absence of information on BMD in women with a previous fragility fracture (a prior vertebral or hip fracture in North America) [bib_ref] Scientific Advisory Council of Osteoporosis Canada (2010) 2010 Clinical practice guidelines for..., Papaioannou [/bib_ref] [bib_ref] Clinician's guide to prevention and treatment of osteoporosis, Cosman [/bib_ref]. Many physicians would also perform a BMD test, but frequently this is for reasons other than to decide on intervention, for example, as a baseline to monitor treatment. There will be other instances where the probability is so low that a decision not to treat can be made without BMD. Thus, not all individuals require a BMD test. The size of the intermediate category in will vary in different countries. In countries that provide reimbursement for DXA, this will be a large category, whereas in a large number of countries with limited or no access to densitometry, the size of the intermediate group will necessarily be small. In other countries (e.g. the UK), where provision for BMD testing is sub-optimal [bib_ref] Requirements for DXA for the management of osteoporosis in Europe, Kanis [/bib_ref] , the intermediate category will lie between the two extremes. ## Intervention thresholds Whereas BMD provides the cornerstone for the diagnosis of osteoporosis, the use of BMD alone is less than optimal as an intervention threshold for several reasons. Firstly, the fracture risk varies markedly in different countries, but the T-score varies only by a small amount. Secondly, the significance of any given T-score to fracture risk in women from any one country depends on age (see and the presence of clinical risk factors. Intervention thresholds will also be determined in part by the cost and benefits of treatment. In addition, since the T-score for BMD decreases with age, a T-score of, say, − 2.5 SD becomes less significant as a risk indicator with age [bib_ref] Intervention thresholds and the diagnosis of osteoporosis, Kanis [/bib_ref] [bib_ref] Incidence of hip fracture in Romania and the development of a Romanian..., Grigorie [/bib_ref] [bib_ref] FRAX-vs. T-score-based intervention thresholds for osteoporosis, Johansson [/bib_ref]. Thus, with advancing age, the difference in the probability of fracture between the general population and those with a T-score of − 2.5 SD diminishes and indeed, from the age of 78 years in the USA and 81 years onwards in Kuwait, the fracture probability becomes progressively lower than that of the age and sex-matched individuals . In other words, a T-score of − 2.5 SD becomes a diminishing risk factor with advancing age. In contrast, a prior fragility fracture is a highly significant risk factor at all ages (see . The use of FRAX in clinical practice demands a consideration of the fracture probability at which to intervene, both for treatment (an intervention threshold) and for BMD testing (assessment thresholds). Many approaches have been used to set intervention thresholds with FRAX [bib_ref] A systematic review of intervention thresholds based on FRAX, Kanis [/bib_ref]. The thresholds used have varied since they depend critically on local factors such as reimbursement issues, health economic assessment, willingness to pay for health care in osteoporosis and access to DXA. For this reason, it is not possible or desirable to recommend a unified intervention strategy. The strategy given below draws on that most commonly applied in Europe in the context of postmenopausal osteoporosis but takes account that access to DXA varies markedly in different European countries [bib_ref] Requirements for DXA for the management of osteoporosis in Europe, Kanis [/bib_ref]. Since many guidelines recommend that women with a prior fragility fracture may be considered for intervention without the necessity for a BMD test (other than to monitor treatment), a prior fracture can be considered to carry a sufficient risk that treatment can be recommended. For this reason, the intervention threshold in women without a prior fracture can be set at the age-specific fracture probability equivalent to women with a prior fragility fracture [bib_ref] Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds..., Kanis [/bib_ref] and therefore rises with age, for example, from a 10-year probability of 8 to 33% in the UK [bib_ref] Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and..., Compston [/bib_ref]. In other words, the intervention threshold is set at the 'fracture threshold'. This is the approach to intervention thresholds proposed or used in Belgium, Finland, France, Italy, Ireland, Poland, Romania, Russia, Spain, Switzerland and by the National Osteoporosis Guideline Group (NOGG) in the UK [bib_ref] A systematic review of intervention thresholds based on FRAX, Kanis [/bib_ref] [bib_ref] Clinical guidelines for the prevention and treatment of osteoporosis: summary statements and..., Tarantino [/bib_ref] and European guidelines for glucocorticoid-induced osteoporosis [bib_ref] A framework for the development of guidelines for the management of glucocorticoid-induced..., Lekamwasam [/bib_ref]. Incidentally, the same intervention threshold is applied to men, since the effectiveness and costeffectiveness of intervention in men is broadly similar to that in women for equivalent risk [bib_ref] Towards a diagnostic and therapeutic consensus in male osteoporosis, Kanis [/bib_ref] [bib_ref] Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and..., Compston [/bib_ref] [bib_ref] Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis, Kanis [/bib_ref]. The approach used has been well validated and the intervention strategy shown to be cost-effective [bib_ref] Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds..., Kanis [/bib_ref] [bib_ref] Optimization of BMD measurements to identify high risk groups for treatment-a test..., Johansson [/bib_ref] [bib_ref] BMD, clinical risk factors and their combination for hip fracture prevention, Johansson [/bib_ref] [bib_ref] The cost-effectiveness of alendronate in the management of osteoporosis, Kanis [/bib_ref]. Using this criterion, the intervention threshold will vary from country to country because the population risks (of fracture and death) vary [bib_ref] International variations in hip fracture probabilities: implications for risk assessment, Kanis [/bib_ref] [bib_ref] International survey on willingness-to-pay (WTP) for one additional QALY gained: what is..., Shiroiwa [/bib_ref]. The fracture probability in women with a prior fracture in the five major EU countries is shown in . Probabilities are highest in the UK and lowest in Spain. The [bib_ref] Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds..., Kanis [/bib_ref] , with kind permission from Springer Science and Business Media difference between countries is most evident at younger ages and becomes progressively less with advancing age. For the purposes of illustration in this guidance, an aggregate value is chosen. Thus, for the countries shown in , the mean probability of a major fracture in women with a prior fracture is 6.3% between the ages of 50 and 55 years. The mean is weighted for population size in each age interval in each country. The probability rises with age and can be taken as an intervention threshold. Countries with much higher or lower probabilities may wish to develop intervention thresholds based on countryspecific risks as has been adopted in several countries in Europe and elsewhere. Note that the example in uses the probability of a major osteoporotic fracture to determine an intervention threshold fracture. In addition to the 10-year probability of a major osteoporotic fracture, intervention thresholds can be based on the 10-year probability of hip fracture. Either or both thresholds can be used as recommended in the recent NOGG guidance. ## Assessment thresholds for bmd testing The assessment strategy outlined in requires the determination of assessment thresholds for making recommendations for the measurement of BMD. There are, in principle, two assessment thresholds [bib_ref] Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds..., Kanis [/bib_ref] : A threshold probability below which neither treatment nor a BMD test should be considered (lower assessment threshold). A threshold probability above which treatment may be recommended irrespective of BMD (upper assessment threshold). Most countries adopt a case-finding strategy where individuals with clinical risk factors are identified for further assessment. For this scenario, the lower assessment threshold can be set to exclude a requirement for BMD testing in women without clinical risk factors, as given in previous European guidelines [bib_ref] Guidelines for diagnosis and management of osteoporosis. The European Foundation for Osteoporosis..., Kanis [/bib_ref] [bib_ref] European guidance for the diagnosis and management of osteoporosis in postmenopausal women, Kanis [/bib_ref] [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] [bib_ref] A framework for the development of guidelines for the management of glucocorticoid-induced..., Lekamwasam [/bib_ref]. The probability equivalents are given in . In a few countries, population-based assessment with BMD is recommended (Germany and France in Europe). In such cases, there would be no lower assessment threshold. An upper threshold can be chosen to minimise the probability that a patient characterised to be at high risk on the basis of clinical risk factors alone would be reclassified to be at low risk with additional information on BMD [bib_ref] Optimization of BMD measurements to identify high risk groups for treatment-a test..., Johansson [/bib_ref]. In the UK, the upper assessment threshold was set at 1.2 times the intervention threshold [bib_ref] Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds..., Kanis [/bib_ref]. The rationale is that reclassification of risk with the addition of a BMD test (from high risk to low risk and vice versa) is high when fracture probabilities estimated without BMD are close to the intervention threshold and the likelihood of reclassification decreases the further away the probability estimate is from the intervention threshold [bib_ref] Optimization of BMD measurements to identify high risk groups for treatment-a test..., Johansson [/bib_ref]. When patients have a fracture probability that is 20% or more than the intervention threshold, almost no individuals will be reclassified (from high to low risk) when probabilities are recomputed with the addition of BMD to FRAX [bib_ref] Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis, Kanis [/bib_ref] [bib_ref] Cost-effective osteoporosis treatment thresholds: the United States perspective, Tosteson [/bib_ref] [bib_ref] Fracture risk assessment without bone density measurement in routine clinical practice, Leslie [/bib_ref] [bib_ref] High fracture probability with FRAX usually indicates densitometric osteoporosis: implications for clinical..., Leslie [/bib_ref]. Thus, a quotient of 1.2 is applied to the intervention, illustrated for the European example in . An attraction of the approach is that efficient use is made of BMD testing. Intervention thresholds as set by FRAX-based 10-year probability (%) of a major osteoporotic fracture equivalent to women with a previous fracture (no other clinical risk factors, a body mass index of 24 kg/m 2 and without BMD). The lower assessment thresholds set by FRAX is based on the 10-year probability (%) of a major osteoporotic fracture equivalent to women without clinical risk factors (a body mass index of 24 kg/m 2 and without BMD). The upper assessment threshold is set at 1.2 times the intervention threshold. Population weighted mean values for the five major EU countries. From [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] , with kind permission from Springer Science and Business Media The 10-year probability of a major osteoporotic fracture by age in women with a prior fracture and no other clinical risk factors in the five major EU countries as determined with FRAX (version 3.5). Body mass index set to 24 kg/m 2 without BMD. From [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] , with kind permission from Springer Science and Business Media ## Application of probability thresholds The application of these assessment thresholds depends critically on the availability (and reimbursement) of densitometry, which vary from country to country. It has been estimated that the requirements to service osteoporosis amount to approximately 11 DXA units/millions of the general population [bib_ref] Requirements for DXA for the management of osteoporosis in Europe, Kanis [/bib_ref] , though this estimate probably requires updating to take account of population demography. The availability of DXA falls above this estimate in a minority of European countries . The large variation in resources for BMD testing demand the consideration of three assessment scenarios that depend on the access to central densitometry. ## Unrestricted access to densitometry Where resources for BMD testing are adequate, BMD tests can be undertaken in women with any clinical risk factors as shown in . Treatment is recommended where fracture probability exceeds the intervention threshold. Note that the lower assessment threshold is set as equivalent to women without clinical risk factors (see above). In those countries where screening of women without risk factors is recommended, there would be no lower assessment threshold. An additional option is to recommend treatment in women with a prior fragility fracture without recourse to BMD (though BMD might be undertaken to monitor treatment). The assessment algorithm is summarised in Box 1. BMD tests are recommended in all postmenopausal women with a clinical risk factor. ## Limited access to densitometry Several countries must take a parsimonious approach to the use of BMD. The guidance recommends that postmenopausal women with a prior fragility fracture may be considered for intervention without the necessity for a BMD test. In women without a fragility fracture but with one or more other CRF, the intervention threshold is set at the age-specific fracture probability equivalent to women with a prior fragility fracture and BMD testing recommended in those in whom fracture probability lies between the upper and lower assessment threshold as described above [bib_ref] Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds..., Kanis [/bib_ref] - Fracture risk should be assessed in postmenopausal women with one or more clinical risk factor where assessment would influence management. - Women with a prior fragility fracture might be considered for treatment without the need for further risk assessment although BMD measurement may sometimes be appropriate. - In women without a prior fragility fracture, the 10-year probabilities of a major osteoporotic fracture (clinical spine, hip, forearm or humerus) and hip fracture should be determined using FRAX without BMD. In the absence of other clinical considerations, men and women with probabilities below the assessment threshold can be reassured. - Those with probabilities above the assessment threshold can be considered for testing with BMD using DXA and their fracture probability reassessed. Thereafter, women with probabilities above the intervention threshold should be considered for treatment. From [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] , with kind permission from Springer Science and Business Media This approach, adapted to the common EU thresholds shown in , is illustrated in . The assessment algorithm is summarised in Box 2. ## No access or patchy access to densitometry In countries with very limited or no access to DXA, FRAX can be used without BMD. For the purpose of risk assessment, a characteristic of major importance is the ability of a technique to predict fractures, traditionally expressed as the increase in relative risk per standard deviation (SD) unit decrease in risk score-termed the gradient of risk. The gradient of risk with FRAX is shown in [fig_ref] Table 7: Gradients of risk [/fig_ref] for the use of the clinical risk factors alone, femoral neck BMD and the combination [bib_ref] The use of clinical risk factors enhances the performance of BMD in..., Kanis [/bib_ref]. The use of clinical risk factors alone provides a GR that lies between 1.4 and 2.1, depending upon age and the type of fracture predicted. These gradients are comparable to the use of BMD alone to predict fractures [bib_ref] Predictive value of BMD for hip and other fractures, Johnell [/bib_ref]. For example, for the prediction of any osteoporotic fracture, the GR at the age of 70 years was 1.5 with femoral neck BMD [32]. With peripheral BMD, the gradient of risk is somewhat, though not significantly lower (GR = 1.4/SD; 95% CI = 1.3-1.5/SD). These data suggest that clinical risk factors alone are of value and can be used, therefore, in the many countries where DXA facilities are insufficient (Box 3). The rationale for the use of FRAX in the absence of access to BMD or limited access has been recently reviewed [bib_ref] FRAXwith and without bone mineral density, Kanis [/bib_ref] [bib_ref] A systematic review of intervention thresholds based on FRAX, Kanis [/bib_ref]. Briefly, most of the risk factors incorporated within FRAX contribute independently from BMD to fracture risk, but are not totally independent of BMD; thus, higher risk is associated with lower underlying BMD [bib_ref] Optimization of BMD measurements to identify high risk groups for treatment-a test..., Johansson [/bib_ref] [bib_ref] High fracture probability with FRAX usually indicates densitometric osteoporosis: implications for clinical..., Leslie [/bib_ref]. In several countries (Finland, Lebanon, Romania, UK), there is a link between the FRAX web site to an independent site that plots the FRAX output against the intervention thresholds for that country and facilitates treatment decisions. The NOGG web site in the UK is widely used (https://www. sheffield.ac.uk/NOGG/) [bib_ref] Access to fracture risk assessment by FRAX® and linked National Osteoporosis Guideline..., Mccloskey [/bib_ref]. ## Alternative approaches to intervention thresholds The NOGG guidelines in the UK have recently been revised [bib_ref] FRAX-based assessment and intervention thresholds-an exploration of thresholds in women aged 50..., Mccloskey [/bib_ref]. The intervention threshold up to age 70 years is set at a risk equivalent to that associated with a prior fracture, in line with current clinical practice, and therefore rises with age. At age 70 years and above, however, a fixed threshold is applied [bib_ref] FRAX-based assessment and intervention thresholds-an exploration of thresholds in women aged 50..., Mccloskey [/bib_ref]. The alternative thresholds equilibrate fracture risk, particularly hip fracture risk, in those with or without prior fracture selected for treatment and reduce BMD usage at older ages. This modification from the age of 70 years is not necessarily applicable to other countries and would require the impact of changes to be evaluated. An alternative approach to intervention thresholds has been applied in Germany, which uses a country-specific algorithm to estimate the 10-year incidence (not probability) of fracture [bib_ref] Investigation and management of osteoporosis in aged trauma patients: a treatment algorithm..., Neuerburg [/bib_ref]. Several guidelines in Europe that use FRAX have recommended that a fixed probability threshold be used as an intervention threshold. Examples include a 20% 10-year probability of a major fracture in several European countries and a 15% probability in Sweden [bib_ref] A systematic review of intervention thresholds based on FRAX, Kanis [/bib_ref]. Many utilise a threshold probability of 20% for a major osteoporotic fracture many of which also mention a hip fracture probability of 3% as an alternative intervention threshold. In nearly all instances, no rationale is provided other than the fact that this was the BOX 2 Assessment of fracture risk with FRAX with limited access to BMD - Fracture risk should be assessed in postmenopausal women with one or more clinical risk factor where assessment would influence management. - Women with a prior fragility fracture should be considered for treatment without the need for further risk assessment although BMD measurement may sometimes be appropriate, particularly in younger postmenopausal women. - In women without a prior fragility fracture, the 10-year probabilities of a major osteoporotic fracture (clinical spine, hip, forearm or humerus) and hip fracture should be determined using FRAX without BMD. In the absence of other clinical considerations, men and women with probabilities below the lower assessment threshold can be reassured and those with probabilities above the upper assessment threshold can be considered for treatment. - Those with probabilities above the lower assessment threshold but below the upper assessment threshold can be considered for testing with BMD using DXA and their fracture probability reassessed. Thereafter, women with probabilities above the intervention threshold should be considered for treatment. Assessment guidelines based on the 10-year probability of a major osteoporotic fracture (%). The dotted line denotes the intervention threshold. Where assessment is made in the absence of BMD, a BMD test is recommended for individuals where the probability assessment lies in the orange region. The intervention threshold and BMD assessment thresholds used are those derived from . From [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] , with kind permission from Springer Science and Business Media threshold used by the National Osteoporosis Foundation of the USA [bib_ref] Clinician's guide to prevention and treatment of osteoporosis, Cosman [/bib_ref]. The rationale for a fixed threshold in the USA was based on the fracture probability at which intervention becomes cost-effective in the USA and is, therefore, not relevant for any other country. The impact of using a fixed intervention threshold is shown in for postmenopausal women in the UK. At high thresholds e.g. > 20% fracture probability 17% of postmenopausal women would be eligible for treatment. A problem that arises is that very few women under the age of 60 years would ever attain this threshold. On the other hand, if a less stringent threshold were chosen, say 5%, then nearly all women at the age of 50 years and above would exceed this threshold. Both scenarios could be justified on health economic criteria in the UK, but both are counterintuitive to clinical practice. Critically, economic criteria should not be used to set intervention thresholds but, more appropriately, to validate the implementation of clinically driven intervention thresholds [bib_ref] Cost-effective but clinically inappropriate: new NICE intervention thresholds in osteoporosis (Technology Appraisal..., Harvey [/bib_ref]. ## Other assessment models As well as the FRAX tool, other fracture risk calculators are available online which include the Garvan fracture risk calculator and QFracture® [bib_ref] Development of prognostic nomograms for individualizing 5-year and 10-year fracture risks, Nguyen [/bib_ref] [bib_ref] Predicting risk of osteoporotic fracture in men and women in England and..., Hippisley-Cox [/bib_ref]. A fundamental difference between these risk models and FRAX is that the parameters of risk differ (incidence vs. probabilities) so that comparative data are not readily interpreted [bib_ref] Pitfalls in the external validation of FRAX, Kanis [/bib_ref]. In FRAX, fracture probability is computed taking both the risk of fracture and the risk of death into account. This is important because some of the risk factors affect the risk of death as well as the fracture risk. Examples include increasing age, sex, low BMI, low BMD, use of glucocorticoids and smoking. ## Effectiveness of risk assessment strategies Until recently, the effectiveness of risk-assessment strategies in which samples of the general population might be evaluated for risk factors and BMD estimation to derive individual estimates of absolute fracture risk, with targeting of anti-osteoporosis therapy on the basis of these estimates, remained uncertain. The publication of the MRC SCOOP trial (SCreening of Older wOmen for the Prevention of fractures) provides strong support for such a strategy [bib_ref] A randomized controlled trial of screening in the community to reduce fractures..., Shepstone [/bib_ref]. This seven-centre pragmatic randomised controlled trial with 5-year follow-up included 11,580 women aged 70-85 years, who were randomised to receive a care algorithm including FRAX and drug targeting (n = 6233) or usual primary care for osteoporosis based on opportunistic case finding (n = 6250). Women were recruited from 100 UK general practices, and the principle outcome measures were major osteoporotic, hip and all fractures. Screening reduced the incidence of hip fractures (0.72, 0.59-0.89, [bib_ref] Management of patients with high baseline hip fracture risk by FRAX reduces..., Mccloskey [/bib_ref]. The screening algorithm resulted in a pronounced increase in the use of anti-osteoporosis medication, and greater compliance with therapy, over the period of follow-up. These findings strongly support a systematic, community-based screening programme of fracture risk in older women. In addition, the strategy appears to be cost-effective [bib_ref] The costeffectiveness of screening in the community to reduce osteoporotic fractures in..., Turner [/bib_ref]. ## General management ## Mobility and falls Immobilisation causes of bone loss. Immobilised patients when confined to bed may lose as much bone in a week than they would otherwise lose in a year. Weight-bearing exercise forms an integral component of osteoporosis management [bib_ref] Exercise for preventing and treating osteoporosis in postmenopausal women, Howe [/bib_ref] [bib_ref] Systematic review of the exercise effect on bone health: the importance of..., Sañudo [/bib_ref] [bib_ref] Prescribing physical activity for the prevention and treatment of osteoporosis in older..., Mcmillan [/bib_ref]. The amount of weight-bearing exercise that is optimal for skeletal health in patients with osteoporosis is not known. Physiotherapy is an important component of rehabilitation after fracture. At all times, exercises to improve muscle strength and balance may The right-hand panel shows the proportion of the total postmenopausal population that exceed a given threshold. From [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] , with kind permission from Springer Science and Business Media prevent falls by restoring confidence and coordination, and additionally maintain bone mass by stimulating bone formation and decreasing bone resorption. Such measures can be coupled with a programme to reduce the likelihood of falls in those at high risk [bib_ref] Exercise for improving balance in older people, Howe [/bib_ref] [bib_ref] Exercise to prevent falls in older adults: an updated systematic review and..., Sherrington [/bib_ref]. Modifiable factors such as correcting decreased visual acuity, reducing consumption of medication that alters alertness and balance, and improving the home environment (slippery floors, obstacles, insufficient lighting, handrails) are important measures aimed at preventing falls [bib_ref] Comparisons of interventions for preventing falls in older adults: a systematic review..., Tricco [/bib_ref]. Fall prevention exercise interventions have been shown to reduce the risk of injurious falls and of fracture [bib_ref] The effect of fall prevention exercise programmes on fall induced injuries in..., El-Khoury [/bib_ref]. Whole body vibration may be beneficial for falls risk reduction, but without effect on BMD or fracture risk [bib_ref] Effect of whole-body vibration exercise in preventing falls and fractures: a systematic..., Jepsen [/bib_ref]. Some randomised trials have shown that wearing hip protectors can reduce hip fracture risk, particularly in the elderly living in nursing homes. A metaanalysis of well-conducted randomised controlled trials has, however, cast some doubt about the anti-fracture efficacy of this preventive measure [bib_ref] Do hip protectors decrease the risk of hip fracture in institutional and..., Sawka [/bib_ref] [bib_ref] Effectiveness of hip protectors for preventing hip fractures in elderly people: systematic..., Parker [/bib_ref] [bib_ref] Efficacy of a HIP protector to prevent HIP fracture in nursing home..., Kiel [/bib_ref] [bib_ref] Hip protectors for preventing hip fractures in older people, Gillespie [/bib_ref]. ## Nutrition At every stage of life, adequate dietary intakes of key bone nutrients such as calcium, vitamin D and protein contribute to bone health and reduce thereby the risk of osteoporosis and of fracture later in life [bib_ref] Nutritional aspect of bone health, Rizzoli [/bib_ref]. Dietary sources of calcium are the preferred option and calcium supplementation should only be targeted to those who do not get sufficient calcium from their diet and who are at high risk for osteoporosis. The Recommended Nutrient Intakes are 800-1000 mg of calcium and 800 IU of vitamin D per day in men and women over the age of 50 years. Combined calcium and vitamin D supplements in a daily dose of 0.5-1.2 g and 400-800 IU, respectively, are generally recommended in patients receiving bone protective therapy, since most randomised controlled trial evidence for the efficacy of interventions is based on co-administration of the agent with calcium and vitamin D supplements [bib_ref] The role of calcium supplementation in healthy musculoskeletal ageing: an expert consensus..., Harvey [/bib_ref]. Calcium and vitamin D supplements may decrease secondary hyperparathyroidism and reduce the risk of proximal femur fracture, particularly in the elderly living in nursing homes [bib_ref] Use of calcium or calcium in combination with vitamin D supplementation to..., Tang [/bib_ref] [bib_ref] Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis..., Weaver [/bib_ref]. In six trials included in the meta-analysis [bib_ref] Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis..., Weaver [/bib_ref] , hip fracture risk was 0.61 (95% CI 0.46-0.62) with calcium and vitamin D supplementation. In contrast, a recent meta-analysis did not find a reduction in fracture risk in communitydwelling older adults receiving calcium, vitamin D, or the combination [bib_ref] Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling..., Zhao [/bib_ref]. The latter included seven trials, but only three among those analysed in [bib_ref] Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis..., Weaver [/bib_ref]. Adding to the controversies over calcium, a meta-analysis has concluded that calcium supplements without co-administered vitamin D were associated with an increase in the risk of myocardial infarction by around 30% [bib_ref] Calcium supplements with or without vitamin D and risk of cardiovascular events:..., Bolland [/bib_ref]. Cardiovascular outcomes were not primary endpoints in any of the studies and the association remains the subject of some controversy [bib_ref] The calcium scare-what would Austin Bradford Hill have thought, Nordin [/bib_ref] [bib_ref] Re: The calcium scare: what would Austin Bradford Hill have thought?, Bolland [/bib_ref] [bib_ref] Misclassification does not explain increased cardiovascular risks of calcium supplements, Bolland [/bib_ref] [bib_ref] Calcium supplementation and the risks of atherosclerotic vascular disease in older women:..., Lewis [/bib_ref] [bib_ref] Adverse events from calcium supplementation: relationship to errors in myocardial infarction self-reporting..., Lewis [/bib_ref] [bib_ref] Response to: Misclassification does not explain increased cardiovascular risks of calcium supplements, Lewis [/bib_ref]. Overall, it can be concluded that (1) calcium and vitamin D supplementation may lead to a modest reduction in fracture risk, although population-level intervention has not been shown to be an effective public health strategy; (2) supplementation with calcium alone does not reduce fracture risk; (3) side effects of calcium supplementation include renal stones and gastrointestinal symptoms; (4) vitamin D supplementation, rather than calcium, may reduce falls risk; and (5) increased cardiovascular risk consequent to calcium supplementation is not convincingly supported by current evidence; (6) calcium and vitamin D supplementation is recommended for patients at high risk of calcium and vitamin D insufficiency, and in those who are receiving treatment for osteoporosis [bib_ref] The role of calcium supplementation in healthy musculoskeletal ageing: an expert consensus..., Harvey [/bib_ref]. This approach appears to be cost-effective [bib_ref] Cost-effectiveness of vitamin D and calcium supplementation in the treatment of elderly..., Hiligsmann [/bib_ref]. Vitamin D supplements alone may reduce the risk of fracture and falls provided the daily dose of vitamin D is greater than 700 IU [bib_ref] Fall prevention with supplemental and active forms of vitamin D: a meta-analysis..., Bischoff-Ferrari [/bib_ref] [bib_ref] Pooled analysis of vitamin D dose requirements for fracture prevention, Bischoff-Ferrari [/bib_ref]. In contrast, studies with large annual doses of vitamin D have reported an increased risk of hip fracture and, in one study, and also of falls [bib_ref] Effect of annual intramuscular vitamin D on fracture risk in elderly men..., Smith [/bib_ref] [bib_ref] Annual high-dose oral vitamin D and falls and fractures in older women:..., Sanders [/bib_ref]. The upper limit of vitamin D dose that is beneficial on falls may be lower than previously estimated [bib_ref] Monthly high-dose vitamin D treatment for the prevention of functional decline: a..., Bischoff-Ferrari [/bib_ref] [bib_ref] Medium doses of daily vitamin D decrease falls and higher doses of..., Smith [/bib_ref]. Whereas a gradual decline in caloric intake with age can be considered as an appropriate adjustment to the progressive reduction in energy expenditure, a parallel reduction in protein intake may be detrimental for maintaining the integrity and function of several organs or systems, including skeletal muscle and bone. Sufficient protein intakes are necessary to maintain the function of the musculoskeletal system, but they also decrease the complications that occur after an osteoporotic fracture [bib_ref] Nutritional aspect of bone health, Rizzoli [/bib_ref] [bib_ref] Benefits and safety of dietary protein for bone health. A position paper..., Rizzoli [/bib_ref]. Correction of poor protein nutrition in patients with a recent hip fracture has been shown to improve the subsequent clinical course by significantly lowering the rate of complications, such as bedsores, severe anaemia and intercurrent lung or renal infection. The duration of hospital stay of elderly patients with hip can thus be shortened [bib_ref] Nutritional aspect of bone health, Rizzoli [/bib_ref]. Dairy products are a source of both protein and calcium, since 1 L of milk provides 32 g of protein and 1200 mg of calcium. Dairy products, some being fortified with calcium or vitamin D, decrease circulating PTH, increase IGF-I and decrease bone resorption markers [bib_ref] Benefits and safety of dietary protein for bone health. A position paper..., Rizzoli [/bib_ref] [bib_ref] Dairy products, yogurts, and bone health, Rizzoli [/bib_ref] [bib_ref] Effects of dairy products consumption on health: benefits and beliefs-a commentary from..., Rozenberg [/bib_ref]. Dairy products are associated with higher bone strength in both men and women [bib_ref] Peripheral skeleton bone strength is positively correlated with total and dairy protein..., Durosier-Izart [/bib_ref] [bib_ref] High dairy protein intake is associated with greater bone strength parameters at..., Langsetmo [/bib_ref]. In older US men and women, higher milk consumption is associated with a lower hip fracture risk [bib_ref] Milk and other dairy foods and risk of hip fracture in men..., Feskanich [/bib_ref]. Fermented milk products like yogurt or soft cheese may provide larger amounts of these nutrients than the same volume of plain milk because of enrichment with milk powder to make the yogurt matrix denser [bib_ref] Greater yogurt consumption is associated with increased bone mineral density and physical..., Laird [/bib_ref] [bib_ref] Effects of fermented milk products on bone, Rizzoli [/bib_ref] [bib_ref] Fermented dairy products consumption is associated with attenuated cortical bone loss independently..., Biver [/bib_ref]. Thus, calcium and vitamin D fortified dairy products (yogurt, milk) providing at least 40% of the RNI of calcium (400 mg) and 200 IU of vitamin D per portion are valuable options for covering the needs in the oldest old. Cheese consumption is associated with lower mortality [bib_ref] Cheese consumption and risk of cardiovascular disease: a meta-analysis of prospective studies, Chen [/bib_ref]. Several studies have concluded to a favourable cost-effectiveness of dairy products in osteoporosis management [bib_ref] Costeffectiveness of personalized supplementation with vitamin D-rich dairy products, Ethgen [/bib_ref] [bib_ref] A scoping review of the public health impact of vitamin Dfortified dairy..., Hiligsmann [/bib_ref] [bib_ref] The projected public health and economic impact of vitamin D fortified dairy..., Hiligsmann [/bib_ref]. ## Major pharmacological interventions The most commonly used agents in Europe are raloxifene, the bisphosphonates alendronate, ibandronate, risedronate and zoledronic acid, agents derived from parathyroid hormone and denosumab. They have all been shown to reduce the risk of vertebral fracture. Some have also been shown to reduce the risk of non-vertebral fractures and, in some cases, agents have been shown specifically to decrease fracture risk at the hip [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] [bib_ref] Effectiveness of anti-osteoporotic drugs to prevent secondary fragility fractures: systematic review and..., Saito [/bib_ref] [bib_ref] Identification and management of patients at increased risk of osteoporotic fracture: outcomes..., Kanis [/bib_ref]. ## Selective oestrogen receptor modulators Selective oestrogen receptor modulators (SERMs) are nonsteroidal agents that bind to the oestrogen receptor and act as oestrogen agonists or antagonists, depending on the target tissue. The concept of SERMs was triggered by the observation that tamoxifen, which is an oestrogen antagonist in breast tissue, is a partial agonist on bone, reducing the rate of bone loss in postmenopausal women [bib_ref] Effects of tamoxifen on bone mineral density in postmenopausal women with breast..., Love [/bib_ref]. Raloxifene is the only SERM widely available for the prevention and treatment of postmenopausal osteoporosis, but several others are in clinical development. Raloxifene prevents bone loss [bib_ref] Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with..., Ettinger [/bib_ref] and reduces the risk of vertebral fractures by 30-50% in postmenopausal women with low bone mass, and with osteoporosis with or without prior vertebral fractures as shown in the MORE trial [bib_ref] Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with..., Ettinger [/bib_ref]. There was no significant reduction of non-vertebral fractures. In women with severe vertebral fractures at baseline (i.e. at highest risk of subsequent fractures), a post hoc analysis showed a significant reduction of nonvertebral fractures [bib_ref] Severity of prevalent vertebral fractures and the risk of subsequent vertebral and..., Delmas [/bib_ref]. In the MORE study and its placebo-controlled 4-year follow-up (CORE), the only severe (but rare) adverse event was an increase of deep venous thromboembolism. Hot flushes and lower limb cramps are commonly reported. There was a significant and sustained decrease of the risk of invasive breast cancer (by about 60%) [bib_ref] The effect of raloxifene on risk of breast cancer in postmenopausal women:..., Cummings [/bib_ref] , that has been subsequently confirmed in two other large cohorts, including the STAR study that showed similar breast cancer incidences with raloxifene and tamoxifen in high-risk populations. The RUTH study, performed in postmenopausal women at high risk of cardiovascular disease [bib_ref] Design and methods of the Raloxifene Use for The Heart (RUTH) study, Mosca [/bib_ref] , showed that raloxifene had no effect on cardiovascular death, and on the incidence of coronary heart disease and stroke [bib_ref] Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women, Barrett-Connor [/bib_ref]. However, an increased risk of death from stroke has been reported in women with or at risk of coronary heart disease. The efficacy of raloxifene has been shown in women with osteopenia [bib_ref] Effect of raloxifene on the risk of new vertebral fracture in postmenopausal..., Kanis [/bib_ref] and is not dependent on the level of fracture risk assessed by FRAX [bib_ref] A metaanalysis of the efficacy of raloxifene on all clinical and vertebral..., Kanis [/bib_ref]. In summary, the overall risk-benefit ratio of raloxifene is favourable and the drug is approved widely for the prevention and treatment of postmenopausal osteoporosis. Bazedoxifene is a selective oestrogen receptor modulator that has been approved in Europe but is only available in Spain and Germany. In phase 3 clinical trials, bazedoxifene was shown to reduce the risk of new vertebral fracture, with favourable effects on bone mineral density, bone turnover markers and the lipid profile [bib_ref] Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women..., Silverman [/bib_ref] [bib_ref] Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women..., Silverman [/bib_ref]. The phase III study was extended up to 7 years [bib_ref] A 7-year randomized, placebo-controlled trial assessing the long-term efficacy and safety of..., Palacios [/bib_ref]. During this period, the efficacy and safety of bazedoxifene were sustained. Two separate network meta-analyses provided an indirect comparison of the effect of bazedoxifene versus oral bisphosphonates, for the prevention of vertebral [bib_ref] Indirect comparison of bazedoxifene vs oral bisphosphonates for the prevention of vertebral..., Ellis [/bib_ref] and nonvertebral fractures [bib_ref] Bazedoxifene versus oral bisphosphonates for the prevention of nonvertebral fractures in postmenopausal..., Ellis [/bib_ref] , respectively. They concluded that bazedoxifene is expected to have at least a comparable relative risk reduction of vertebral [bib_ref] Indirect comparison of bazedoxifene vs oral bisphosphonates for the prevention of vertebral..., Ellis [/bib_ref] and non-vertebral fracture [bib_ref] Bazedoxifene versus oral bisphosphonates for the prevention of nonvertebral fractures in postmenopausal..., Ellis [/bib_ref] as alendronate, ibandronate and risedronate. In a post hoc study in a subgroup of women at increased risk of fracture, bazedoxifene decreased non-vertebral fracture risk. In contrast to raloxifene, the efficacy of bazedoxifene is dependent on the level of fracture risk assessed by FRAX [bib_ref] Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk..., Kanis [/bib_ref]. In common with raloxifene, venous thromboembolic events, primarily deep vein thromboses, leg cramps and hot flushes were more frequently reported in the active treatment groups compared with the placebo group [bib_ref] Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of..., De Villiers [/bib_ref]. Bazedoxifene has been combined with conjugated equine oestrogen to create a tissue selective oestrogen complex for the management of vasomotor symptoms and the prevention of osteoporosis associated with menopause [bib_ref] Bazedoxifene and conjugated equine estrogen: a combination product for the management of..., Umland [/bib_ref]. A series of five phase III studies known as the Selective estrogen, Menopause And Response to Therapy (SMART) trials led to the approval, by the US Food and Drug Administration (FDA) and in Europe, of a daily dose of bazedoxifene 20 mg/ conjugated equine oestrogen 0.45 mg. This association improved vasomotor symptoms whilst opposing breast and endometrial proliferation, preventing bone resorption and improving lipid profiles [bib_ref] Bazedoxifene and conjugated equine estrogen: a combination product for the management of..., Umland [/bib_ref]. Over 12 months, this combination product improved BMD at the spine and at the hip, reduced markers of bone turnover and significantly improved vasomotor function score in a population of European postmenopausal women without effects on fracture risk [bib_ref] CE/BZA effects on bone and quality of life in European postmenopausal women:..., Hadji [/bib_ref]. ## Bisphosphonates Bisphosphonates are stable analogues of pyrophosphate characterised by a P-C-P bond. A variety of bisphosphonates has been synthesised, the potency of which depends on the length and structure of the side chain [bib_ref] Bisphosphonates for post-menopausal osteoporosis: are they all the same?, Rizzoli [/bib_ref]. Bisphosphonates have a strong affinity for bone apatite, both in vitro and in vivo, which is the basis for their clinical use. They are potent inhibitors of bone resorption and produce their effect by reducing the recruitment and activity of osteoclasts and increasing their apoptosis. The potency and chemical affinity to bone of bisphosphonates determines their effect to inhibit bone resorption and varies greatly from compound to compound. Potency differences can range 10,000-fold in vitro, so that the doses used clinically also vary. The mechanism of action on osteoclasts includes inhibition of the proton vacuolar adenosine triphosphatase (ATPase) and alteration of the cytoskeleton and the ruffled border. Amino-bisphosphonates also inhibit the farnesyl pyrophosphate synthase step in the mevalonate pathway, thereby modifying the isoprenylation of guanosine triphosphate binding proteins. Oral bioavailability of bisphosphonates is low, around 1% of the dose ingested, and is impaired by food, calcium, iron, coffee, tea and orange juice. Bisphosphonates are quickly cleared from plasma, about 50% being deposited in bone and the remainder excreted in urine. Their half-life in bone is very prolonged [bib_ref] Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis, Khan [/bib_ref]. Alendronate 70 mg once weekly and risedronate 35 mg once weekly are the most commonly used bisphosphonates worldwide. In the Fracture Intervention (FIT) study, alendronate was shown to reduce the incidence of vertebral, wrist and hip fractures by approximately half in women with prevalent vertebral fractures [bib_ref] Randomised trial of effect of alendronate on risk of fracture in women..., Black [/bib_ref] [bib_ref] Meta-analyses of therapies for postmenopausal osteoporosis. IX: summary of meta-analyses of therapies..., Cranney [/bib_ref] [bib_ref] A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and..., Stevenson [/bib_ref]. In women without prevalent vertebral fractures, there was no significant decrease in clinical fractures in the overall population, but the reduction was significant in the one third of patients that had a baseline hip BMD T-score lower than − 2.5 SD [bib_ref] Effect of alendronate on risk of fracture in women with low bone..., Cummings [/bib_ref]. In a population of more than 90,000 men and women aged 80 years and older and who had sustained a prior fracture, a case-control analysis revealed that alendronate use was associated with a 34% decrease in hip fracture risk, and a 12% lower mortality risk but with a 58% increase in the risk of mild upper gastrointestinal symptoms [bib_ref] Hip fracture risk and safety with alendronate treatment in the oldest-old, Axelsson [/bib_ref]. Risedronate has been shown to reduce the incidence of vertebral and non-vertebral fractures by 40-50% and 30-36%, respectively, in women with prevalent vertebral fractures [bib_ref] Effects of risedronate treatment on vertebral and nonvertebral fractures in women with..., Harris [/bib_ref] [bib_ref] Randomized trial of the effects of risedronate on vertebral fractures in women..., Reginster [/bib_ref]. In a large population of elderly women, risedronate decreased significantly the risk of hip fractures by 30%, an effect that was greater in osteoporotic women age 70-79 years (− 40%), and not significant in women over the age of 80 years without evidence of osteoporosis [bib_ref] Effect of risedronate on the risk of hip fracture in elderly women...., Mcclung [/bib_ref]. A delayed-release formulation of 35 mg risedronate weekly, given before or immediately following breakfast, showed a similar or greater effect on spine and hip BMD than traditional immediate-release 5 mg risedronate daily. This formulation allows osteoporotic patients to take their weekly risedronate dose immediately after breakfast, hence offering a potential for improved adherence and persistence to treatment [bib_ref] Treatment of postmenopausal osteoporosis with delayedrelease risedronate 35 mg weekly for 2..., Mcclung [/bib_ref]. Ibandronate given daily (2.5 mg) reduces the risk of vertebral fractures by 50-60%. An effect on non-vertebral fractures was only demonstrated in a post hoc analysis of women with a baseline of BMD T-score below − 3 SD [bib_ref] Effects of oral ibandronate administered daily or intermittently on fracture risk in..., Chesnut [/bib_ref] [bib_ref] Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction..., Delmas [/bib_ref] [bib_ref] Ibandronate and the risk of non-vertebral and clinical fractures in women with..., Harris [/bib_ref]. Bridging studies have shown that oral ibandronate 150 mg once monthly is equivalent or superior to daily ibandronate in increasing BMD and decreasing biochemical markers of bone turnover, giving rise to its approval for the prevention of vertebral fracture in postmenopausal osteoporosis [bib_ref] Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year..., Reginster [/bib_ref]. The efficacy and safety of oral monthly ibandronate was confirmed for up to 5 years in women with postmenopausal osteoporosis [bib_ref] Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year..., Reginster [/bib_ref] [bib_ref] Efficacy of monthly oral ibandronate is sustained over 5 years: the MOBILE..., Miller [/bib_ref]. Similarly, bridging studies comparing intermittent intravenous ibandronate to daily oral treatment has led to the approval of intravenous ibandronate 3 mg every 3 months for the same indication [bib_ref] Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the..., Delmas [/bib_ref]. A post hoc analysis of pooled individual patient data from the studies assessing the long-term (5 years) efficacy of oral [bib_ref] Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year..., Reginster [/bib_ref] and intravenous [bib_ref] Long-term administration of quarterly IV ibandronate is effective and well tolerated in..., Bianchi [/bib_ref] ibandronate concluded that for ibandronate regimens with annual cumulative exposure ≥ 10.8 mg, time-tofracture was significantly longer for all clinical fractures, nonvertebral and clinical vertebral fractures versus placebo and that for all fracture types, the rate of fracture appeared stable up to 5 years [bib_ref] Longterm fracture rates seen with continued ibandronate treatment: pooled analysis of DIVA..., Miller [/bib_ref]. Based on the result of a phase II study [bib_ref] Intravenous zoledronic acid in postmenopausal women with low bone mineral density, Reid [/bib_ref] , a large phase III trial in over 7700 postmenopausal osteoporotic patients assessed the efficacy of yearly infusion of zoledronic acid 5 mg over 3 years. As compared to the placebo group, zoledronic acid was found to reduce the incidence of vertebral fractures by 70% and that of hip fractures by 40% [bib_ref] Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis, Black [/bib_ref] and is now available for the treatment of postmenopausal osteoporosis. Intravenous zoledronic acid has also been shown to decrease the risk of fracture and mortality when given shortly after a first hip fracture [bib_ref] Zoledronic acid and clinical fractures and mortality after hip fracture, Lyles [/bib_ref]. The phase III trial was extended to 6 [bib_ref] The effect of 3 versus 6 years of zoledronic acid treatment of..., Black [/bib_ref] and 9 [bib_ref] The effect of 6 versus 9 years of zoledronic acid treatment in..., Black [/bib_ref] years. The overall conclusion was that pursuing treatment beyond 3 years only provided marginal benefits [bib_ref] The effect of 6 versus 9 years of zoledronic acid treatment in..., Black [/bib_ref]. Some authors even argue that an annual administration of 5 mg zoledronic acid might represent over treatment [bib_ref] Intravenous zoledronate for osteoporosis: less might be more, Grey [/bib_ref]. A single dose of 5 mg zoledronic acid given to frail elderly women improved spine and total hip BMD over 2 years, compared to placebo but the treated group had an increase in fractures, multiple falls and mortality [bib_ref] Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly..., Greenspan [/bib_ref] suggesting that zoledronic acid may not be an appropriate treatment for such patients. ## Safety of bisphosphonates The overall safety profile of bisphosphonates is favourable. Oral bisphosphonates are associated with mild gastrointestinal disturbances, and some amino-bisphosphonates (alendronate and pamidronate) can rarely cause oesophagitis. A network meta-analysis compared the gastrointestinal safety of all oral and injectable bisphosphonates given to osteoporotic patients. It concluded that zoledronic acid has the highest probability of causing gastrointestinal adverse events, possibly related to nausea [bib_ref] Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis, Tadrous [/bib_ref]. Intravenous amino-bisphosphonates can induce a transient acute phase reaction with fever, bone and muscle pain that ameliorates or disappears after subsequent courses [bib_ref] Adverse reactions and drug-drug interactions in the management of women with postmenopausal..., Rizzoli [/bib_ref]. Osteonecrosis of the jaw has been described in cancer patients receiving high doses of intravenous pamidronate or zoledronate. The incidence in osteoporotic patients treated with oral and intravenous bisphosphonates appears to be very rare (in the order of 1/100,000 patient-year), only slightly higher than the incidence in the general population [bib_ref] Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task..., Adler [/bib_ref] [bib_ref] Case-based review of osteonecrosis of the jaw (ONJ) and application of the..., Khan [/bib_ref]. The risk of osteonecrosis of the jaw is reported to be greater with a longer duration of bisphosphonate therapy [bib_ref] Time to onset of bisphosphonaterelated osteonecrosis of the jaws: a multicentre retrospective..., Fung [/bib_ref] [bib_ref] Osteoporosis drug treatment: duration and management after discontinuation. A position statement from..., Meier [/bib_ref] , but this finding is not consistent [bib_ref] Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task..., Adler [/bib_ref]. Possible explanations relate to the class of bisphosphonate, differences in potency and route of administration. The time to onset of osteonecrosis of the jaw may be shorter for intravenous zoledronic acid compared to oral alendronate [bib_ref] Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis, Rizzoli [/bib_ref]. Concerns have been raised about a possible association between bisphosphonate therapy and atrial fibrillation. Subsequent studies have produced conflicting results, but have not excluded the possibility of such an association in people at increased risk of fracture [bib_ref] Atrial fibrillation and bisphosphonate therapy, Pazianas [/bib_ref]. Patients to whom zoledronic acid was administered for up to 9 years had a higher risk of cardiac arrhythmias compared to those who discontinued the treatment after 6 years [bib_ref] The effect of 6 versus 9 years of zoledronic acid treatment in..., Black [/bib_ref]. The possibility that bisphosphonate therapy is associated with increased risk of oesophageal cancer has been raised. Two studies from the General Practice Research Database in the UK have produced conflicting results, one failing to show any association but another concluding that there was an increased risk with extended use over 5 years [bib_ref] Exposure to oral bisphosphonates and risk of esophageal cancer, Cardwell [/bib_ref] [bib_ref] Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control..., Green [/bib_ref]. Finally, bisphosphonate use may be associated with atypical subtrochanteric fractures [bib_ref] Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical..., Rizzoli [/bib_ref] [bib_ref] Increasing occurrence of atypical femoral fractures associated with bisphosphonate use, Meier [/bib_ref]. Likewise, associations between bisphosphonate exposure and lower risks of mortality and cancer also require further scrutiny [bib_ref] Oral bisphosphonate use and breast cancer incidence in postmenopausal women, Chlebowski [/bib_ref] [bib_ref] Reduced colon cancer incidence and mortality in postmenopausal women treated with an..., Pazianas [/bib_ref] [bib_ref] Bisphosphonate therapy, death, and cardiovascular events among female patients with CKD: a..., Hartle [/bib_ref] [bib_ref] Analysis of the association between bisphosphonate treatment survival in Danish hip fracture..., Bondo [/bib_ref]. The risk-benefit ratio remains favourable for the use of bisphosphonates to prevent fractures [bib_ref] Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical..., Rizzoli [/bib_ref]. Many authors recommend that patients be reviewed after 3 years (IV) or 5 years (oral) treatment with bisphosphonate [bib_ref] Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task..., Adler [/bib_ref] [bib_ref] Osteoporosis drug treatment: duration and management after discontinuation. A position statement from..., Meier [/bib_ref]. It is appropriate that periodic assessment of fracture risk should use FRAX with femoral neck BMD. Fracture risk should be reassessed after a new fracture, regardless of when it occurs. Although some advocate a 'drug holiday', prospective and retrospective analyses report that the risk of new clinical fractures was 20-40% higher in subjects who stopped treatment [bib_ref] Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday, Curtis [/bib_ref] [bib_ref] Bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk, Mignot [/bib_ref] and vertebral fracture risk was approximately doubled [bib_ref] The effect of 3 versus 6 years of zoledronic acid treatment of..., Black [/bib_ref] [bib_ref] Randomized trial of effect of alendronate continuation versus discontinuation in women with..., Ensrud [/bib_ref]. A substantial body of evidence indicates that some generic formulations of alendronate are more poorly tolerated than the proprietary preparations, which results in significantly poorer adherence and thus effectiveness [bib_ref] A reappraisal of generic bisphosphonates in osteoporosis, Kanis [/bib_ref]. ## Peptides of the parathyroid hormone family The continuous endogenous production of parathyroid hormone (PTH), as seen in primary or secondary hyperparathyroidism, or its exogenous administration can lead to deleterious consequences for the skeleton, particularly on cortical bone. However, intermittent administration of PTH (e.g. with daily subcutaneous injections) results in an increase of the number and activity of osteoblasts, leading to an increase in bone mass and in an improvement in skeletal architecture at both cancellous and cortical skeletal sites [bib_ref] Parathyroid hormone analogues in the treatment of osteoporosis, Kraenzlin [/bib_ref]. The 1-34 N-terminal fragment (teriparatide) is used for the management of osteoporosis. The marketing authorisation for the 1 to 84 intact molecule has been withdrawn at the request of the marketing authorisation holder. Treatment with teriparatide has been shown to reduce significantly the risk of vertebral fractures and also non-vertebral fractures. There is no convincing evidence that teriparatide reduces hip fracture, but this may reflect absence of evidence, not evidence of absence. Thus, the recommendation for its use in high-risk people is particularly strong in patients with vertebral fracture. The recommended dose is 20 μg of teriparatide, given as a subcutaneous injection [bib_ref] Effect of parathyroid hormone (1-34) on fractures and bone mineral density in..., Neer [/bib_ref]. Treatment with PTH has been studied when given for 18 to 24 months and beneficial effects on non-vertebral fracture with teriparatide have been shown to persist for up to 30 months after stopping teriparatide [bib_ref] Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment, Prince [/bib_ref]. The most common reported adverse events in patients treated withPTHorteriparatidearenausea,paininthelimbs,headacheand dizziness. In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have been observed followingtheinjectionteriparatide.Serumcalciumconcentrationsreacha maximum between 4 and 6 h and return to baseline 16 to 24 h after each dose. The change is small and routine monitoring of serum calcium during therapy is not required. PTH and teriparatide may cause small increases in urine calcium excretion but the incidence of hypercalciuria does not differ from that in placebo-treated patients. However, these agents should be used with caution in patients with active or recent urolithiasis because of their potential to exacerbate the disorder. Isolated episodes of transient orthostatic hypotension are also reported. They typically resolve within minutes to a few hours, and do not preclude continued treatment. The use of peptides of the PTH family is contraindicated in conditions characterised by abnormally increased bone turnover (e.g. pre-existing hypercalcaemia, metabolic bone diseases other than primary osteoporosis, including hyperparathyroidism and Paget's disease of bone, unexplained elevation of alkaline phosphatase, prior external beam or implant radiation therapy to the skeleton or in patients with malignancies or bone metastasis). Severe renal impairment is also a contraindication. Studies in rats have indicated an increased incidence of osteosarcoma, with long-term administration of very high doses of teriparatide [bib_ref] Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid..., Vahle [/bib_ref] [bib_ref] Defining a noncarcinogenic dose of recombinant human parathyroid hormone 1-84 in a..., Jolette [/bib_ref]. These findings have not been considered relevant for patients treated with very much smaller doses of teriparatide. ## Denosumab Critical molecules for the differentiation, activation and survival of osteoclasts are the receptor activator of nuclear factor NFkB (RANK), its ligand RANKL, a member of the tumour necrosis factor (TNF) superfamily, and osteoprotegerin (OPG), which acts as a decoy receptor for RANKL. A fully human antibody against RANKL has been developed. This antibody, denosumab, has been shown to specifically bind to RANKL with a very high affinity, preventing its interaction with the receptor RANK [bib_ref] Current options for the management of postmenopausal osteoporosis, Lecart [/bib_ref]. The anti-fracture efficacy of 60 mg denosumab given subcutaneously every 6 months has been evaluated in postmenopausal osteoporotic women. After 3 years, there was a 68% reduction in the incidence of new vertebral fractures. The incidence of clinical vertebral fractures was similarly reduced by 69%. The incidence of non-vertebral fractures was reduced by 20% and of hip fractures by 40% [bib_ref] Denosumab for prevention of fractures in postmenopausal women with osteoporosis, Cummings [/bib_ref]. After completing the first 3 years of the study, women from the denosumab group had 7 more years of denosumab treatment (long-term group) and those from the placebo group had 7 years of denosumab exposure (cross-over group) [bib_ref] 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from..., Bone [/bib_ref]. The yearly incidence of new vertebral fractures remained low during the extension, whereas non-vertebral fractures further significantly decreased in year 4 [bib_ref] Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the..., Ferrari [/bib_ref] and thereafter remained stable (approximately 1.5% per year for both vertebral and non-vertebral fractures) [bib_ref] Osteoporosis drug treatment: duration and management after discontinuation. A position statement from..., Meier [/bib_ref] [bib_ref] 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from..., Bone [/bib_ref]. The incidence of vertebral and non-vertebral fracture observed during the extension was similar to that observed in the denosumab group during the first 3 years and lower than rates projected from a virtual long-term placebo cohort [bib_ref] 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from..., Bone [/bib_ref]. Discontinuation of denosumab is associated with a rapid offset of action: Markers of bone turnover increased to above baseline levels, which returned to baseline values within 1 to 2 years after stopping treatment [bib_ref] Effects of denosumab treatment and discontinuation on bone mineral density and bone..., Bone [/bib_ref] and BMD decreased to baseline values by 12-18 months, independently of the duration of treatment [bib_ref] Effects of denosumab treatment and discontinuation on bone mineral density and bone..., Bone [/bib_ref]. In a sample of 1000 patients who discontinued denosumab during the 3-year pivotal study [bib_ref] Denosumab for prevention of fractures in postmenopausal women with osteoporosis, Cummings [/bib_ref] or its extension [bib_ref] 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from..., Bone [/bib_ref] , the vertebral fracture rate increased to a value similar to that observed in participants who received and then discontinued placebo [bib_ref] Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the..., Cummings [/bib_ref]. The proportion of patients developing multiple vertebral fractures after stopping treatment was higher in the denosumab group than in the placebo group. In addition, the odds of developing multiple vertebral fractures after stopping denosumab was increased in patients with prior vertebral fracture sustained before or during treatment, or in those with the longer exposure to denosumab [bib_ref] Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the..., Cummings [/bib_ref]. No increase in non-vertebral fracture after denosumab cessation was reported. A short duration of bisphosphonate therapy could be considered when discontinuing denosumab to prevent the rebound effect [bib_ref] Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement..., Tsourdi [/bib_ref]. In women transitioning from oral bisphosphonates to injectable treatments, denosumab was associated with greater BMD increases at all skeletal sites and greater inhibition of bone remodelling, compared with zoledronic acid [bib_ref] Osteoporosis drug treatment: duration and management after discontinuation. A position statement from..., Meier [/bib_ref] [bib_ref] Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with..., Miller [/bib_ref]. The incidence of adverse events for all individuals who received denosumab for 10 years [bib_ref] 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from..., Bone [/bib_ref] tended to decrease over time whereas serious adverse events were stable. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the cross-over group [bib_ref] 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from..., Bone [/bib_ref]. In a meta-analysis of four clinical trials, the relative risk of serious adverse events for the denosumab group compared with the placebo group was 1.33, of serious adverse events related to infection 2.10, of neoplasm 1.11, of study discontinuation due to adverse events 1.10, and of death 0.78. These risks were all non-significant [bib_ref] Clinical efficacy and safety of denosumab in postmenopausal women with low bone..., Von Keyserlingk [/bib_ref]. ## Summary of effects The effects of the major pharmacological interventions on vertebral and hip fracture risk are summarised in . ## Combination and sequential treatments These treatment regimens include the concomitant or sequential use of compounds sharing the same mode of action (e.g. two or more inhibitors of bone resorption) or agents with Study details and anti-fracture efficacy (relative risk (RR and 95% confidence intervals (CI)) of the major pharmacological treatments used for postmenopausal osteoporosis when given with calcium and vitamin D, as derived from randomised controlled trials Intervention differing activities (e.g. an inhibitor of resorption plus an anabolic agent). None of the available studies has been powered so far, to assess differences in fracture incidence between combination therapy and monotherapy, but results obtained with BMD, bone histomorphometry, finite element analysis or markers of bone turnover shifted the treatment paradigm towards a greater use of combination or sequential therapies. Whereas the first attempts to combine alendronate and PTH were disappointing [bib_ref] The effects of parathyroid hormone and alendronate alone or in combination in..., Black [/bib_ref] , combination of teriparatide and denosumab generated greater increments in BMD and calculated bone strength compared to either drug alone [bib_ref] Response to therapy with teriparatide, denosumab, or both in postmenopausal women in..., Leder [/bib_ref] , supporting further investigation of this combination. Similarly, in alendronate-treated women, 3-month teriparatide cycles followed by 3-month off improve BMD similarly to daily continuous treatment with teriparatide, an observation which was not confirmed in alendronate-naive women [bib_ref] Daily or cyclical teriparatide treatment in women with osteoporosis on no prior..., Cosman [/bib_ref]. In a controlled comparison of women who switched from alendronate to teriparatide versus those who added teriparatide to ongoing alendronate, the effect on hip BMD and on hip strength was greater with combination therapy. Continuing a potent anti-resorptive agent when starting a bone-forming agent might thus improve hip outcomes [bib_ref] Treatment sequence matters: anabolic and antiresorptive therapy for osteoporosis, Cosman [/bib_ref]. In patients at high risk of fracture, starting treatment with an anabolic agent seems most appropriate to promptly reduce the fracture risk [bib_ref] Identification and management of patients at increased risk of osteoporotic fracture: outcomes..., Kanis [/bib_ref]. Given that treatments with anabolic agents are limited to 18-24 months and that efficacy will wane once treatment is stopped, the real potential of the anabolic treatments is whether their greater effect on BMD and fracture can be maintained with the inhibitors of bone turnover once treatment is stopped [fig_ref] Figure 2: Screen page for input of data and format of results in the... [/fig_ref] [bib_ref] Review of the guideline of the American College of Physicians on the..., Kanis [/bib_ref]. In the absence of a subsequent prescription of an anti-resorptive agent, the benefits obtained during treatment with teriparatide progressively disappear [bib_ref] One year of alendronate after one year of parathyroid hormone (1-84) for..., Black [/bib_ref] , whereas they are maintained when denosumab [bib_ref] Response to therapy with teriparatide, denosumab, or both in postmenopausal women in..., Leder [/bib_ref] is prescribed, as soon as possible after stopping the anabolic intervention. ## Other pharmacological interventions ## Menopausal hormone therapy Oestrogens reduce the accelerated bone turnover induced by the menopause and prevent bone loss at all skeletal sites regardless of age and duration of therapy. Results from observational studies and randomised placebo-controlled trials have shown that estrogens decrease the risk of vertebral and nonvertebral fractures (including hip fracture) by about 30%, regardless of baseline BMD [bib_ref] Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized..., Torgerson [/bib_ref] [bib_ref] Effects of estrogen plus progestin on risk of fracture and bone mineral..., Cauley [/bib_ref]. When hormone replacement therapy is stopped, bone loss resumes at the same rate as after the menopause, but fracture protection may persist arguably for several years [bib_ref] Effect of withdrawal of hormone replacement therapy on bone mass and bone..., Sornay-Rendu [/bib_ref] [bib_ref] Two to three years of hormone replacement treatment in healthy women have..., Bagger [/bib_ref]. The original analyses of the Women's Health Initiative (WHI) suggested, however, that the long-term risks of menopausal hormone therapy (MHT) outweighed the benefits. In this large cohort of postmenopausal women in their 60s, the combined use of conjugated oestrogen and medroxyprogesterone acetate was originally associated with a 30% increased risk of coronary heart disease (CHD), and breast cancer and with a 40% increase in stroke [bib_ref] Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal..., Roussow [/bib_ref] [bib_ref] Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's..., Wassertheil-Smoller [/bib_ref] [bib_ref] Influence of estrogen plus progestin on breast cancer and mammography in healthy..., Chlebowski [/bib_ref]. There was also a slight increase in the risk of dementia [bib_ref] Estrogen plus progestin and the incidence of dementia and mild cognitive impairment..., Shumaker [/bib_ref] , and no clinically meaningful effect on healthrelated quality of life such as sleep disturbance or vasomotor symptoms [bib_ref] Effects of estrogen plus progestin on health-related quality of life, Hays [/bib_ref]. In a subsequent analysis, the increase in breast cancer risk was much less in women not previously exposed to MHT [bib_ref] Influence of estrogen plus progestin on breast cancer and mammography in healthy..., Chlebowski [/bib_ref]. In hysterectomized women receiving conjugates oestrogen alone, there was also an increase in stroke, but not of CHD and breast cancer, suggesting a deleterious effect of medroxyprogesterone acetate. It has been postulated that the benefits of HRT outweigh the risks in younger postmenopausal women [bib_ref] The Women's Health Initiative-a decade of progress, Fenton [/bib_ref] [bib_ref] Have we come full circle-or moved forward? The Women's Health Initiative 10..., Langer [/bib_ref] , but so far there is no placebocontrolled study showing the long-term safety of such approaches. However, in a recent publication, re-assessing the long-term outcomes of the WHI, MHT with conjugated oestrogen and medroxyprogesterone acetate for a median of 5.6 years or with conjugated oestrogen alone for a median of 7.2 years was not associated with an increased risk of all-cause, cardiovascular, or cancer mortality during a cumulative followup of 18 years [bib_ref] Menopausal hormone therapy and long-term allcause and cause-specific mortality: the Women's Health..., Manson [/bib_ref]. This may challenge the current recommendation to use HRT only for climacteric symptoms, at a dose as small as possible and for a limited period of time [bib_ref] Menopausal hormone therapy for primary prevention: why the USPSTF is wrong, Langer [/bib_ref]. In scenario A, treatment with a bone-forming agent induces a marked effect on fracture risk over an 18 months exposure compared with placebo. On stopping the bone-forming agent, the effect on fracture wanes off over a similar time interval of 18 months. In scenario C, placebo group remains untreated, whereas the group treated with a bone-forming agent is transitioned to an inhibitor of bone turnover, which maintains the efficacy up to 4 years. In scenario B, both the treatment and the placebo groups are treated after the exposure with an inhibitor of bone turnover [bib_ref] Review of the guideline of the American College of Physicians on the..., Kanis [/bib_ref]. With kind permission from Springer Science and Business Media ## Vitamin d derivatives Alfacalcidol is a synthetic analogue of the vitamin D metabolite calcitriol (1,25-dihydroxyvitamin D 3 ) and it is metabolised to calcitriol by its 25-hydroxylation in the liver. It is somewhat less potent than calcitriol. Both alfacalcidol and calcitriol are used in some countries for the treatment of osteoporosis. Several but not all studies show decreases in vertebral fracture risk [bib_ref] Efficacy of alphacalcidol and calcitriol in primary and corticosteroid-induced osteoporosis: a meta-analysis..., Richy [/bib_ref] [bib_ref] Vitamin D analogs versus native vitamin D in preventing bone loss and..., Richy [/bib_ref]. A meta-analysis suggested that combined treatment with alendronate and alfacalcidol prevented all osteoporotic fractures more than alfacalcidol or alendronate alone [bib_ref] Treatment of postmenopausal osteoporosis with calcitriol or calcium, Tilyard [/bib_ref]. The effects on bone mineral density have been less extensively studied. A few reports have suggested that alfacalcidol and calcitriol exert a direct action on muscle strength and decreases the likelihood of falling in elderly subjects [bib_ref] An age-related decrease in creatinine clearance is associated with an increase in..., Gallagher [/bib_ref] [bib_ref] Effects of combined alendronate and alfacalcidol on prevention of fractures in osteoporosis..., Shao [/bib_ref]. The major problem with the use of the vitamin D derivatives is the risk of hypercalcaemia and hypercalciuria. Adverse effects of prolonged hypercalcaemia include impairment of renal function and nephrocalcinosis. The narrow therapeutic window demands the frequent surveillance of serum and possibly urine calcium in patients exposed to these agents. Calcium supplementation of the diet should be avoided or used with care. ## Clodronate Clodronate is a relatively weak bisphosphonate, but has been shown to decrease the risk of vertebral and non-vertebral fractures in randomised controlled studies [bib_ref] Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis:..., Mccloskey [/bib_ref] [bib_ref] Clodronate reduces the incidence of fractures in communitydwelling elderly women unselected for..., Mccloskey [/bib_ref]. It is widely available for the treatment of neoplastic bone disease but licensed for use in osteoporosis in only a few countries. ## Local osteo-enhancement procedure Local osteo-enhancement procedure (LOEP) is a local treatment, which requires a minimally invasive injection in the femoral neck of a resorbable synthetic bone graft substitute, containing a proprietary triphasic calcium sulphate/calcium phosphate implant [bib_ref] Long-term prospective cohort study of a local osteo-enhancement procedure (LOEP) to treat..., Howe [/bib_ref]. In postmenopausal women with low hip BMD (mean T-score = − 3.1), femoral neck BMD in treated hips increased by 58% compared to contralateral control hips, during 5-7 years of follow-up [bib_ref] Long-term prospective cohort study of a local osteo-enhancement procedure (LOEP) to treat..., Howe [/bib_ref]. X-ray and QCT analyses demonstrated that the implant material was completely resorbed in all patients and replaced with bone that integrated with the surrounding trabecular and cortical bone [bib_ref] QCT demonstrates long-term proximal femur trabecular density increases in osteoporotic women following..., Engelke [/bib_ref]. QCT scans were used to conduct patient-specific, nonlinear finite element analysis to estimate hip strength in simulated sideways fall and stance loading conditions. Femoral strength in sideway fall was 36% higher in treated than control femurs 5-7 years after the procedure [bib_ref] FEA-estimated proximal femur strength increases through 5-7 year follow-up in osteoporotic women..., Keaveny [/bib_ref]. No safety issues were reported during the study [bib_ref] Long-term prospective cohort study of a local osteo-enhancement procedure (LOEP) to treat..., Howe [/bib_ref] [bib_ref] QCT demonstrates long-term proximal femur trabecular density increases in osteoporotic women following..., Engelke [/bib_ref] [bib_ref] FEA-estimated proximal femur strength increases through 5-7 year follow-up in osteoporotic women..., Keaveny [/bib_ref]. Data on fracture outcomes are not yet available. ## Vertebroplasty and kyphoplasty In patients with recent vertebral fracture in whom pain persists for 2 to 3 weeks despite a well-conducted analgesic programme, injection of cement in the fractured vertebral body without (vertebroplasty) or with preceding balloon inflation (kyphoplasty) may lead to reduction of pain and positive functional outcomes [bib_ref] Balloon kyphoplasty for the treatment of acute vertebral compression fractures: 2-year results..., Boonen [/bib_ref] [bib_ref] Comparison of percutaneous vertebroplasty and balloon kyphoplasty for the treatment of single..., Wang [/bib_ref]. Whether pain relief is related to the cement itself or to local anaesthetic is still unclear [bib_ref] Comparing effects of kyphoplasty, vertebroplasty, and nonsurgical management in a systematic review..., Papanastassiou [/bib_ref] [bib_ref] Vertebroplasty versus sham procedure for painful acute osteoporotic vertebral compression fractures (VERTOS..., Firanescu [/bib_ref]. Heterogeneity in treatment recommendations is, in part, explained by an insufficient clinical evidence base for vertebral augmentation and heterogeneity of patients, leading to undue reliance on expert opinion [bib_ref] Analysis of reporting bias in vertebral augmentation, Beall [/bib_ref] [bib_ref] Appropriateness criteria for treatment of osteoporotic vertebral compression fractures, Luthman [/bib_ref]. An increase in new vertebral fracture rates at non-treated levels, especially those adjacent to the treated vertebrae, has been reported [bib_ref] Comparison of percutaneous vertebroplasty and balloon kyphoplasty for the treatment of single..., Wang [/bib_ref] [bib_ref] Analysis of risk factors for secondary new vertebral compression fracture following percutaneous..., Bae [/bib_ref] but not consistently [bib_ref] Does percutaneous vertebroplasty or balloon kyphoplasty for osteoporotic vertebral compression fractures increase..., Zhang [/bib_ref] following both vertebroplasty and kyphoplasty. ## Fracture liaison services Fracture liaison services (FLS), also known as osteoporosis coordinator programmes and care manager programmes, provide a system for the routine assessment and management of postmenopausal women and older men who have sustained a fragility fracture [bib_ref] An osteoporosis clinical pathway for the medical management of patients with low-trauma..., Chevalley [/bib_ref] [bib_ref] The fracture liaison service: success of a program for the evaluation and..., Mclellan [/bib_ref] [bib_ref] Models of care for the secondary prevention of osteoporotic fractures: a systematic..., Ganda [/bib_ref]. Since the majority of patients presenting with fragility fracture do not receive appropriate assessment and treatment, fracture liaison services address this need through a systematic approach to identify cases, assess risk of further fractures and the need for treatment. Most fracture liaison services are based in secondary care although models in primary care have also been described. A dedicated coordinator, often a nurse, working closely with the patient, primary care physician, orthopaedic and trauma department and osteoporosis and falls service is central to the development of a successful service. An example of the structure of a fracture liaison service is shown in . The IOF has launched a global campaign ('Capture the frac-ture®') to promote this approach for the prevention of a second fracture [bib_ref] Capture the fracture: a best practice framework and global campaign to break..., Akesson [/bib_ref] [bib_ref] Effective secondary fracture prevention: implementation of a global benchmarking of clinical quality..., Javaid [/bib_ref]. This initiative aims to set internationally endorsed standards for best practice by facilitating the implementation of fracture liaison services involving best practice frameworks, multidisciplinary models and FLS questionnaires. The benefits of coordinator-based systems to ensure appropriate management of patients following a fracture are well established [bib_ref] Practice patterns in the diagnosis and treatment of osteoporosis after a fragility..., Elliot-Gibson [/bib_ref] [bib_ref] Capture the fracture: a best practice framework and global campaign to break..., Akesson [/bib_ref] [bib_ref] Effective secondary fracture prevention: implementation of a global benchmarking of clinical quality..., Javaid [/bib_ref] [bib_ref] Coordinator-based systems for secondary prevention in fragility fracture patients, Marsh [/bib_ref] [bib_ref] HipWatch: osteoporosis investigation and treatment after a hip fracture: a 6-month randomized..., Davis [/bib_ref] [bib_ref] Improvement in the undertreatment of osteoporosis following hip fracture, Gardner [/bib_ref] [bib_ref] Use of a case manager to improve osteoporosis treatment after hip fracture:..., Majumdar [/bib_ref] [bib_ref] Fracture prevention in Kaiser Permanente Southern California, Dell [/bib_ref]. Use of a systematic coordinator approach in the Kaiser Permanente Healthy Bones Program was associated with a 40% reduction in hip fractures [bib_ref] Fracture prevention in Kaiser Permanente Southern California, Dell [/bib_ref]. Recent studies from the UK [bib_ref] Implementation of secondary fracture prevention services after hip fracture: a qualitative study..., Drew [/bib_ref] [bib_ref] Clinical effectiveness of orthogeriatric and fracture liaison service models of care for..., Hawley [/bib_ref] [bib_ref] Anti-osteoporosis medication prescriptions and incidence of subsequent fracture among primary hip fracture..., Hawley [/bib_ref] reported that the initiation of FLS reduced the 30-day and 1-year mortality rates following hip fracture, led to a significant reduction in second fracture rate and increased the utilisation of anti-osteoporosis treatment by 15%. Although the health economic analyses that have been published so far have shown that osteoporosis management programmes are a cost-effective intervention for the prevention of fractures [bib_ref] Fracture prevention in Kaiser Permanente Southern California, Dell [/bib_ref] [bib_ref] Fracture liaison services for the evaluation and management of patients with osteoporotic..., Mclellan [/bib_ref] [bib_ref] Cost effectiveness of the Concord minimal trauma Fracture Liaison service, a prospective,..., Cooper [/bib_ref] [bib_ref] Costeffectiveness of orthogeriatric and fracture liaison service models of care for hip..., Leal [/bib_ref] , larger and longer-term studies will be needed to further quantify the effect of FLS care on subsequent fracture risk [bib_ref] Fracture liaison services: do they reduce fracture rates?, De Bruin [/bib_ref]. ## Adherence and monitoring of treatment Adherence to treatment When discussing adherence, there is a need to define the terminology [bib_ref] Adherence to treatment of osteoporosis: a need for study, Lekkerkerker [/bib_ref] , since a wide variety of definitions is used in the literature. ## 1. Adherence is a general term encompassing the aspects mentioned below. 2. Persistence describes for how long the medication is taken. Persistence could be expressed as number of days until discontinuation or the proportion of the cohort still on the medication after a given time since first prescription. Nonpersistence is assumed to be the same as discontinuation if a treatment gap is longer than a set number of days. 3. Compliance denotes the proximity to the treatment recommendation as given in the official product information (SPC). It is often simplified to mean the number of doses taken divided by the number of prescribed doses. This simplification does not include some important aspects of compliance, such as taking medication with food (for the oral bisphosphonates), at the correct time of the day, too large doses to compensate for forgotten doses, pill dumping, etc. 4. Primary non-adherence is when the patient is prescribed a drug and then never fills the prescription. Non-adherence to medical therapy is a widespread public health problem. It is estimated that only half of the patients comply with long-term therapy of which a substantial minority do not even redeem their prescription. Overcoming non-adherence presents particular challenges in asymptomatic bone diseases and other chronic, asymptomatic conditions. In such settings, the level of perceived threat to health does not motivate the patient to adhere to therapy. In addition, risk of non-adherence with any therapy increases with increased duration of treatment [bib_ref] Compliance with osteoporosis medications, Solomon [/bib_ref]. Poor adherence to medication is associated with adverse effects on outcomes in osteoporosis or osteopenia, and nonadherent patients have smaller decreases in rates of bone turnover, smaller gains in BMD and a significantly greater risk of fracture [bib_ref] Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women, Rabenda [/bib_ref] [bib_ref] Cost-effectiveness of osteoporosis screening followed by treatment: the impact of medication adherence, Hiligsmann [/bib_ref] [bib_ref] A meta-analysis of osteoporotic fracture risk with medication nonadherence, Ross [/bib_ref]. Partial adherence also has a significant impact on cost-effectiveness [bib_ref] Incorporating adherence into health economic modelling of osteoporosis, Strom [/bib_ref]. Further research is required to optimise thresholds of compliance and persistence, the impact of gap length, offset times, and fraction of benefit [bib_ref] Partial adherence: a new perspective on health economic assessment in osteoporosis, Kanis [/bib_ref]. Improving adherence to osteoporosis therapy requires effective patient/provider communication and close patient monitoring for the early identification of declining adherence. Patients' belief in a medication contributes to better adherence and can be improved by firmly associating treatment with expected benefits such as reduced risk of fracture and thereby an improved quality of life. Patients may be encouraged to adhere when presented with measurements of biochemical markers of bone turnover or their BMD results together with an explanation of how these measures relate to risk reduction. Another primary component of improving adherence is to use simplified or user-friendly treatment programmes [bib_ref] The impact of compliance with osteoporosis therapy on fracture rates in actual..., Caro [/bib_ref] [bib_ref] Overcoming problems with adherence to osteoporosis medication, Rabenda [/bib_ref]. Frequency of dosing is another determinant of adherence [bib_ref] A review of patient preferences for osteoporosis drug treatment, Hiligsmann [/bib_ref] [bib_ref] Systematic literature review and meta-analysis of medication adherence with once-weekly versus once-daily..., Iglay [/bib_ref]. A recent IOF and ECTS taskforce suggested that screening to detect a lack of adherence with oral bisphosphonates should involve the measurement of P1NP and CTX at baseline and 3 months after starting therapy. In the absence of a decrease above the least significant change (i.e. − 38% for P1NP and − 56% for CTX), a low adherence should be suspected [bib_ref] International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for..., Diez-Perez [/bib_ref]. It should be noted that inadequate adherence can also take the form of improper drug administration, even when doses are not missed. An example is the malabsorption of oral bisphosphonates when taken with food. Such non-adherence poses the potential problems of decreased drug absorption and increased risk of adverse effects [bib_ref] Factors associated with adherence and persistence to bisphosphonate therapy in osteoporosis: a..., Carr [/bib_ref]. ## Monitoring of treatment with densitometry The goal of bone-targeted drug therapy in a patient with osteoporosis is to increase bone strength, in order to decrease the risk of fracture. In untreated men and women, BMD is one of the major determinants of bone strength, and low BMD is an important predictor of fracture. Whether the long-term antifracture efficacy of anti-osteoporotic drugs depends on the extent to which treatment can increase or maintain BMD is controversial [bib_ref] Relationship between bone mineral density changes and risk of fractures among patients..., Rabenda [/bib_ref]. Meta-regressions, based on summary statistics, demonstrate a stronger correlation between the change in BMD and fracture risk reduction than results based on the individual patient data [bib_ref] Changes in bone density and turnover explain the reductions in incidence of..., Hochberg [/bib_ref] [bib_ref] Relationship between changes in bone mineral density and fracture risk reduction with..., Delmas [/bib_ref]. Whereas 16% of vertebral fracture risk reduction after treatment with alendronate was attributed to an increase in BMD at the lumbar spine [bib_ref] Improvement in spine bone density and reduction in risk of vertebral fractures..., Cummings [/bib_ref] , larger increases in BMD at both the spine and hip, observed with alendronate, were associated with greater reductions in the risk of non-vertebral fractures. However, for patients treated with risedronate or raloxifene, changes in BMD predict even more poorly the degree of reduction in vertebral (raloxifene) or non-vertebral (risedronate) fractures. Twelve percent and 7% of the effects of risedronate to reduce non-vertebral fractures were attributed to changes in the spine and femoral neck BMD, respectively [bib_ref] Relationship between changes in BMD and nonvertebral fracture incidence associated with risedronate:..., Watts [/bib_ref]. For raloxifene, the percentage changes in BMD accounted for 4% of the observed vertebral fracture risk reduction [bib_ref] Relationships between bone mineral density and incident vertebral fracture risk with raloxifene..., Sarkar [/bib_ref]. Percent changes in total hip BMD at month 36 explained up to 35% of the effect of denosumab to reduce new or worsening vertebral fractures and up to 84% of the reduction in non-vertebral fracture risk [bib_ref] Relationship between bone mineral density changes with denosumab treatment and risk reduction..., Austin [/bib_ref]. It is reasonable to conclude, however, that early monitoring of BMD has limited value in the prediction of treatment responses with inhibitors of bone resorption. For bone-forming agents, increases in BMD account for approximately one third of the vertebral fracture risk reduction with teriparatide [bib_ref] Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated..., Chen [/bib_ref]. Further data are needed on the role of BMD monitoring patients treated with bone-forming agents but appears to be of greater value than their use with inhibitors of bone resorption. In postmenopausal osteoporosis, treatment-induced increments in BMD with inhibitors of bone turnover are modest (typically 2% per year) in comparison to the precision error of repeat measurements (typically 1-2%) so that the time interval of repeat estimates must be sufficiently long in order to determine whether any change is real [bib_ref] Precision assessment and radiation safety for dual-energy X-ray absorptiometry: position paper of..., Baim [/bib_ref]. In the absence of other clinical imperatives, a 5-year interval may be appropriate. For other agents such as and PTH derivatives, the treatmentinduced increment is much more rapid and more frequent BMD tests may be considered. ## Monitoring of treatment with biochemical markers of bone turnover The most informative biochemical markers of bone turnover for the monitoring of osteoporosis are procollagen I Nterminal extension peptide (P1NP) for assessing bone formation, and C-telopeptide breakdown products (especially serum CTX) to assess bone resorption [bib_ref] The use of biochemical markers of bone turnover in osteoporosis. Committee of..., Delmas [/bib_ref] [bib_ref] Markers of bone turnover for the prediction of fracture risk and monitoring..., Vasikaran [/bib_ref] [bib_ref] A meta-analysis of reference markers of bone turnover for prediction of fracture, Johansson [/bib_ref]. Treatment-induced changes in bone markers are more rapid than changes in BMD and are typically measured 3-6 months or so after starting treatment when treatment-induced changes are expected to be most evident. In a research setting, a significant association has been reported between the short-term decrease in markers of bone turnover with the use of antiresoptive agents and gains in BMD [bib_ref] Six and twelve month changes in bone turnover are related to reduction..., Bjarnason [/bib_ref] [bib_ref] Effects of denosumab on bone turnover markers in postmenopausal osteoporosis, Eastell [/bib_ref]. More importantly, significant associations have been reported between the short-term decrease in markers of bone turnover and the reduction in risk of vertebral and non-vertebral fractures with the use of anti-resorptive agents (raloxifene and bisphosphonates). For the bisphosphonates, a screening strategy has been proposed by the IOF based on the response of P1NP and CTX after 3 months of therapy [bib_ref] International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for..., Diez-Perez [/bib_ref]. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug. More research is required using standardised analytes before robust evidence-based recommendations can be given [bib_ref] Markers of bone turnover for the prediction of fracture risk and monitoring..., Vasikaran [/bib_ref]. Despite limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone turnover markers are not suppressed by anti-resorptive therapy and where bone mineral density continues to decrease [bib_ref] Cooper C for the IOF CSA Inadequate Responders Working Group (2012) Treatment..., Diez-Perez [/bib_ref]. ## Investigation of patients with osteoporosis ## Diagnostic work up The same diagnostic approach should be undertaken in all patients with osteoporosis irrespective of the presence or absence of fragility fractures. However, the range of clinical and biological tests will depend on the severity of the disease, the age at presentation and the presence or absence of vertebral fractures. & To perform baseline measurements for subsequent monitoring of treatment. The procedures that may be relevant to the investigation of osteoporosis are shown in [fig_ref] Table 10: Routine procedures proposed in the investigation of osteoporosis [/fig_ref]. These investigations may be used to: & Establish the diagnosis of osteoporosis (e.g. DXA or Xrays); & Establish the cause (e.g. thyroid function tests for hyperthyroidism, and urinary free cortisol for Cushing syndrome); & Establish differential diagnosis (e.g. protein electrophoresis for myeloma, and serum calcium and alkaline phosphatase for osteomalacia). Investigations commonly conducted in secondary care include a full blood count, ESR, serum calcium and phosphate, liver function tests and tests of renal function. Additional measurements include the biochemical indices of bone turnover, serum parathyroid hormone, serum 25-hydroxyvitamin D, serum or urine protein electrophoresis, fasting and 24-h urinary calcium, urinary free cortisol, thyroid function tests, IgA antitissue transglutaminase antibody or IgA endomysial antibody, tryptase and (rarely) transiliac bone biopsy. Free testosterone, gonadotrophin and prolactin measurements may be of value in men. Assessment is guided by the clinical findings, and some patients who apparently have primary osteoporosis are subsequently found to have mild hyperparathyroidism or hyperthyroidism, systemic mastocytosis, the late appearance of osteogenesis imperfecta or osteomalacia. ## Differential diagnosis of osteoporosis Osteomalacia and malignancy commonly induce bone loss and fractures. Osteomalacia is characterised by a defect of mineralisation of bone matrix most commonly attributable to impaired intake, production or metabolism of vitamin D. Other causes include impaired phosphate transport or the chronic use of some drugs such as aluminium salts (and other phosphate binding antacids), high doses of fluoride or etidronate, and the chronic use of some anticonvulsants. In most cases, the diagnosis of osteomalacia is suspected by the clinical history and by abnormalities in biochemical tests such as low values of serum and urinary calcium, serum phosphate and 25-hydroxyvitamin D, and high values for alkaline phosphatase and parathyroid hormone. A transiliac bone biopsy after double tetracycline labelling may be necessary to demonstrate unequivocally a defect in mineralisation. Diffuse osteoporosis with or without pathological fracture is common in patients with multiple myeloma, a condition suspected by the severity of bone pain, increased sedimentation rate and Bence Jones proteinuria and identified by marrow aspirate, and serum and urine (immuno-) electrophoresis of proteins. Similarly, pathological fractures resulting from metastatic malignancies can mimic osteoporosis and can be excluded by clinical and radiological examination, biological tests such as tumour markers, and scintigraphy or other imaging techniques. Vertebral fractures in osteoporosis should be differentiated from vertebral deformities attributable to other disorders such as scoliosis, osteoarthrosis and Scheuermann's disease. ## Health economics There is an increasing need for management strategies to be placed in an appropriate health economic perspective for guideline development and for reimbursement. The type of evaluation used is principally cost-utility analysis as a measure of cost-effectiveness. In the context of evaluating treatments, this takes account, not only of fractures avoided, but also of any change in morbidity and mortality from both beneficial and unwanted effects. QALYs are the accepted unit of measurement in health economic assessment of interventions using cost-utility analysis. In order to estimate QALYs, each year of life is valued according to its utility to the patient. Values range from 0, the least desirable health state, to 1, or perfect health. The decrement in utility associated with fractures is the cumulative loss of utility over time. There is at present little international consensus as to when treatment can be considered to be cost-effective [bib_ref] Thresholds for the cost-effectiveness of interventions: alternative approaches, Marseille [/bib_ref] [bib_ref] Looking for willingness to pay (wtp) threshold for a qaly-does it make..., Gyrd-Hansen [/bib_ref]. One approach is to base the threshold value on a measure of a country's economic performance and a value of about 2 times GDP/capita has been suggested as a threshold that can be applied to Western economies [bib_ref] Economic evaluation of interventions for osteoporosis, Kanis [/bib_ref]. On this basis, threshold values would be about €32,000 in the UK, close to the recommendation of the National Institute for Health and Clinical Excellence. Although the GDP per capita provides an index of affordability, there is also a marked heterogeneity in the proportion of GDP that countries are willing to devote to health care, and in the proportion of the population at risk from ## Studies of intervention There has been a rapid expansion of research in Europe on the cost-utility of interventions in osteoporosis, which has been the subject of several reviews [bib_ref] Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis, Kanis [/bib_ref] [bib_ref] A systematic review of cost-effectiveness analyses of drugs for postmenopausal osteoporosis, Hiligsmann [/bib_ref] [bib_ref] An evaluation of the NICE guidance for the prevention of osteoporotic fragility..., Kanis [/bib_ref] [bib_ref] Health technology assessment in osteoporosis, Hiligsmann [/bib_ref] [bib_ref] The application of health technology assessment in osteoporosis, Kanis [/bib_ref]. A useful tabular summary of studies up to April 2012 is provided in Brandão et al. [bib_ref] Pharmacoeconomic analysis of strategies to treat postmenopausal osteoporosis: a systematic review, Brandão [/bib_ref]. Despite the use of different models, different settings and payer perspectives, analyses suggest that there are cost-effective scenarios that can be found in the context of the management of osteoporosis for all but the most expensive interventions [fig_ref] Table 11: Comparison of the cost-effectiveness [/fig_ref] [bib_ref] The cost-effectiveness of alendronate in the management of osteoporosis, Kanis [/bib_ref]. A pan-European study from 2004 estimated the cost-effectiveness of branded alendronate in nine countries [bib_ref] Cost-effectiveness of alendronate in the treatment of postmenopausal women in 9 European..., Strom [/bib_ref]. Alendronate was shown to be cost-saving compared to no treatment in women with osteoporosis (with and without previous vertebral fracture) from the Nordic countries (Norway, Sweden and Denmark). The cost-effectiveness of alendronate compared to no treatment was also within acceptable ranges in Belgium, France, Germany, Italy, Spain, Switzerland and the UK. However, with the markedly decrease in price of generic bisphosphonates, analyses based on a branded drug price have become obsolete. For example, the cost of alendronate (70 mg weekly) assumed in [fig_ref] Table 11: Comparison of the cost-effectiveness [/fig_ref] was £95 per annum (2007) and in 2017 had fallen to a yearly cost of £8.64 in the UK. NICE have recently reappraised the cost-effectiveness of oral and intravenous bisphosphonates. Treatment with oral bisphosphonates was cost-effective of women with a 10-year probability of a major osteoporotic fracture of 1% or more. For intravenous bisphosphonates, the threshold for cost-effectiveness was a 10-year probability of 10%. The advent of probability-based assessment has prompted the cost-effectiveness of interventions as a function of fracture probability. Several studies have examined the cost-effectiveness of intervention thresholds expressed in terms of fracture probability [bib_ref] A framework for the development of guidelines for the management of glucocorticoid-induced..., Lekamwasam [/bib_ref] [bib_ref] The cost-effectiveness of alendronate in the management of osteoporosis, Kanis [/bib_ref] [bib_ref] Cost-effective osteoporosis treatment thresholds: the United States perspective, Tosteson [/bib_ref] [bib_ref] At what hip fracture risk is it cost-effective to treat? International intervention..., Borgstrom [/bib_ref] [bib_ref] Cost-effective intervention thresholds against osteoporotic fractures based on FRAX(R) in Switzerland, Lippuner [/bib_ref]. In studies from the UK [bib_ref] Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds..., Kanis [/bib_ref] [bib_ref] The cost-effectiveness of alendronate in the management of osteoporosis, Kanis [/bib_ref] , generic alendronate was shown to be cost-effective in the prevention and treatment of fractures in postmenopausal women with a 10-year fracture probability for a major fracture that exceeded 7.5% . It is interesting that in the different European countries where such studies have been performed, the probabilities of major fractures selected as making generic alendronate a cost-effective intervention are quite similar: 7.5% in the UK [bib_ref] The cost-effectiveness of alendronate in the management of osteoporosis, Kanis [/bib_ref] , 8.8% in Portugal [bib_ref] Cost-effectiveness of osteoporosis treatment intervention thresholds for the treatment of osteoporosis based..., Marques [/bib_ref] , 13.8% in Switzerland [bib_ref] Cost-effective intervention thresholds against osteoporotic fractures based on FRAX(R) in Switzerland, Lippuner [/bib_ref] and 10-15%, depending on age, in Greece [bib_ref] Costeffective osteoporosis treatment thresholds in Greece, Makras [/bib_ref]. This is quite remarkable, given the disparities in the clinical and economic epidemiology of factures and, especially, the willingness to pay adopted for each country: the UK €27,786, Switzerland €115,000, Portugal €32,000 and Greece €30,000. The recent appraisal by NICEindicated that all oral bisphosphonates were cost-effective in women with a 10-year probability of 1% or more. Thus, the all treatment scenarios with alendronate can be considered as cost-effective (see and . This raises an important issue in that the health economic thresholds espoused by NICE simply demarcate a level of risk above which the respective oral and IV bisphosphonate treatments are cost-effective but that the thresholds used to decide treatment should be based on clinical appropriateness [bib_ref] Cost-effective but clinically inappropriate: new NICE intervention thresholds in osteoporosis (Technology Appraisal..., Harvey [/bib_ref] [bib_ref] Bisphosphonates in osteoporosis: NICE and easy?, Harvey [/bib_ref]. A special need for the incorporation of FRAX into health economic models arises from studies that have examined the interaction between FRAX-based probabilities with 14 Correlation between the 10-year probability of a major fracture (calculated with BMD) and cost-effectiveness of generic alendronate at the age of 50 years in women (BMI set to 26 kg/m 2 ). Each point represents a particular combination of BMD and clinical risk factors (all possible combinations of CRFs at BMD T-scores between 0 and − 3.5 SD in 0.5 SD steps-512 combinations) with a BMI set to 26 kg/m 2 . The horizontal line denotes the threshold for cost-effectiveness (a willingness to pay of £20,000/QALY gained). From [bib_ref] Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds..., Kanis [/bib_ref] , with kind permission from Springer Science and Business Media effectiveness. Interventions studied include raloxifene [bib_ref] A metaanalysis of the efficacy of raloxifene on all clinical and vertebral..., Kanis [/bib_ref] [bib_ref] Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk..., Kanis [/bib_ref] , bazedoxifene [bib_ref] Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk..., Kanis [/bib_ref] , clodronate [bib_ref] Ten-year fracture probability identifies women who will benefit from clodronate therapyadditional results..., Mccloskey [/bib_ref] , daily and weekly teriparatide [bib_ref] FRAX and the effect of teriparatide on vertebral and non-vertebral fracture, Harvey [/bib_ref] [bib_ref] Efficacy of weekly teriparatide does not vary by baseline fracture probability calculated..., Harvey [/bib_ref] , denosumab [bib_ref] Denosumab reduces the risk of all osteoporotic fractures in postmenopausal women, particularly..., Mccloskey [/bib_ref] , alendronate [bib_ref] Effect of alendronate for reducing fracture by FRAX score and femoral neck..., Donaldson [/bib_ref] , as well as a basket of interventions used by general practitioners in the UK [bib_ref] A randomized controlled trial of screening in the community to reduce fractures..., Shepstone [/bib_ref]. Most of these were post hoc but, in the case of denosumab, was a pre-planned analysis. In addition, the 'screening for prevention of fractures in older women' (SCOOP) study was a prospective randomised study that demonstrated efficacy for hip fracture in women selected on the basis of hip fracture probability assessed using FRAX [bib_ref] A randomized controlled trial of screening in the community to reduce fractures..., Shepstone [/bib_ref]. Several of these studies have shown greater efficacy against fracture in individuals at higher risk treated with clodronate, bazedoxifene, denosumab and in the SCOOP study. This FRAX-dependency has marked economic consequences, illustrated when comparing the cost-effectiveness of the two selective oestrogen receptor modulators, raloxifene and bazedoxifene. The overall effectiveness of these two agents on vertebral fracture risk is rather comparable but the efficacy of bazedoxifene increases in women with the higher the baseline fracture probability. In contrast, the relative risk reduction with raloxifene is constant over the range of fracture probabilities studied. As a consequence, raloxifene has better cost-effectiveness at low fracture probabilities whereas bazedoxifene has the better cost-effectiveness at high baseline fracture probabilities [bib_ref] Comparative cost-effectiveness of bazedoxifene and raloxifene in the treatment of postmenopausal osteoporosis..., Kim [/bib_ref] [bib_ref] Costeffectiveness of bazedoxifene compared with raloxifene in the treatment of postmenopausal osteoporotic..., Hiligsmann [/bib_ref]. The contrasting effect of FRAX-dependent and FRAX-independent interactions with efficacy on fractures averted is shown in. Despite differences in apparent cost-effectiveness, there is, however, no proven difference in efficacy between the majority of treatments shown in [fig_ref] Table 11: Comparison of the cost-effectiveness [/fig_ref] and head to head comparisons of interventions with fracture outcomes are few and recent [bib_ref] Effects of teriparatide and risedronate on new fractures in post-menopausal women with..., Kendler [/bib_ref]. For these reasons, the value of an incremental analysis between the individual treatments is questionable, since any resulting hierarchy of treatments is dependent largely on price, but otherwise meaningless in clinical terms. In addition, the large number of untreated patients makes 'no treatment' a relevant comparator. Notwithstanding, alendronate has been considered as a first line intervention. The view arises, not because of apparent differences in efficacy between treatments, but because of cost. However, the poor effectiveness and side effect profile of many generic formulations challenge this view [bib_ref] A reappraisal of generic bisphosphonates in osteoporosis, Kanis [/bib_ref]. The advent of new anabolic agents given for relatively short periods followed by maintenance with sequential inhibitors of bone resorption will offer new challenges for health economic appraisal. Acknowledgements We are grateful to the IOF Committee of Scientific Advisors and the Committee of National Societies to the ESCEO Scientific Advisory Board for their review of this paper and its endorsement. The paper updates the earlier guidance of 2013 [bib_ref] on behalf of the Scientific Advisory Board of the European Society for..., Kanis [/bib_ref] 'European guidance for the diagnosis and management of osteoporosis in postmenopausal women' and many sections of text are reproduced with kind permission of from Springer Science and Business Media B.V. The summary and recommendations are in close accord with those established by the UK National Osteoporosis Guideline Groupof which JAK and CC are members. ## Compliance with ethical standards Conflict of interests JAK reports grants from Amgen, Eli Lilly and Radius Health; non-financial support from Medimaps, and Asahi; and other support from AgNovos. JAK is the architect of FRAX® but has no financial interest. CC reports personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda and UCB. RR has received consulting fees or advisory board fees from Radius Health, Labatec, Danone, Nestlé, CNIEL and Sandoz. J-YR has received advisory board or consulting fees from IBSA-Genévrier, Pierre Fabre, Radius Health, TEVA and Mylan; and lecture fees from Anovos, IBSA-Genévrier, Mylan, CNIEL, Dairy Research Council (DRC) and Theramex; and institutional grant support from IBSA-Genévrier, Mylan, CNIEL and Radius Health. 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 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:// creativecommons.org/licenses/by-nc/4.0/.Contrasting effects on the number of fractures saved with an intervention, the efficacy of which the relative risk reduction (RRR) is independent or dependent on FRAX (average RRR set at 40%) [fig] Figure 2: Screen page for input of data and format of results in the UK version of the FRAX® tool (UK model, version 3.5. http://www.shef.ac.uk/FRAX). [With permission of the Centre for Metabolic Bone Diseases, University of Sheffield Medical School, UK] [/fig] [fig] Figure 5, Figure 4: Ten-year probabilities (%) of a major osteoporotic fracture for women from Kuwait at a T-score of − 2.5 SD (open triangle), − 1.5 SD (open square) and prior fracture (open diamond). The shaded area represents fracture probabilities in women with no clinical risk factors and average BMD. From [120] with kind permission from Management algorithm for the assessment of individuals at risk of fracture [/fig] [fig] Figure 8, Figure 7: Assessment of major osteoporotic fracture risk in countries with high access to DXA. DXA is undertaken in women with a clinical risk factor. Assessment with DXA and/or treatment is not recommended where the FRAX probability is lower than the lower assessment threshold (green area). BMD is recommended in other women and treatment recommended where the fracture probability exceeds the intervention threshold (dotted line). The intervention threshold used is that derived fromTable 6. From [3], with kind permission from Springer Science and Business Media DXA (units/million) The density of central DXA equipment (units/million of the general population in the EU countries in 2010 [Kanis JA, data on file] BOX 1 Assessment of fracture risk with FRAX with unlimited access to BMD* [/fig] [fig] FRAX Australia v3. 1, Figure 11: Female The risk of hip fracture with age in a model that considers 10-year fracture risk alone (the Garvan tool) and FRAX, which computes the probability of hip fracture from the fracture and death hazards (FRAX). The Tscores are set differently in the two models so that the risks are approximately equal at the age of 60 years. Data are computed from the respective web sites[137]. [/fig] [fig] FN: femoral neck, TH total hip, LS lumbar spine, [/fig] [fig] Figure 12: Schematic diagram showing the effects of a bone-forming agent on the relative fracture risk reduction (RRR) compared with placebo. [/fig] [table] Table 4: Clinical risk factors used for the assessment of fracture probability [12] Centre for Metabolic Bone Diseases, University of Sheffield Medical School, UK, University of Sheffield, UK] [/table] [table] Table 7: Gradients of risk (the increase in fracture risk per SD change in risk score) with 95% confidence intervals with the use of BMD at the femoral neck, clinical risk factors or the combination[90], with kind permission from Springer Science and Business Media B.V [/table] [table] Table 10: Routine procedures proposed in the investigation of osteoporosis. From[2], with kind permission from Springer Science and Business MediaRoutineHistory including the FRAX clinical risk factors Examination including height and weight Blood cell count, sedimentation rate, serum calcium, albumin, creatinine, phosphate, alkaline phosphatase and liver transaminases Lateral radiograph of lumbar and thoracic spine Bone densitometry (dual energy X-ray absorptiometry at hip and spine) Other procedures Lateral imaging DXA for vertebral fracture assessment (VFA) Markers of bone turnover, when available osteoporotic fracture (i.e. elderly people). In a systematic review, the ratio between WTP per QALY and GDP per capita varies widely from 0.05 to 5.40, depending on scenario outcomes. The average ratio of WTP per QALY and GDP per capita for extending life or saving life was 2.03[352]. [/table] [table] Table 11: Comparison of the cost-effectiveness (£/QALY gained) of alendronate with other interventions in women aged 70 years from the UK [data for treatments other than alendronate from[127], with permission from Elsevier] [/table]	None	https://link.springer.com/content/pdf/10.1007/s00198-008-0599-x.pdf	None
b3119c890994c6a6aae26a7c8e28053c06a65a4c	pubmed	AAPM Medical Physics Practice Guideline 2.a: Commissioning and quality assurance of X‐ray‐based image‐guided radiotherapy systems	AAPM Medical Physics Practice Guideline 2.a: Commissioning and quality assurance of X‐ray‐based image‐guided radiotherapy systems # Introduction Image-guided radiation therapy (IGRT), in its many forms, is an important tool in improving the effectiveness of clinical radiation oncology. IGRT involves the use of patient images to localize and reposition the patient or delivery system prior to treatment to ensure that the therapeutic beam is correctly directed toward the target. IGRT imaging strategies have utilized X-rays, ultrasound, and other means. In particular, IGRT has been most commonly facilitated using X-rays, beginning with use of megavoltage (MV) portal and/or orthogonal setup images some decades ago. These images provide a means of evaluating the position of the treatment isocenter and field edges relative to the patient position. Because of the poor low-contrast resolution of MV images, bony anatomy may be taken as a surrogate of the target volume, which is frequently soft-tissue-equivalent and not clearly visible within the image. However, as many studies have shown, the target volume can exhibit a different relative location to bony anatomy than expected. One solution to clinical scenarios in which improved soft-tissue targeting is desired was the introduction of in-room kilovoltage (kV) imaging systems. Such systems have included computed tomography (CT) scanners located within the treatment room (e.g., "CT-onrails") and kV imaging systems affixed to the floor/ceiling or to the linear accelerator gantry itself. These systems have provided improved low-contrast localization of soft-tissue targets and -in the case of in-room CT scanners and gantry-mounted imaging systems -allowed for acquisition of pretreatment volumetric images. The specific choice and application of IGRT strategy depends on the complexity and requirements of the treatment in question. It may serve as an enhancement to an established technique (as in the case of three-dimensional conformal radiation therapy or intensity-modulated radiation therapy) or as a necessary and critical component of the treatment process (as in the case of stereotactic body radiation therapy (1) ). Currently, IGRT strategies are being used more than ever before, and various forms of IGRT have been, are, and will continue to be important tools in radiation therapy. The report of AAPM Task Group 104provides an instructive overview the various uses of X-ray imaging in radiation therapy. As the clinical treatment process continues to rely more heavily on IGRT strategies, the Qualified Medical Physicist (QMP) is under increasing pressure to maintain patient safety and treatment quality through quality assurance programs that are in step with the rapid pace of technological development. Many clinical practice environments now utilize treatment delivery systems with one or more IGRT systems that fall under the responsibility of the QMP. A variety of guidance documents and task groups reports have been issued that include additional recommendations for commissioning and quality assurance of IGRT systems.However, these reports do not clearly delineate best practice from minimum practice standards. ## A. goals and rationale This document is part of a series of medical physics practice guidelines commissioned by the American Association of Physicists in Medicine (AAPM) intended to succinctly state the minimum acceptable standards for various aspects of clinical medical physics. While implementation of robust and comprehensive quality assurance programs recommended in other reports from the AAPM is encouraged, the purpose of this particular report is to describe the minimum acceptable practice standards for the commissioning and quality assurance of X-ray-based image-guidance systems utilized in radiotherapy. This document is not intended to replace or revise previous AAPM Task Group Reports, but to assist the QMP in establishing and maintaining a safe and effective IGRT program by providing an overview of the minimum requirements and needs of X-ray-based IGRT systems. Indeed, the reader is referred to the appropriate technical reference documents or task group reports in instances when additional recommendations beyond minimum practice guidelines are desired. (1-8) Finally, the standards and procedures described in this document are applicable to the imaging guidance system insofar as its resulting images are used to position the patient and/or localize the target volume. Use of IGRT system hardware and software for other purposes, such as dose calculation, are beyond the scope of this report. Technologies covered by these guidelines include: - Gantry-mounted two-dimensional MV imaging systems - Gantry-mounted three-dimensional MV imaging systems - Gantry-mounted two-dimensional kV imaging systems - Gantry-mounted three-dimensional kV imaging systems - Room-mounted two-dimensional kV imaging systems - Room-mounted three-dimensional kV imaging systems In this context, "gantry-mounted" imaging systems are those in which the mechanical movement of the imaging hardware is coupled with mechanical movement of the treatment delivery device (e.g., Varian/Elekta/Siemens on-board kV imaging systems, electronic portal MV imaging systems, TomoTherapy megavoltage CT, etc.). "Room-mounted" systems include all imaging systems not coupled with the treatment delivery device (e.g., ExacTrac, CyberKnife, in-room CT, etc.). Fluoroscopy modes are also within the scope of this report. ## B. intended users The intended users of this report are QMPs who seek to understand the technical requirements of clinical implementation and quality assurance of a safe IGRT practice, and administrators interested in the resources required for IGRT. ## Definitions and abbreviations - CBCT -cone-beam computed tomography - IGRT -image-guided radiotherapy - kV -kilovoltage - MV -megavoltage - OIS -oncology information system - QA -quality assurance - TPS -treatment planning system ## Staff qualifications and responsibilities Implementation of a successful IGRT program requires contributions from each member of the treatment team. Recommendations for staff qualifications and responsibilities are consistent with those described by the ACR-ASTRO practice guideline for clinical use of IGRT.a. Medical Physicist -The qualified medical physicist (QMP) must be competent to practice independently in the subfield of therapeutic radiological physics. The individual must be certified either by the American Board of Radiology, American Board of Medical Physicists, or the Canadian College of Medical Physicists. Responsibilities of the qualified medical physicist in an IGRT program include: - Acceptance testing and commissioning - Implementing and managing a quality assurance program - Developing and implementing standard operating procedures (including imaging protocols and repositioning thresholds) The QMP may be assisted by medical physics residents or medical physicist assistants with these responsibilities provided 1) these individuals have been appropriately trained to perform the assigned tasks, and 2) the QMP provides general supervision of all work performed. b. Radiation Oncologist -The radiation oncologist should meet qualifications outlined in the ACR-ASTRO practice guideline for clinical use of IGRT.In short, the responsibilities of the radiation oncologist in an IGRT program include: - Specifying patient positioning procedures - Specifying imaging modalities and frequencies - Identifying registration targets and repositioning thresholds - Conducting timely review of clinical IGRT images - Conducting regular reviews of the IGRT program - Implementing and managing a quality assurance program - Developing and implementing standard operating procedures (including imaging protocols and repositioning thresholds) c. Medical Dosimetrist -The medical dosimetrist should meet the qualifications outlined in the Scope of Practice of a Medical Dosimetrist approved by the Board of Directors of the American Association of Medical Dosimetrists.Responsibilities of the medical dosimetrist or treatment planner in an IGRT program include: - Creating and transferring to the OIS all patient-specific data necessary for IGRT implementation d. Radiation Therapist -The radiation therapist should meet the qualifications outlined in Radiation Therapy Practice Standards issued by the American Society of Radiologic Technologists.Responsibilities of the radiation therapist in an IGRT program include: - Understanding the use of positioning devices in IGRT - Preparing the IGRT system for acquisition of patient-specific positioning verification images - Implementing the IGRT treatment protocol under the supervision of the radiation oncologist and medical physicist - Acquiring positioning verification images for review by the radiation oncologist - Assisting in periodic review of the stability of the IGRT system (e.g., daily QA) e. Information Technologist -It is important that each facility identify an individual that is responsible for providing and maintaining resources necessary for storing, archiving and retrieving images generated during IGRT. This may be accomplished by a dedicated Information Specialist or duties assigned to another team member. ## Implementation guidelines ## A. minimum required resources and equipment ## I. staffing Approximate time requirements needed for implementation, maintenance and quality assurance of each IGRT program type (per each IGRT system) are provided below. Estimates are provided as general reference values only, and are not intended to justify site-specific staffing models or physics time for specific billing codes. "Acceptance/ commissioning" includes all activities needed for IGRT program implementation, including documentation. "Documentation" refers to creation of a formal commissioning report, and drafting of policies and procedures specific to clinical use and routine quality assurance of IGRT (including creating QA forms and templates). "Ongoing support" includes all activities needed for maintenance of an established IGRT program (e.g., routine quality assurance, troubleshooting, upgrades, service/repairs ii. Equipment Quality assurance phantoms and tools must provide reliable values of the measured parameters and can be used to judge whether tolerance criteria have been achieved. In many cases, manufacturers of IGRT systems provide quality assurance phantoms which can be used for quality assurance purposes. In-house and commercial phantoms specifically designed for IGRT are also available and, when coupled with automated image analysis tools, may improve efficiency. At a minimum, quality assurance tools must be capable of assessing the following IGRT characteristics: - Image quality - Spatial accuracy (scaling) - Congruence of imaging and treatment isocenters - Accuracy of registration/couch movements - Imaging dose ## B. staff training Training for the operation of the IGRT system must be provided. The IGRT system vendor typically provides on-site training to the physicist and therapists for use of the equipment. Prior to initial use of IGRT, the treatment team should meet to discuss staff responsibilities, clinical goals, and process workflows. The physicist should also review the image acquisition procedures with the therapists and radiation oncologists. In general, IGRT training will require additional dedicated staff time that is not included in the estimated time requirements of Section 4.a.1. ## C. process descriptions Example procedures for each of the tests recommended in [fig_ref] Table 1: Recommended minimum practices for commissioning and QA of an IGRT system [/fig_ref] are described below. The approximate time needed to complete each procedure is noted in parenthesis following the process description. In some cases, customer acceptance procedures provided by the equipment vendor satisfactorily meet the stated practice standards; however, it is the responsibility of the QMP to judge the adequacy and completeness of all measurements needed for use of a particular IGRT system. It is important to note that these are only example procedures, and a variety of methods may be used to complete the recommended tests. Certain commercially available products are referred to by name. These references are for informational purposes only, and imply neither endorsement by the AAPM nor that these are the best or the only products available for the stated purpose. ## I. customer acceptance procedures (all systems) The QMP must provide direct supervision during the acceptance testing process.Customer acceptance tests procedures are intended to ensure that the imaging equipment satisfies the performance requirements stated in the purchase agreement. In some cases, measurements completed as part of the acceptance procedures may also serve as components in establishing the routine quality assurance program. The vendor must demonstrate acceptable system performance. ## V. ois integration and connectivity (3d systems) Volumetric IGRT image fields (CBCT, MVCT, CT-on-rails) created for a test patient within the oncology information system are properly loaded and recognized by the imaging hardware and software. Acquired images are assigned to the correct patient, if applicable. (Time: 2-3 hours) ## Vi. routine qa baselines (all systems) Measurements taken at the time of IGRT system commissioning which characterize IGRT system performance will serve as reference values for the routine QA program. See [fig_ref] Table 1: Recommended minimum practices for commissioning and QA of an IGRT system [/fig_ref] for recommended QA tests requiring reference measurements. (Time: 2-3 hours) ## Vii. igrt qa program documentation (all systems) All acceptance and commissioning procedures and results must be contained within a formal report. Furthermore, a formal policy for routine IGRT QA program and ## Semi-annually ## Image scaling 2 mm Annually Imaging dose 2D MV ± 1 cGy of baseline value 2D kV (static imaging mode) ± 3 mGy of baseline value 2D kV (fluoroscopy mode) ± 1 cGy/min of baseline value All 3D imaging modes ± 1 cGy of baseline value Image quality 2D (spatial resolution, contrast) Baseline value 3D (uniformity, spatial resolution, contrast) ## Upgrade/repair/service Verify / Reestablish QA baselines (as appropriate) SRS = stereotactic radiosurgery; SBRT = stereotactic body radiation therapy. procedures for performing routine QA measurements must be developed. (Time: ## 4-8 hours) ## Viii. safety/interlocks (all systems) With image acquisition initiated, ensure beam termination occurs when the treatment room door is opened (if applicable) and when any termination keys are depressed. If images are to be acquired with the treatment room door open, then measurements and calculations of exposure should be performed at the treatment console to ensure safe operating conditions. Also ensure that gantry rotation is terminated when touch guards are depressed. Verify that indicator lamps are illuminated during image acquisition (Time: 5 minutes) ## Ix. contrast (2d kv systems) A phantom with low-contrast objects (such as the Leeds phantom) is placed on the treatment couch at isocenter. A planar kV image is acquired using a reference technique determined at the time of acceptance testing. ## Xii. spatial resolution (2d kv systems) A phantom with high-contrast objects (such as the Leeds phantom) is placed on the treatment couch. A planar kV image is acquired using a reference technique determined at the time of acceptance testing. The number of frequency groups that are clearly distinguished is recorded, with more frequency groups indicating better spatial resolution. (Time: 15 minutes) ## Xiii. spatial resolution (2d mv systems) A phantom with high-contrast objects (such as the Las Vegas phantom) is placed on the treatment couch. A planar MV image is acquired using a reference technique determined at the time of acceptance testing. The number of visible disks of greatest contrast is recorded, with more disks indicating better spatial resolution. (Time: 15 minutes) ## Xiv. spatial resolution (3d systems) An appropriate volumetric image quality phantom (such as the Catphan) is positioned on the treatment table using the room lasers. A volumetric image is acquired using a reference technique determined at the time of acceptance testing. The number of frequency groups that are clearly distinguished is recorded, with more frequency groups indicating better spatial resolution. (Time: 15 minutes) ## Xv. scaling (all systems) A phantom of known dimensions is placed on the treatment table using the room lasers. A planar or volumetric image is acquired. Window and level are adjusted such that phantom is clearly visible. The distance between two objects of known separation in the horizontal and vertical axes is recorded and compared with the known distance. For 3D imaging systems, scaling must be measured in all 3 dimensions. [fig_ref] Table 1: Recommended minimum practices for commissioning and QA of an IGRT system [/fig_ref] ## Xx. imaging dose (3d systems) Several different methods are currently used to characterize the dose from 3D IGRT systems. The traditional metric for dose from CT imaging, the computed tomography dose index (CTDI), has been applied to IGRT imaging. More recently, the AAPM Task Group 111report has introduced a new metric, the cumulative dose. These two different metrics use different measurement equipment and irradiation geometries to characterize the dose. Measurement equipment used to measure CTDI includes a calibrated 100 mm long pencil ionization chamber and an appropriate phantom, one simulating a head and the other a large pelvis. For each imaging mode, the phantom that matches the mode's target anatomy is used. The phantom is positioned at isocenter and the pencil chamber is centered in the phantom. The radiation field length must be constrained to be less than the active length of the pencil ionization chamber. For each imaging mode, measurements are repeated for the central and peripheral phantom locations. Measurement equipment used to measure the cumulative imaging dose includes a Farmer-type ionization chamber calibrated in the appropriate energy range and several acrylic CTDI phantoms. For each imaging mode, the phantoms that match the mode's target anatomy are used. The CTDI phantoms are abutted until their length exceeds the length of the radiation field. The phantom is centered at isocenter and the Farmer chamber is centered in the phantom. For each imaging mode, measurements are repeated for the central and peripheral phantom locations. Measured imaging dose must be documented and its management should be approached with the goal of keeping it as low as necessary to achieve clinically useful images. (Time: 15-60 minutes, depending on the number of techniques measured) ## Xxi. imaging dose (2d systems) Imaging dose from 2D kV systems is most typically characterized using entrance surface air kerma (skin exposure). Measurement equipment used to measure the entrance air kerma includes a calibrated ionization chamber and a phantom. The ionization chamber is placed between the source and the phantom in such a way as to minimize scatter radiation to the ionization chamber. The field size is set to cover the detector. A clinically relevant beam is delivered, and the air kerma rate is calculated for static and fluoroscopic imaging modes, respectively. Measured imaging dose should be documented and its management should be approached with the goal of keeping it as low as necessary to achieve clinically useful images. (Time: 15-60 minutes, depending on the number of techniques measured) ## D. continuing quality improvement Ongoing review and audit of the IGRT program should occur at regular intervals. In particular, periodic review of clinical image registration, the use of appropriate imaging techniques/frequencies, adherence to stated QA programs, and revision of IGRT strategies based on pertinent changes in clinical practices should be assessed. ## Recommendations Recommended minimum practices for commissioning and QA of an IGRT system are shown in [fig_ref] Table 1: Recommended minimum practices for commissioning and QA of an IGRT system [/fig_ref]. Test frequencies and tolerance values were developed based on relevant AAPM Task Group reports and the experience of the MPPG members in relation to the stability and importance of each parameter to the IGRT process. Sample process descriptions are included in Section 5.c. The "baseline value" shown in the table refers to the IGRT system manufacturer's minimum performance standard stated in the customer acceptance procedure documentation. If unavailable or not specified, then "baseline value" can be taken as the value measured at the time of commissioning. For example, most IGRT system manufacturers have stated performance specifications for image quality and, in such cases; those may serve as the tolerance values for routine QA measurements of image quality. However, most IGRT system manufacturers do not have stated performance specifications for imaging dose and, in such cases, the imaging dose measured at the time of commissioning may serve as the baseline value to which future measurements are compared. In general, the frequency of routine QA tests is proportional to the importance of their performance for the purpose of patient alignment. As such, evaluation of imaging-treatment isocenter coincidence and positioning/repositioning is considered critical. While daily checks of these parameters are preferred, weekly checks are considered acceptable for IGRT systems used with standard fractionation schemes. For IGRT systems used for SRS/SBRT, daily QA testing frequency must also be required on days when procedures are scheduled. The imaging dose from an IGRT system must be measured for at least one acquisition technique of each mode of clinical operation. For example, a gantry-mounted kV system used to acquire both 2D and 3D clinical images must have documented imaging doses for both 2D and 3D modes. If imaging dose is only measured for one acquisition technique, then the chosen technique should serve to provide the most conservative value (e.g., choose the acquisition technique that results in the greatest imaging dose). For 2D kV systems operated in fluoroscopy mode, the entrance exposure rate should be measured for the technique expected to produce the highest value. These recommendations must also be augmented with procedures required by state regulations (such as measurement of X-ray tube voltage accuracy, where applicable). Furthermore, IGRT systems with known recurring problems should be subjected to more frequent QA at the discretion of the QMP. Annual end-to-end tests are also an effective method of assessing overall IGRT system accuracy, but are not required in this report. # Conclusions IGRT is a powerful and increasingly essential component of clinical radiation oncology practice. Proper use and quality assurance of clinical IGRT systems are of critical importance to maximizing the benefits and minimizing the risks of the technology. The minimum technical requirements for managing a clinical IGRT program stated in this document will help to achieve a more uniform standard of practice that improves the safety and quality of care of patients for whom IGRT is needed. [table] Table 1: Recommended minimum practices for commissioning and QA of an IGRT system. [/table]	None	https://europepmc.org/articles/pmc5711227?pdf=render	The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8,000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized.
4058f2ed9c80bf69465ad1fb96c80e8a3ed4d834	pubmed	Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus	Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus ## Step 3: identify key areas for revisions and define the structure and methodology of the updated guideline The chairman of the guideline committee (D.B. Sacks) acted as editor and assigned lead authors to each section. Authors reviewed the 2002 edition of the NACB DM guideline (1) and identified key areas for revisions and updating. The guideline team discussed the scope and methods of the updating process at a face-to-face meeting, which was followed by numerous teleconferences and e-mail exchanges among authors that were coordinated by the editor and the NACB. The guideline group decided that the structure of the guideline would remain the same as the 2002 document and that it would cover virtually all key analytes that are used primarily in the diagnosis and management of individuals with DM. As before, the testing of lipids and related cardiovascular risk factors is not covered in this update but is addressed in a separate NACB guideline. For each area of testing discussed, the guideline highlights the clinical use and rationale for the test or tests; the preanalytical, analytical, and interpretive aspects of each test; and, where relevant, emerging considerations for future research. ## Step 4: define and prioritize key questions The lead authors used the review process outlined above to define specific key questions to enter on a standard form developed for this process. These questions were sent to all members of the guideline committee for independent review and prioritization, a process that used preset criteria related to the relationship between testing and outcomes (see [fig_ref] Table 2: Criteria for prioritization of key questions [/fig_ref]. Authors used the categories and explanatory notes provided (see [fig_ref] Table 2: Criteria for prioritization of key questions [/fig_ref] to document the rationale for prioritization or individually provided their own reasoning. Authors assigned priority scores on a scale of 1 to 4 (most important, important, moderately important, or least important, respectively). The independent replies collected from all authors were the basis for drafting a consensus priority list. Final key questions with priority scores and categories of reasoning are presented in the evidence tables (see . ## Step 5: search the literature systematically for high-priority questions and select relevant key publications Key questions that earned the highest priority score were covered by a more systematic approach during the search and evaluation of the evidence currently available in the literature. Other topics that were considered less important were dealt with in a less rigorous way. Because this guideline is an update of the 2002 version, authors limited their searches to the period beginning in January 2002. Guidelines related to the topic were searched in the Agency for Healthcare Research and Quality National Guideline Clearinghouse database (http://www.guideline.gov/). Systematic reviews and metaanalyses were searched by using the Clinical Queries-Find Systematic Reviews function of PubMed. If no such publications were found, PubMed, Embase, and other databases were used to search the primary literature. Because the group of authors included leading experts in their fields, the authors' personal files, communications with experts, and unpublished or ongoing-trial data were also made available to be used in the guideline-updating process. Additional literature citations were added during the comment periods (see below). Authors selected relevant key publications for updating each section, and the editor of the guideline (D.B. Sacks) and lead authors of other sections (D.E. Bruns, M.S. Kirkman, D.M. Nathan) acted as independent expert reviewers to avoid biased selection of papers. When the guideline team retrieved and agreed with existing guideline recommendations that had already covered the key question comprehensively and had reached concordant conclusions, the guideline team simply adopted and referenced the published recommendations in order to avoid duplicate publication. ## Step 6: subject selected key publications to critical expert review; extract data into evidence tables Critical review of selected key publications formed the basis for establishing the level and quality of the evidence underlying each recommendation (see STEP 7 for details). Section authors and a methodology expert (A.R. Horvath) extracted data into evidence tables (see . These tables list all key questions together with their priority scores (STEP 4). Related recommendations and their grades from the 2002 guideline were aligned with those of the new updated recommendations (see columns 1 and 2 in . In the updated recommendation, authors highlighted changes to the original text in boldface and provided explanation for the changes where necessary (column 3). Key references supporting the new recommendation were listed (column 4). ## Step 7: define the quality of evidence underlying each recommendation To our knowledge, no uniformly accepted grading scheme exists for rating the quality of evidence and the strength recommendations when questions related to laboratory testing for the screening, diagnosis, prognosis, and monitoring of a condition are addressed [bib_ref] Grading quality of evidence and strength of recommendations for diagnostic tests and..., Horvath [/bib_ref]. The guideline group agreed that the grading scheme of the ADA, which was used in the 2002 version of this guideline (1), is applicable predominantly to therapeutic recommendations and that its use in this diagnostic guideline was thus impracticable. Therefore, we developed a grading system by adapting the key elements of evidence-rating frameworks employed by various international guideline agencies, the US Preventive Services Task Force, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group (6-12). In this system, the overall quality of the body of evidence (STEP 7) and the strength of recommendations (STEP 9) are graded separately. Rating the quality of the body of evidence is based on (a) the level of evidence of individual studies defined by their study design and methodological quality; (b) the consistency of results across various studies; (c) the directness of comparisons; and (d) the precision-of-effect estimates. Supplementary provides a detailed explanation of evidence-level categories and these elements of the rating scheme for the quality of evidence. Members of the guideline committee received detailed explanations and guidance, as well as methodological support, on how to use the grading scheme. At this stage of the guideline-development process, section authors indicated the study design (see column 5 in and the level of evidence (column 6) of all individual studies listed in the evidence tables. The quality of the totality of the evidence underlying each recommendation was established by means of the criteria mentioned above (column 7). ## Step 8: release the first draft of the guideline for public comments The first draft of the guideline was released on the NACB Web site for soliciting of public review and feedback. The still nongraded draft recommendations were sent to a number of external organizations (see for peer review and expert comments that could be submitted either via the NACB Web site or by mail. The draft guideline was also presented at the Arnold O. Beckman consensus conference in 2007, and the discussions at this conference were recorded. ## Step 9: incorporate comments, grade recommendations, and prepare the second draft of the guideline The guideline team reviewed and discussed the comments that were received and made many changes to the first draft to reflect the views of external peers, organizations, or individuals. The amended draft of the guideline was also presented at the 2009 AACC annual meeting and used for grading recommendations. The grade or strength of recommendation refers to the extent of collective confidence that the desirable effects of a recommendation outweigh the potential undesirable effects. Desirable effects of a recommendation may include improved health-related, organizational, or economic outcomes or aspects of care. The quality of evidence (STEP 7, Supplementary is only one element in making recommendations for practice. Scientific evidence was supplemented with considered judgment that balanced the potential clinical benefits and harms with perceived patients' preferences, bioethical considerations, and organizational and economic impacts of testing . Considered judgment therefore may have upgraded or downgraded a recommendation. Categories for grading recommendations are shown in . During the considered-judgment process, the guideline committee was primarily driven by 2 core bioethical values-beneficence and nonmalevolence. The guideline group also observed the first principle of bioethics, i.e., respect for patients' autonomy and the decision-making capacities of individuals to make their own choices. The guideline group assumes that the target users will also deal with this core bioethical principle when using these guidelines in practice (13). The guideline committee acknowledges that it was not able to cover universally other bioethical principles, such as justice and equity. As mentioned above, the members of the guideline team, as well as individuals who commented on the recommendations, were mostly from North America and other developed countries. Their views and experiences therefore unavoidably affected the considered-judgment and consensus processes involved in formulating recommendations. The guideline team also could not consider explicitly the cost implications of the recommendations in various resource settings, although recommendations were formulated in a generic way and in a cost-conscious manner. Recommendations in diagnostic guidelines frequently are supported primarily by expert consensus. This reflects the often poor quality of evidence, or the lack or indirectness of evidence that the intervention is relevant to patient outcomes. To avoid the influence of dominant personalities and overrepresentation of the individual opinions or views of experts, the guideline team reached consensus when the evidence base was inconsistent, weak, or lacking. The matrix in assisted in the assignment of final grades to recommendations. The methodology expert pregraded recommendations by using the information in columns 5, 6, and 7 of the evidence tables provided by committee members (see . Authors reviewed these grades and returned the amended evidence tables to the methodology expert for completion. Committee members added comments or explanatory notes when necessary (column 8) to enhance the transparency and reproducibility of the considered-judgment and consensus process of grading and to address the adaptability and applicability of the final recommendations. All sections were reviewed by the ADA representative (M.S. Kirkman), a clinical expert (D.M. Nathan), and a methodology expert (A.R. Horvath) and were edited by the chairman of the guideline committee (D.B. Sacks). ## Step 10: release the second draft of the guideline for public comments and submit the final draft to the nacb for review and approval The second draft of the guideline with graded recommendations was posted on the NACB Web site for a last call for public comments. The guideline recommendations were also reviewed by the Professional Practice Committee of the ADA. Several comments were received and incorporated, and the final guideline draft was submitted for review by the joint Evidence-Based Laboratory Medicine Committee of the AACC and the NACB. After addressing the reviewers' comments, the guideline committee referred the guideline to the NACB Board of Directors, which approved it before its official release for publication. ## Implementation and review To assist implementation, the guideline committee has listed the key recommendations of the guideline in an executive summary. Key diagnostic and risk-assessment criteria are presented in tables, and a diagnostic algorithm is provided for urinary albumin testing. Most recommendations are worded to represent standards of care and thus can be easily converted to key performance indicators for local audit purposes. Although recommendations have been developed for national and international use and are intended to be generic, certain elements of this guideline will not reflect views that are universally held, and other elements may have limited applicability in healthcare settings that lack sufficient resources for adopting the recommendations. The guideline committee advises users to adapt recommendations to their local settings. During such adaptation processes, the evidence tables provided (see might assist users in making informed decisions. The next review of this guideline is planned in 5 years, unless substantial new evidence emerges earlier for high-priority areas in the laboratory management of patients with DM. Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate and the recommendation. The body of evidence is of low level and comes from studies with serious design flaws or with evidence that is indirect. Very low: Any estimate of effect is very uncertain. Recommendation may change when higherquality evidence becomes available. Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information. ## Supplementary table 5. grading the strength of recommendations. ## A. the nacb strongly recommends adoption Strong recommendations for adoption are made when: - There is high-quality evidence and strong or very strong agreement of experts that the intervention improves important health outcomes and that benefits substantially outweigh harms; or - There is moderate-quality evidence and strong or very strong agreement of experts that the intervention improves important health outcomes and that benefits substantially outweigh harms. Strong recommendations against adoption are made when: - There is high-quality evidence and strong or very strong agreement of experts that the intervention is ineffective or that benefits are closely balanced with harms, or that harms clearly outweigh benefits; or - There is moderate-quality evidence and strong or very strong agreement of experts that the intervention is ineffective or that benefits are closely balanced with harms, or that harms outweigh benefits. ## B. the nacb recommends adoption Recommendations for adoption are made when: - There is moderate-quality evidence and level of agreement of experts that the intervention improves important health outcomes and that benefits outweigh harms; or - There is low-quality evidence but strong or very strong agreement and high level of confidence of experts that the intervention improves important health outcomes and that benefits outweigh harms; or - There is very low-quality evidence but very strong agreement and very high level of confidence of experts that the intervention improves important health outcomes and that benefits outweigh harms. Recommendations against adoption are made when: - There is moderate-quality evidence and level of agreement of experts that the intervention is ineffective or that benefits are closely balanced with harms, or that harms outweigh benefits; or - There is low-quality evidence but strong or very strong agreement and high level of confidence of experts that the intervention is ineffective or that benefits are closely balanced with harms, or that harms outweigh benefits; or - There is very low-quality evidence but very strong agreement and very high level of confidence http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc11-9998/-/DC1 of experts that the intervention is ineffective or that benefits are closely balanced with harms, or that harms outweigh benefits. ## C. the nacb concludes that there is insufficient information to make a recommendation Grade C is applied in the following circumstances: - Evidence is lacking, scarce, or of very low quality, the balance of benefits and harms cannot be determined, and there is no or very low level of agreement of experts for or against adoption of the recommendation. - At any level of evidence-particularly if the evidence is heterogeneous or inconsistent, indirect, or inconclusive-if there is no agreement of experts for or against adoption of the recommendation. ## Gpp. the nacb recommends it as good practice point Good practice points (GPPs) are recommendations mostly driven by expert consensus and professional agreement and are based on the information listed below and/or professional experience, or widely accepted standards of best practice. This category applies predominantly to technical (e.g., preanalytical, analytical, postanalytical), organizational, economic, or qualitymanagement aspects of laboratory practice. In these cases, evidence often comes from observational studies, audit reports, case series or case studies, nonsystematic reviews, guidance or technical documents, non-evidence-based guidelines, personal opinions, expert consensus, or position statements. Recommendations are often based on empirical data, usual practice, quality requirements, and standards set by professional or legislative authorities or accreditation bodies, etc. [fig] 3: and represented the NACB (D.B. Sacks, D.E. Bruns) and the ADA (M.S. Kirkman). The guideline committee included clinical experts (G.L. Bakris, A. Lernmark, B.E. Metzger, D.M. Nathan) and laboratory experts (D.B. Sacks, D.E. Bruns, M. Arnold, A.R. Horvath) whose key area of research and practice is DM. Some members of the committee provided additional support in evidence-based guideline-development methodology (D.E. Bruns, A.R. Horvath, D.B. Sacks). [/fig] [table] Table 2: Criteria for prioritization of key questions [/table]	None	http://care.diabetesjournals.org/content/diacare/34/6/e61.full.pdf	BACKGROUND Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. APPROACH An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence-Based Laboratory Medicine Committee of the American Association for Clinical Chemistry jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. CONTENT In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A1c (HbA1c) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended.
2adcb2b336ad8ac1f347243a3c43763d595751b5	pubmed	Recommendations Of The Brazilian Society Of Nephrology Regarding Pediatric Patients On Renal Replacement Therapy During The Covid-19 Pandemic	Recommendations Of The Brazilian Society Of Nephrology Regarding Pediatric Patients On Renal Replacement Therapy During The Covid-19 Pandemic # Abstract Introduction: The impact of the new coronavirus (SARS-COV-2) and its worldwide clinical manifestations (COVID-19) imposed specific regional recommendations for populations in need of specialized care, such as children and adolescents with kidney diseases, particularly in renal replacement therapies (RRT). We present the recommendations of the Brazilian Society of Nephrology regarding the treatment of pediatric patients with kidney diseases during the COVID-19 pandemic. Methods: Articles and documents from medical societies and government agencies on specific recommendations for children on RRT in relation to COVID-19 as well as those focused on epidemiological aspects of this condition in Brazil Were evaluated and analyzed. Results: We present recommendations on outpatient care, transportation to dialysis centers, peritoneal dialysis, hemodialysis, and kidney transplantation in children and adolescents during the COVID-19 pandemic in Brazil. Discussion: Despite initial observations of higher mortality rates in specific age groups (the elderly) and with comorbidities (obese, diabetics, and those with cardiovascular diseases), patients with chronic kidney disease (CKD) on RRT are particularly prone to develop COVID-19. Specific measures must be taken to reduce the risk of contracting SARS-CoV-2 and developing COVID-19, especially during transport to dialysis facilities, as well as on arrival and in contact with other patients. ## Keywords # Introduction The pandemic involving the new coronavirus SARS-CoV-2 and its clinical manifestations (COVID-19) to the World Health Organization recommending procedures in order to limit the spread as well as minimize the sudden and increasing lethality in distinct population groups. The Department of Pediatric Nephrology of the Brazilian Society of Nephrology (SBN in Portuguese) prepared this manuscript regarding recommendations for children and adolescents with kidney diseases and their respective families to mitigate the risk of acquiring and spreading the disease in Brazil. In Brazil, different profiles of children with chronic kidney disease (CKD) were described by Konstantiner et al emphasizing that areas with lower social and economic indexes have unsatisfactory access to medical facilities, which is corroborated by a higher proportion of patients with undefined etiology for CKD in such areas. Fernandes et al have reported that as much as 30% of patients live more than 50 km away from the referral Nephrology center. Each country has its own particularities regarding the management of COVID-19 in children and adolescents with kidney diseases. Nephrology Societies around the globe have adapted WHO recommendations 3 to local conditions and realities, such as the Sociedad Española de Nefrología 4 , the British Association for Paediatric Nephrology 5 , the EUDIAL Working Group of ERA-EDTA 6 , the Chinese Society of Pediatric Nephrology 7 , and the National Kidney ## Recommendations The care for pediatric patients involves many family and social aspects that should be considered by the Nephrology Center, which, in turn, must also be a center for continuing education regarding knowledge in all aspects of the COVID-19 pandemic, including isolation, prevention, and waste disposal at home. ## Patients on hemodialysis Transport to dialysis facilities by bus or other mode provided by health authorities (with other patients) is a common practice by children and their families. 1. Transportation to dialysis facilities should be provided by health authorities when not possible by the patient/family; standing patients during transport should not be allowed. The following procedures are recommended during transport to dialysis facilities 10,11 : ## Patients with chronic kidney disease under evaluation for a kidney transplant At the present time, Brazil is under quarantine and the urge for kidney transplantation must be evaluated on an individual basis, according to the Brazilian Association of Organ Transplantation recommendations. Donor and recipient must be considered at risk. ## Pediatric kidney transplant recipients In order to minimize the exposure to the virus, nonemergency consultations and hospital visits should be avoided. Use of a surgical mask when at hospitals or for blood sampling is advisable. In case of respiratory symptoms and/or fever, the transplantation center must be communicated. In confirmed cases, the same procedures as for children with COVID-19 on dialysis should be followed: health professionals should wear N95 or FFP2 masks preferably (or disposable surgical masks), eye protection (goggles or face shield), gloves, and gown. Immunosuppression therapy will be changed according to the Center's preferences. The most common approach is stopping the antimetabolite drug. In vitro studies showed that calcineurin inhibitors may play a protective role in coronavirus infections [bib_ref] Covid-19 and Calcineurin Inhibitors: Should They Get Left Out in the Storm?, Willicombe [/bib_ref]. Clinical evidence of this approach for COVID-19 remains to be defined. Hospital admission is advisable in specific cases. ## Pediatric patients on peritoneal dialysis (pd) Children and adolescents on PD with fever and/or respiratory symptoms must notify the referral center. The patient's condition must be reviewed and the dialysate aspect has to be evaluated (fever can be the only initial sign of peritonitis). Social isolation for at least 14 days is recommended (including from house contacts). Dyspnea should be promptly evaluated in the dialysis facility, and the health staff should be notified of the patient's arrival in order to minimize contamination risks at the unit. The delivery team (for dialysis materials) should be warned in order to minimize contact (avoid entering the patient's house, use of surgical mask, and handwashing by the driver/ delivery team is strictly recommended). # Conclusions Considering the continental proportion of Brazil, regional differences will demand emphasis on specific aspects of nephrology care of pediatric patients, mainly outpatient dialysis units (such as during transport). The interface between the health team and patients on any form of RRT should be maintained and strengthened during the pandemic. The present recommendations will need to be updated in the future as more research on COVID-19 is conducted. [fig] Foundation 8: The Brazilian Society of Nephrology is the main medical society involved in the care of this pediatric population on dialysis and nephrology care. The present article summarizes the main recommendations for specific care and management of children and adolescents with chronic kidney disease, dialysis, transplantation, and under immunosuppression during the COVID-19 pandemic.The present recommendations are based on documents of the Brazilian Society of Nephrology and Brazilian Association of Organ Transplantation (ABTO)9 , both dated March 16 th , 2020, and are in accordance with the Technical Note of the Brazilian Agency of Sanitation Surveillance (ANVISA) n.04/2020 from March 21st, 2020, and based on a brief review of medical literature and recommendations of other medical societies. [/fig] [fig] Figure 1: Flow chart of management of suspect and confirmed cases of COVID-19 in pediatric patients on hemodialysis facilities. [/fig]	None	https://www.scielo.br/j/jbn/a/9mWDbLN4qCZxTgDdpDPWP5s/?lang=en&format=pdf	ABSTRACT Introduction The impact of the new coronavirus (SARS-COV-2) and its worldwide clinical manifestations (COVID-19) imposed specific regional recommendations for populations in need of specialized care, such as children and adolescents with kidney diseases, particularly in renal replacement therapies (RRT). We present the recommendations of the Brazilian Society of Nephrology regarding the treatment of pediatric patients with kidney diseases during the COVID-19 pandemic. Methods Articles and documents from medical societies and government agencies on specific recommendations for children on RRT in relation to COVID-19 as well as those focused on epidemiological aspects of this condition in Brazil Were evaluated and analyzed. Results We present recommendations on outpatient care, transportation to dialysis centers, peritoneal dialysis, hemodialysis, and kidney transplantation in children and adolescents during the COVID-19 pandemic in Brazil. Discussion Despite initial observations of higher mortality rates in specific age groups (the elderly) and with comorbidities (obese, diabetics, and those with cardiovascular diseases), patients with chronic kidney disease (CKD) on RRT are particularly prone to develop COVID-19. Specific measures must be taken to reduce the risk of contracting SARS-CoV-2 and developing COVID-19, especially during transport to dialysis facilities, as well as on arrival and in contact with other patients.
d029181d90c2c855f58f4d2efbcc744239800c94	pubmed	Summary version of the Standards, Options and Recommendations for the management of adult patients with intracranial glioma (2002)	Summary version of the Standards, Options and Recommendations for the management of adult patients with intracranial glioma (2002) # Methods The general methodology used has already been described . 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 Cancer -FNCLCC) and the Association of French-speaking Neurooncologists (Association des Neuro-Oncologues d'Expression Franc¸aise -ANOCEF) to review the best available evidence on the management of adult patients with glioma. Medline s and Cancerlit s were searched using a specific strategy, for the period 1990 -2000. In addition, the members of the working group provided references from their personal sources up to 2001. The majority of the articles thus identified were in English or French. Many of the articles identified reported results for heterogeneous populations of patients (adults and children, and types of glioma), and therefore, when possible, information had to be extracted for specific populations and tumours. However, as this was not possible in all publications, not all the available literature could be analysed. Following the selection and critical appraisal of the articles, the working group produced a document with the proposed 'Standards', for the management of adult patients with glioma, based on scientific evidence or expert agreement. The document was then peer-reviewed by independent experts, and their comments were integrated in the final version. 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' Standards Procedures or treatments that are... [/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 [fig_ref] Table 2: Definition of level of evidence [/fig_ref]. When no clear scientific evidence exists, judgement is made according to the professional experience and consensus of the expert group ('expert agreement' 1 ), and this is validated by the peer-review process. This summary version has been translated from the French summary version, which was based on the integral version that will be published on the internet (http://www.fnclcc.fr). ## Incidence and risk factors for intracranial glioma An increased incidence of intracranial glioma has been reported (level of evidence: C). With the exception of phacomatosis, familial predisposition to these tumours has been reported in fewer than 5% of patients, and extensive family screening is therefore not warranted. Exposure to nitrate derivatives has been identified as a risk factor, and this constitutes occupational illness (level of evidence: C). No clear relationship between exposure to mobile telephones and increased risk of brain tumours has been documented (level of evidence: C). Exposure to low-frequency electromagnetic fields is thought to be associated with an increased risk (level of evidence: C). A national register of primary brain tumours should be created (recommendation). ## Diagnosis: histology, molecular biology and cytogenetics To avoid misclassification (generally lower grade), the surgeon should ensure that the samples are representative of the lesion, particularly of any area of contrast enhancement present (standard). The quality of the sample should be sufficient to allow histological diagnosis, that is, type of glioma and grade (standard), and also molecular-biological and cytogenetic investigations (option). ## Sample processing Some techniques require specific processing, therefore the sample taken by the surgeon should be processed immediately by the pathologist (recommendation). For histological diagnosis, the sample should be fixed with a 10% formaldehyde or zinc formaldehyde solution before embedding in paraffin (standard). Alcohol -formaldehyde -acetic acid (AFA) can be used for fixation (option) and is recommended for some molecular-biological investigations. Smear samples can be prepared from fresh tissue for diagnosis (recommendation). If the tissue is to be used for research purposes, a smear sample can be used to confirm tumour involvement of the processed tissue. For electronic microscopy, fixation with a 2% glutaraldehyde solution is possible (option). Sterile cell culture can be used for cytogenetic investigations (option). The sample can be immediately frozen in liquid nitrogen for molecular -biological investigations and for inclusion in a tumour tissue bank (option). ## Histological diagnosis The 2000 World Health Organization (WHO) classification is the standard for diagnosis and histoprognostic grading of glioma. Other classification systems (e.g. Smith, Daumas -Duport) can be used to complement the type and grading of oligodendroglioma (option). Diagnostic or prognostic immunohistochemistry (GFAP, Ki67, etc.) can be performed (option). A search for deletions of 1p and 19q chromosome should be undertaken, particularly in patients with oligodendroglial tumours (recommendation). Comparison of the results from histology and imaging can help to establish the diagnosis (option). Review of the histology by an expert committee is recommended in all difficult samples and in all clinical trials (recommendation). ## 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 ## Imaging diagnosis Preoperative imaging should be performed with and without intravenous contrast medium (standard). MRI should be used in preference to CT scanning (standard, expert agreement). Threedimensional scans should be taken using the same technique (standard). T1-weighted (with and without contrast medium), T2weighted MR images and/or fluid-attenuated inversion recovery (FLAIR) imaging should be undertaken (standard). MR images should be converted into a digital format on a numerical support system (e.g. CD) for possible subsequent dosimetric studies (recommendation). This imaging can be combined with functional MR, MR diffusion imaging, MR perfusion studies and/or with proton MR spectroscopy (options). In the setting of clinical trials, it is possible to perform a positron emission tomography (PET) scan or a single photon emission computed tomography (SPECT) scan (options). ## Post-therapeutic and follow-up imaging After surgical removal, imaging can be used to assess any residual tumour (option). MRI should be used, if possible (recommendation, level of evidence: B2), within 72 h, with and without contrast medium (recommendation). MRI is preferable to CT-scanning for follow-up of disease progression (recommendation). ## Treatment modalities surgery Histological confirmation Histological confirmation of the diagnosis should be obtained, because neuroradiological investigations are not sufficiently specific (standard, expert agreement). In exceptional situations, for example, elderly patients with a deepseated lesion, presenting a very poor systemic or neurological condition, the clinician may consider that the risk from biopsy outweighs the risk from misdiagnosis and decide not to perform biopsy (option, expert agreement). However, this should remain exceptional. Surgery Criteria for surgery include the patient's age, general health performance status, as well as investigations (anatomical/ functional data, presumed tumour type) and the technical support for surgery available (expert agreement). Tumour resection should be optimal, that is with margins as wide as possible, avoiding any major functional risks (standard, expert agreement). Surgical excision is the best means to obtain tissue samples that are representative of the whole lesion and to reduce the mass effect, if present (standard). The use of technical aids (preoperative functional MR, ultrasound aspiration, surgical microscope, neuro-navigation, intraoperative brain mapping) can optimise surgical resection (option, expert agreement). A biopsy (stereotactic, open skull) can be performed when surgical excision is not planned (standard). ## Radiotherapy External-beam radiotherapy Irradiation should be targeted using conventional external-beam radiotherapy (standard, level of evidence: B1). The gross tumour volume, or GTV, corresponds to contrast-enhanced image or, after complete excision, to the edges of the operative cavity (standard, expert agreement). For heterogeneous tumours (with hypo-intense and hyper-intense regions), and for hypo-intense tumours on T1-weighted images, the hypo-intense tumour volume is included in the GTV (recommendation, expert agreement). The clinical tumour volume, or CTV, should include a safety margin of 20 mm outside the GTV limit in all three dimensions (standard, expert agreement). This safety margin can be reduced, depending on the grade, histological type and the tumour volume, (option, expert agreement). Noncoplanar focalised multiple beam (3 -5) should be used to minimise the total fractionated dose delivered to the non-diseased brain (standard). Dose -volume histograms can be useful for defining the best treatment plan (option). All fields should be irradiated the same day with a fractionated dose varying from 1.8 to 2 Gy per fraction and per day, five times per week (standard). The dose should be adapted according to the histological type and the grade of the lesion and should not exceed a total of 60 Gy (standard). Prophylactic corticosteroid treatment should not be prescribed routinely (option, expert agreement), but can be used to reduce the risk of acute or early -delayed encephalopathy (radiation-induced oedema). Complications following external-beam radiotherapy Clinical and/or radiological deterioration in the 2 months after the end of radiotherapy should be interpreted with caution and not automatically be considered as a treatment failure (standard, level of evidence: C). The irradiation protocol (volume, total dose and particularly the dose per fraction), the presence of risk factors such as age (over 50 years old) and/or previous vascular disease (hypertension, diabetes, hyperlipidaemia) are associated with an increased risk for late neurological complications (radionecrosis, radiation-induced leucoencephalopathy) (level of evidence: C). The results from FDG-PET scanning, proton MR spectroscopy or 99m Tc methoxy isobutyl isonitrile (MIBI) brain scintigraphy can help the differential diagnosis between recurrence and radionecrosis (option). Other irradiation modalities Brachytherapy (level of evidence: B2), stereotactic radiotherapy (expert agreement), use of radiopotentiation (level of evidence: B1) and heavy particles (expert agreement) should only be used in the setting of clinical trials since their efficacy has not been proved (recommendation). ## Chemotherapy Efficacy of systemic chemotherapy The efficacy of the following nitrosourea derivatives has been reported: 1,3-bis(2-chloroethyl)-1-(BCNU) (level of evidence: A); 1-(2-chloroethyl)-3-cyclohexyl-1nitrosourea (CCNU) (level of evidence: C) and fotemustine (level of evidence: C). Nitrosourea molecules, particularly carmustine, have only been evaluated in clinical trials using definitions of response that are no longer used. Nitrosourea derivatives can be used in the PCV combination: procarbazine, CCNU and vincristine (option, level of evidence: B2). For second-line treatment, temozolomide (level of evidence: variable depending on the histology of the tumour), platinum derivatives either as a mono-or poly-chemotherapy (level of evidence: C) or procarbazine (expert agreement) can be considered. It is also possible to use another nitrosourea, if the time between the first-and second-line treatment is sufficiently long (level of evidence: D). Efficacy of local chemotherapy A local implant of BCNU can be considered in patients with recurrent disease (option, level of evidence: C). Other regional drug delivery strategies should only be envisaged in the setting of clinical trials (recommendation). ## Biological treatments (currently being evaluated) Pharmacological agents with specific modes of action (e.g. protein kinase C inhibitors) targeting with monoclonal antibodies or ligands, immunotherapy and/or gene therapy should only be used in the setting of clinical trials (recommendation). ## Concomitant medical treatments Treatment of oedema Patients with clinical or radiological evidence of brain oedema should be treated (standard, expert agreement). The minimal effective dose should be determined and regularly re-evaluated (standard, expert agreement). Treatment with corticosteroid or, less frequently, an osmotic agent can be considered (option, expert agreement). Patients should be monitored for side effects (standard, expert agreement). Methylprednisolone and prednisolone should be prescribed if possible, as single daily doses, in the morning (recommendation, expert agreement). If lymphoma is suspected, corticosteroid therapy should be avoided prior to obtaining histological confirmation, except for those patients whose neurological status requires this therapy (standard, expert agreement). The clinical and radiological evaluation of the tumour evolution should take into account the variations in the dose of corticosteroid (standard, expert agreement). Preventive treatment for gastrointestinal complications Perioperative H2-receptor blockers or proton pump inhibitors can be used to prevent gastrointestinal complications in patients receiving high doses of corticosteroids and/or in those with risk factors for ulcers (e.g. previous ulcers, concomitant anticoagulant or NSAID) (recommendation). ## Treatment of epilepsy Peri-operative treatment: Treatment for epilepsy can be prescribed routinely during the perioperative period for patients who have had seizures (standard). In other patient, peri-operative anticonvulsant treatment is an option (option, level of evidence: C). Post-operative treatment: In patients with previous seizures, anticonvulsant treatment should be continued in the postoperative period (standard). Since the efficacy of antiepileptic treatment in patients who have not had seizures has not been demonstrated, its prescription should be tailored to each patient (option, expert agreement). There are no data to guide the choice of which drug(s) should be used for antiepileptic treatment (recommendation). Any inducing and/or potentiating effect on the toxic effects of the chemotherapy should be taken into consideration (recommendation, expert agreement). First-line treatment should be single-drug treatment (recommendation). Analgesic treatment Appropriate analgesic treatment should be prescribed when necessary: for example, for intracranial hypertension, neoplastic meningitis, pain associated with retractions due to permanent deficit (standard). Anticoagulant treatment Surveillance, prevention and treatment for thromboembolism should be performed, since this occurs frequently in patients with glioma (standard). Prophylactic use of low-molecular weight heparin and compression stockings is recommended for preventing perioperative thromboembolic complications (recommendation, level of evidence: B2). After 4 -5-days of surgery, in the event of a thromboembolic complication, anticoagulant treatment at a therapeutic dose can be prescribed, without undue haemorrhagic risk (recommendation, expert agreement). ## Specific treatment strategies The management of patients with suspected glioma should be discussed with a multidisciplinary neuro-oncology team (standard). ## Grade 3 and 4 glioma Prognostic factors Age and preoperative functional status, as well as histological type and grade of the tumour are recognised prognostic factors (level of evidence: A). In patients with oligodendroglioma, deletion of chromosome 1p (particularly when there is also a deletion of chromosome 19q) is a favourable prognostic factor for survival and probably for treatment response (level of evidence: B2). Diagnosis and initial treatment For biopsy or surgery, all patients should be routinely transferred to a specialist centre (standard). All patients, except those with a high physiological age, and/or those with co-morbidities and/or with a poor performance status, and/or with lesions in functional, multifocal or centrally localised zones, should be offered optimal surgical resection when technically feasible, and if there is a low risk of permanent postoperative functional deterioration (standard, expert agreement). If this is not possible, histological evidence should be obtained by biopsy (standard). Investigations to assess residual tumour after surgical resection can be undertaken (see section on Post-therapeutic and follow-up imaging), but their prognostic value, in terms of survival, is controversial (option, expert agreement). Optimal cancer treatment plans are not feasible in only a low percentage of patients (high physiological age, multiple pathologies, poor functional status, centrally localised lesion, etc.) and in this rare situation biopsy is not mandatory (option). In this situation, palliative treatment, radiotherapy or chemotherapy can be offered, tailored to the individual patient (options) [fig_ref] Figure 1: Supratentorial grade 3 -4 glioma -initial management [/fig_ref]. Postoperative treatment [fig_ref] Figure 2: Supratentorial grade 3 -4 glioma -postoperative treatment [/fig_ref] All histology and findings from imaging and clinical examinations should be taken into account before initiating any additional anticancer treatment to verify the coherence of the clinical picture (recommendation). Additional treatment should be started within a month (recommendation). The modalities of radiotherapy and chemotherapy should be adapted to the patient's status. Patients should be included in clinical trials to evaluate postoperative treatment for high-grade glial tumours (recommendation). First-line external-beam radiotherapy should be offered to patients with high-grade glioma since it has been shown to improve survival (standard, level of evidence: A) although these clinical trials excluded patients with poor prognostic factors, such as a low Karnofsky score and/or advanced physiological age and/or large or multifocal tumours. A total dose of 60 Gy should be delivered, with a fractionation from 1.8 to 2 Gy per fraction and per day (recommendation). Glioblastoma and anaplastic astrocytoma: Radiotherapy should be offered (standard, level of evidence: A). This can be combined with chemotherapy with a nitrosourea-based chemotherapy (option, level of evidence: B1). When chemotherapy is selected, mono-drug chemotherapy with a nitrosourea should be offered to patients with glioblastoma (standard, level of evidence: A) and either mono-drug chemotherapy with a nitrosourea (BCNU), or multidrug chemotherapy with procarbazine, lomustine, and vincristine (PCV) for patients with anaplastic astrocytoma (recommendation, level of evidence: C). Anaplastic oligodendroglioma and oligoastrocytoma: Radiotherapy should be proposed for patients with anaplastic oligodendroglioma and oligoastrocytoma (standard, level of evidence: B2). Chemotherapy (PCV) has been shown to be efficacious in patients with oligodendroglioma. A combination of radiotherapy and chemotherapy can be considered, although the optimal timing of chemotherapy (neoadjuvant treatment vs adjuvant treatment vs treatment when the tumour recurs) has not been defined (option, level of evidence: B2). In selected patients with large unresectable tumours, and/or those who are elderly, and/or those who have had a complete response to neoadjuvant chemotherapy, it is not necessary to administer radiotherapy routinely (option, expert agreement). Treatment of tumour recurrence [fig_ref] Figure 3: Supratentorial grade 3 -4 glioma -treatment for tumour recurrence [/fig_ref] Patients should be included in clinical trials to evaluate treatment of tumour recurrence (recommendation). Five therapeutic options can be considered (options, expert agreement): surgery, systemic chemotherapy, local chemotherapy, second-line radiotherapy or palliative care without specific anticancer treatment. The decision to perform surgery should only be taken after multidisciplinary consultation (recommendation). For selected patients, newer irradiation techniques can be considered, using different modalities (brachytherapy, stereotactic radiotherapy) (option). Glioblastoma: There is no standard. Five therapeutic options can be considered (options, expert agreement): surgery, systemic chemotherapy, local chemotherapy, second-line radiotherapy or palliative care without specific anticancer treatment. The following drugs have shown moderate efficacy, and can be used if chemotherapy is indicated: temozolomide (option, level of evidence: C), nitrosourea molecules (option) and carmustine implants (option, level of evidence: C). Anaplastic astrocytoma: There is no standard. Five therapeutic options can be envisaged (options, expert agreement): surgery, systemic chemotherapy, local chemotherapy, second-line radiotherapy or palliative care without specific anticancer treatment. Temozolomide, which has been shown to have significant efficacy (option, level of evidence: C), and carmustine implants, which have been shown to have moderate efficacy, can be administered if chemotherapy is indicated (option, level of evidence: C). Nitrosourea molecules can be proposed, if the patient has not received them previously (option, expert opinion). Anaplastic oligodendroglioma and oligoastrocytoma: The second-line strategy depends on the first-line treatment used: In patients with recurrence after radiotherapy alone: chemotherapy with PCV can be considered (option, level of evidence: B2); In patients with recurrence after radiotherapy and chemotherapy with PCV: chemotherapy with temozolomide can be considered (option, level of evidence: C); In patients with recurrence after chemotherapy alone: radiotherapy should be considered when possible (option). If radiotherapy is not possible (older patients in poor condition with extensive tumour), second-line chemotherapy (option) can be considered. Grade 2 glioma [fig_ref] Figure 4: Grade [/fig_ref] The therapeutic decision must weigh the benefit of providing relief for distressing symptoms and avoiding or delaying anaplastic transformation, against the iatrogenic risk from treatment, particularly in patients whose tumour may fail to progress for a long time. Prognostic factors The factors for poor prognosis in patients with grade 2 glioma are: age X35 -40 years (level of evidence: B1), low Karnofsky score (level of evidence : B1), intracranial hypertension, functional deficit (level of evidence: C), uncontrolled epilepsy (level of evidence: C), large or rapidly increasing tumour volume and mass effect (level of evidence: C), localisation in a functional zone (level of evidence: C), involvement of deep structures (level of evidence: C), contrast enhancement on MR images (level of evidence: C). Diagnosis and initial treatment Radiological evaluation of grade 2 glioma should be based on MRI, both for diagnosis and followup (standard). For patients with a grade 2 glioma, optimal resection involves a total or subtotal removal of the tumour volume defined in T2 and/ or the FLAIR sequence on MRI (expert agreement). The prognostic value of complete resection is uncertain, but when it is possible to aim for radiologically complete resection safely, surgery should be undertaken (standard, expert agreement). When radiotherapy is proposed, the dose should be between 45 and 54 Gy (standard, level of evidence: B2). It is recommended to use a dose between 50 and 54 Gy (recommendation, expert agreement). Chemotherapy can be proposed, in symptomatic oligodendroglial tumours, preferentially in clinical trials, since its role in this indication is uncertain (option, level of evidence: D). The therapeutic strategy is based on the operability of the tumour and prognostic factors. If optimal resection is possible: In the presence of at least one poor prognostic factor, surgical resection should be undertaken (standard). In the absence of poor prognostic factors, surgical resection or surveillance with or without biopsy can be considered (options). If optimal resection is not possible: In the presence of at least one poor prognostic factor, partial resection, partial resection followed by radiotherapy, radiotherapy alone and chemotherapy can be proposed (options). The last two options should only be considered after histological confirmation. In the absence of poor prognostic factors, follow-up with or without biopsy, partial resection, partial resection followed by radiotherapy or biopsy followed by radiotherapy can be considered (options). Patients should be included in clinical trials to evaluate therapeutic strategies (recommendation). ## Gliomatosis cerebri The diagnosis of gliomatosis cerebri should be based on a comparison of the biopsy and radiological results (standard, expert agreement). Three treatment options can be considered: chemotherapy alone (option, level of evidence: D); follow-up for asymptomatic patients, without radiological signs of progression (option); and wholebrain radiotherapy (option). ## Pilocytic astrocytoma, subependymoma and xanthoastrocytoma Pilocytic astrocytoma Pilocytic astrocytoma should no longer be called low-grade astrocytoma or glioma. The growth of pilocytic astrocytoma is slow, and sometimes absent, particularly for neurofibromatosis type 1. Complete surgical resection significantly improves survival and often cures these patients (level of evidence: C). Optimal surgical resection should be offered to patients satisfying the operability criteria (standard). Even if complete resection is not possible, surgery can be considered, if the operability criteria are satisfied (option). Postoperative evaluation of the quality of the surgical resection should be performed with MRI (standard, expert agreement). If the MRI confirms complete resection, simple clinical follow-up is indicated (option, expert agreement). If the resection is incomplete, annual follow-up, over many years (clinical and MRI), should be undertaken (option, expert agreement). When resection is incomplete or not possible, and there is progression of the tumour, radiotherapy and/or chemotherapy can be considered although the indications and optimal modalities are uncertain (option). Pleomorphic xanthoastrocytoma [fig_ref] Figure 6: Pleomorphic [/fig_ref] Optimal surgical resection should be undertaken in all patients (standard, level of evidence: C). If the histological examination reveals anaplastic change (grade 3), postoperative external-beam radiotherapy should be undertaken, irrespective of the quality of the surgical excision (standard, level of evidence: C). If clinical or radiological tumour progression is observed, surgery and/or external-beam radiotherapy can be considered (option, level of evidence: C). Clinical follow-up should include MRI (recommendation). A pleomorphic xanthoastrocytoma register should be established (recommendation). ## Subependymoma (figure 7) First-line treatment for a symptomatic subependymoma is optimal resection (standard). In patients with recurrence, further optimal resection or radiotherapy can be considered (option). The histological grade can be taken into consideration, but it has an uncertain prognostic value (option). The work-up can include a spinal MRI and a lumbar puncture in patients with infratentorial tumours (option). Localised lesions Surgery is the standard treatment (standard, level of evidence: B) and complete surgical resection confirmed by early postoperative MRI is a good prognostic factor (level of evidence: B2). If radiotherapy is administered, localised radiotherapy, not craniospinal radiotherapy, should be proposed (standard, expert agreement). In patients with complete resection and a grade 2 tumour, no complementary treatment is necessary (standard). For patients with a grade 3 tumour, focalised postoperative radiotherapy (option, level of evidence: C) or follow-up (option) can be offered. In patients with incomplete resection and a grade 2 tumour, the treatment options are: follow-up, further resection or localised postoperative radiotherapy (options, level of evidence: C). If the tumour is grade 3, localised radiotherapy should be offered (standard). In this case, further resection or chemotherapy can be considered (options). In patients with recurrence, further resection, radiotherapy, chemotherapy or palliative treatment can be considered (options). Metastatic lesions Patients with metastatic disease at presentation have a poor prognosis (level of evidence: B2). Craniospinal radiotherapy should be offered (standard, expert agreement). Optimal surgical resection can be undertaken before radiotherapy (option). Chemotherapy can be offered (option). ## Brain stem glioma (figure 9) In patients with hydrocephalus, a cerebrospinal fluid shunt should be offered (standard). Lesions with different prognoses can be Diffuse lesions Biopsy can be considered (option). The patient's clinical status should be considered in any treatment decision (recommendation): Only progressive tumours, as diagnosed from clinical symptoms and/or radiological images, should be treated with radiotherapy (option, level of evidence: C). Chemotherapy can be considered after failure of radiotherapy (option). For certain patients, palliative treatment only can be considered (option). Focal exophytic lesions Biopsy or resection can be considered (option). Depending on the histology (if this can be determined: see section on each histological type), age and MRI results, optimal resection, radiotherapy or follow-up alone can be considered (options). An optimal resection should be undertaken whenever possible (recommendation). Tectal plate lesions No treatment, with follow-up alone, can be considered (option). Neurofibromatosis type 1 Follow-up alone can be considered for patients with non-progressive brain stem glioma (option). Radiotherapy and/or chemotherapy can be considered for patients with progressive brain stem glioma (option). ## Figure 9 Brain stem glioma. [fig] Figure 1: Supratentorial grade 3 -4 glioma -initial management. [/fig] [fig] Figure 2: Supratentorial grade 3 -4 glioma -postoperative treatment. [/fig] [fig] Figure 3: Supratentorial grade 3 -4 glioma -treatment for tumour recurrence. [/fig] [fig] Figure 4: Grade [/fig] [fig] Figure 6: Pleomorphic [/fig] [fig] Figure 8: Intracranial of Cancer (2003) 89(Suppl 1), S73 -S83 & 2003 FNCLCC identified from their localisation and their neuro-radiological appearance. [/fig] [table] Table 1: Definition of 'Standards, options and recommendations' Standards 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 of harmful by a majority, based on the best available evidence [/table] [table] Table 2: Definition of level of evidence [/table]	None	https://www.nature.com/articles/6601087.pdf	None
fb89f822a6091a2882411556d53fbc4268b3a568	pubmed	2020 update of the WSES guidelines for the management of acute colonic diverticulitis in the emergency setting	2020 update of the WSES guidelines for the management of acute colonic diverticulitis in the emergency setting Acute colonic diverticulitis is one of the most common clinical conditions encountered by surgeons in the acute setting. An international multidisciplinary panel of experts from the World Society of Emergency Surgery (WSES) updated its guidelines for management of acute left-sided colonic diverticulitis (ALCD) according to the most recent available literature. The update includes recent changes introduced in the management of ALCD. The new update has been further integrated with advances in acute right-sided colonic diverticulitis (ARCD) that is more common than ALCD in select regions of the world. # Introduction Acute left-sided colonic diverticulosis is common in Western countries with its prevalence increasing throughout the world, which is likely due to changes in lifestyle [bib_ref] Diverticular disease: epidemiology and management, Weizman [/bib_ref]. Although left-sided colonic diverticulosis remains more common among elderly patients, a dramatic rise of its incidence has been seen in younger age groups in recent years [bib_ref] Diverticular disease of the colon: a century-old problem, Schoetz [/bib_ref]. Recent evidence suggests that lifetime risk of developing acute left-sided colonic diverticulitis (ALCD) is about 4% among patients with diverticulosis [bib_ref] Long-term risk of acute diverticulitis among patients with incidental diverticulosis found during..., Shahedi [/bib_ref] , and data from Western populations suggest that up to one fifth of patients with acute diverticulitis are under 50 years of age [bib_ref] Modern concepts in diverticular disease, Collins [/bib_ref] [bib_ref] Fourteen-year study of hospital admissions for diverticular disease in Ontario, Warner [/bib_ref] [bib_ref] Major increase in admission-and incidence rates of acute colonic diverticulitis, Talabani [/bib_ref]. ALCD is a common problem encountered by Western surgeons in the acute setting. The sigmoid colon is usually the most commonly involved part, while acute rightsided diverticulitis (ARCD) is rarer but much more common in non-Western populations. # Methods The World Society of Emergency Surgery (WSES) guidelines for management of ALCD were published in 2016 [bib_ref] WSES guidelines for the management of acute left sided colonic diverticulitis in..., Sartelli [/bib_ref]. In 2020, the guidelines were revised and updated. The present guidelines have been developed according to the GRADE methodology [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] [bib_ref] Grading quality of evidence and strength of recommendations in clinical practice guidelines:..., Brozek [/bib_ref]. The GRADE system is a hierarchical, evidence-based tool, which systematically evaluates the available literature and focuses on the level of evidence based upon the types of studies included. The quality of evidence can be marked as high, moderate, low, or very low. This could be either downgraded in case of significant bias or upgraded when multiple high-quality studies showed consistent results. The highest quality of evidence studies (systematic reviews with meta-analysis of randomized controlled trials) was assessed first. If the meta-analysis was of sufficient quality, it was used to answer the research question. If no meta-analysis of sufficient quality was found, randomized controlled trials (RCTs) and non-randomized cohort studies (n-RCS) were evaluated. The strength of the recommendation was based on the level of evidence and qualified as weak or strong. A multidisciplinary panel of experts, coordinated by a central coordinator, was selected to serve as experts in this 2020 update of the WSES guidelines for the management of acute left-sided colonic diverticulitis (ALCD). The experts reviewed and updated the original list of key questions on the diagnosis and treatment of ALCD addressed in the previous version of the guidelines. For each statement, a consensus among the panel of experts was reached using a Delphi approach. Statements were approved with an agreement of ≥ 80%. After the approval of the statements, the expert panel met via email to prepare and revise the definitive guidelines. The manuscript was successively reviewed by all members and ultimately revised as the present manuscript. Which classification should be used in patients with ALCD? There are multiple classification systems for ALCD. None has been conclusively proven to be superior in predicting patient outcomes, and therefore, a specific recommendation cannot be provided. ALCD ranges in severity from uncomplicated phlegmonous diverticulitis to complicated diverticulitis including abscess and/or perforation. For the past three decades, the Hinchey classification has been the most used classification in the international literature [bib_ref] Treatment of perforated diverticular disease of the colon, Hinchey [/bib_ref]. In patients with surgical findings of abscesses and peritonitis, Hinchey et al. classified the severity of acute diverticulitis into four levels: 1 Pericolic abscess 2 Pelvic, intra-abdominal, or retroperitoneal abscess 3 Generalized purulent peritonitis 4 Generalized fecal peritonitis In recent years, the management of ALCD has changed dramatically. Computer tomography (CT) imaging has become a primary diagnostic tool in the diagnosis and staging of patients with ALCD, and more detailed information provided by CT scans led to several modifications of the Hinchey classification [bib_ref] Modern concepts in diverticular disease, Collins [/bib_ref] [bib_ref] Diagnosis and treatment, Neff [/bib_ref] [bib_ref] Colonic diverticulitis: impact of imaging on surgical management-a prospective study of 542..., Ambrosetti [/bib_ref] [bib_ref] The management of complicated diverticulitis and the role of computed tomography, Kaiser [/bib_ref] [bib_ref] Application of a modified Neff classification to patients with uncomplicated diverticulitis, Lopez [/bib_ref] [bib_ref] Staging of acute diverticulitis based on clinical, radiologic, and physiologic parameters, Sallinen [/bib_ref]. In 1989, Neff et al. presented a new classification of ALCD based on CT findings. It consisted of five stages, ranging from radiological diagnosis of uncomplicated (stage 0) to pneumoperitoneum with abundant free liquid (stage 4) [bib_ref] Diagnosis and treatment, Neff [/bib_ref] : 0 Uncomplicated diverticulitis; diverticula, thickening of the wall, increased density of the pericolic fat 1 Locally complicated with local abscess 2 Complicated with pelvic abscess 3 Complicated with distant abscess 4 Complicated with other distant complications In 2002, Ambrosetti et al. [bib_ref] Colonic diverticulitis: impact of imaging on surgical management-a prospective study of 542..., Ambrosetti [/bib_ref] classified ALCD into severe or moderate disease. In this classification, the CT scan determined the grade of severity guiding the physician in the treatment of acute complications. Moderate diverticulitis was defined by wall thickening of ≥ 5 mm and signs of pericolic fat inflammation. Severe diverticulitis was defined by wall thickening accompanied by abscess, extraluminal gas, or extraluminal contrast: [bib_ref] Application of a modified Neff classification to patients with uncomplicated diverticulitis, Lopez [/bib_ref] a modification of the previous Neff classification dividing Neff stage 1 into stage 1a (localized pneumoperitoneum in the form of gas bubbles) and 1b (abscess < 4 cm). 0Uncomplicated diverticulitis. Diverticula, thickening of the wall, increased density of the pericolic fat 1Locally complicated diverticulitis 1aLocalized pneumoperitoneum in the form of gas bubbles 1bAbscess (< 4 cm) 2Complicated diverticulitis with pelvic abscess. Abscess > 4 cm in pelvis 3Complicated diverticulitis with distant abscess. Abscess in abdominal cavity (outside pelvis) 4Complicated diverticulitis with other distant complications. Abundant pneumoperitoneum and/or intraabdominal free liquid Recently, Sallinen et al. [bib_ref] Staging of acute diverticulitis based on clinical, radiologic, and physiologic parameters, Sallinen [/bib_ref] published an interesting retrospective study of patients treated for ALCD, setting the stage for the treatment of acute diverticulitis based on clinical, radiologic, and physiologic parameters: 1Uncomplicated diverticulitis 2Complicated diverticulitis with small abscess (< 6 cm) 3Complicated diverticulitis with large abscess (≥ 6 cm) or distant intraperitoneal or retroperitoneal gas 4Generalized peritonitis without organ dysfunction 5Generalized peritonitis with organ dysfunction Finally, a proposal for a CT-guided classification of ALCD was published in 2015 by the WSES acute diverticulitis working group [bib_ref] WSES guidelines for the management of acute left sided colonic diverticulitis in..., Sartelli [/bib_ref]. It is a simple classification system of ALCD based on CT scan findings. It may guide clinicians in the management of acute diverticulitis and may be universally accepted for day to day practice. The WSES classification divides acute diverticulitis into 2 groups: uncomplicated and complicated. In the event of uncomplicated acute diverticulitis, the infection only involves the colon and does not extend to the peritoneum. In the event of complicated acute diverticulitis, the infectious process proceeds beyond the colon. Complicated acute diverticulitis is divided into 4 stages, based on the extension of the infectious process: Uncomplicated 0Diverticula, thickening of the wall, increased density of the pericolic fat Complicated 1APericolic air bubbles or small amount of pericolic fluid without abscess (within 5 cm from inflammed bowel segment) 1BAbscess ≤ 4 cm 2AAbscess > 4 cm 2BDistant gas (> 5 cm from inflammed bowel segment) 3Diffuse fluid without distant free gas 4Diffuse fluid with distant free gas What is the best way to make a diagnosis of ALCD? In patients with suspected ALCD, we suggest a complete assessment of the patients using clinical history, signs, laboratorial inflammation markers, and radiological findings (weak recommendation based on very low-quality evidence, 2D). In patients with suspected, ALCD we suggest against diagnosis based only on clinical examination (weak recommendation based on very low-quality evidence, 2D). Clinical findings of patients having ALCD include acute pain or tenderness in the left lower quadrant that may be associated with increased inflammatory markers, including C-reactive protein (CRP) and white blood cell count (WBC). Clinical diagnosis of ALCD usually lacks accuracy. In a prospective analysisconducted on 802 consecutive patients who presented with abdominal pain to the emergency department, positive and negative predictive values of clinical diagnosis were 0.65 and 0.98, respectively. Additional cross-sectional imaging had a positive and negative predictive value of 0.95 and 0.99, respectively. Additional radiology examinations improved the diagnostic accuracy in 37% of the patients, but changed the management in only 7%. In 2010, using logistic regression analysis, Laméris et al. [bib_ref] A clinical decision rule to establish the diagnosis of acute diverticulitis at..., Laméris [/bib_ref] developed a clinical decision rule for diagnosis of ALCD, based on 3 criteria: (1) direct tenderness only in the left lower quadrant, (2) CRP > 50 mg/l, and (3) absence of vomiting. Of 126 clinically suspected patients enrolled in this prospective study, 30 patients had all 3 features (24%), of whom 29 had a final diagnosis of acute diverticulitis (97%; 95% CI 83-99%). Of the 96 patients without all 3 features, 45 (47%) did not have diverticulitis. In a quarter of patients with suspected diverticulitis, the diagnosis could be made clinically based on the combination of the three criteria. Andeweg et al. in 2011 [bib_ref] How to diagnose acute left-sided colonic diverticulitis: proposal for a clinical scoring..., Andeweg [/bib_ref] , using retrospective data from 287 patients, developed a clinical scoring system for the diagnosis of ALCD with diagnostic accuracy of 86%. It was based on independent predictors of ALCD including age, a clinical history of one or more previous episodes, localization of symptoms in the lower left abdomen, aggravation of pain on movement, the absence of vomiting, localization of abdominal tenderness on examination in the lower left abdomen, and C-reactive protein of 50 mg/l or higher. CRP has been identified as a useful biomarker of inflammation, and it may be useful in the prediction of the clinical severity of acute diverticulitis as demonstrated by several recent studies [bib_ref] The role of C-reactive protein in the prediction of the clinical severity..., Kechagias [/bib_ref] [bib_ref] The value of inflammation markers and body temperature in acute diverticulitis, Van De Wall [/bib_ref] [bib_ref] The role of C-reactive protein in prediction of the severity of acute..., Mäkelä [/bib_ref]. To investigate the value of CRP and of other laboratory parameters of the patients in the prediction of the clinical severity of acute diverticulitis, a retrospective study was published in 2014 [bib_ref] The role of C-reactive protein in the prediction of the clinical severity..., Kechagias [/bib_ref]. A CRP cutoff value of 170 mg/l significantly discriminated severe from mild diverticulitis (87.5% sensitivity, 91.1% specificity, area under the curve 0.942, p < 0.00001). The authors concluded that CRP is a useful tool in the prediction of the clinical severity of acute diverticulitis. A mild episode is very likely in patients with CRP less than 170 mg/l. Those with higher CRP values have a greater probability of undergoing surgery or percutaneous drainage. In another study, the diagnostic value of serological infection markers and body temperature, in discriminating complicated from uncomplicated diverticulitis, was assessed [bib_ref] The value of inflammation markers and body temperature in acute diverticulitis, Van De Wall [/bib_ref]. A total of 426 patients were included in this study of which 364 (85%) presented with uncomplicated and 62 (15%) with complicated diverticulitis. Only CRP was of sufficient diagnostic value (area under the curve 0.715). The median CRP in patients with complicated diverticulitis was significantly higher than in patients with uncomplicated disease (224 mg/l, range 99-284, vs. 87 mg/l, range 48-151, respectively). Patients with a CRP of 25 mg/l had a 15% chance of having complicated diverticulitis. This increased from 23% at a CRP value of 100 mg/l to 47% for 250 mg/l or higher. The optimal threshold was reached at 175 mg/l with a positive predictive value of 36%, negative predictive value of 92%, sensitivity of 61%, and specificity of 82%. Mäkelä et al. [bib_ref] The role of C-reactive protein in prediction of the severity of acute..., Mäkelä [/bib_ref] published a study comparing the CRP values of 350 patients who presented for the first time with symptoms of acute diverticulitis with the CT findings and clinical parameters by means of both univariate and multivariate analyses. CRP cutoff value of 149.5 mg/l significantly discriminated acute uncomplicated diverticulitis from complicated diverticulitis (specificity 65%, sensitivity 85%, area under the curve 0.811, p = 0.0001). In multivariate analysis, a CRP value over 150 mg/l and old age were independent risk factors for acute complicated diverticulitis. The mean CRP value was significantly higher in the patients who died (mean CRP of 207 mg/l) than in those who survived (mean CRP of 139 mg/l). In addition, a CRP value over 150 mg/l and free abdominal fluid in CT were independent variables predicting postoperative mortality. The study confirmed that CRP is useful for predicting the severity of acute diverticulitis on admission. The authors concluded that patients with a CRP value higher than 150 mg/l have an increased risk of complicated diverticulitis and should always undergo a CT examination. In 2018, a prospective study of patients with ALCD was published [bib_ref] Index C-reactive protein predicts increased severity in acute sigmoid diverticulitis, Kechagias [/bib_ref]. All patients underwent CT. Index parameters obtained at the initial evaluation in the emergency unit were analyzed to assess the association with the outcome. Ninety-nine patients were analyzed. Eighty-eight had mild radiological grading (Hinchey Ia/ Ib), and 11 had severe radiological grading (Hinchey > Ib) (median index CRP 80 mg/l vs. 236 mg/l, p < 0.001). The median CRP level for Hinchey III/IV was 258.5 mg/l (201-297 mg/l). WBC, neutrophils/lymphocytes, serum creatinine, serum glucose, generalized peritonitis, generalized abdominal tenderness, urinary symptoms, and index CRP were related to severe disease. Index CRP was the only independent predictor for Hinchey > Ib (p = 0.038). The optimal cutoff value calculated by receiver operating characteristic curve analysis was found to be 173 mg/l (sensitivity 90.9%, specificity 90.9%, p < 0.001). All patients who underwent radiologic-guided percutaneous or surgery had an index CRP > 173 mg/l and Hinchey > Ib. However, the authors concluded that CRP should not be used as a predictor of severity if there are concomitant conditions that may affect its baseline levels. The expert panel states that in very acutely onset disease, CRP values might not have rised yet, since there is a delay of 6-8 h from the onset of the disease, reaching peak at 48 h. Therefore, caution should be used in using low CRP as excluding out acute diverticulitis [bib_ref] C-reactive protein and the acute phase response, Gewurz [/bib_ref]. What is the best imaging technique in patients with suspected ALCD? What is the role of ultrasound (US) in patients with ALCD? In patients with suspected ALCD, we suggest contrastenhanced CT scan of the abdomen as the imaging technique of first choice (weak recommendation based on moderate-quality evidence, 2B). We suggest to use US in the initial evaluation of patients with suspected ALCD where it is performed by an expert operator. It has wide availability and easy accessibility. A step-up approach with CT performed after an inconclusive or negative US may be a safe approach for patients suspected of acute diverticulitis (weak recommendation based on moderate-quality evidence, 2B). Radiological imaging techniques that are used for diagnosing ALCD in the emergency setting are US and CT. Currently, CT is the established method of choice when compared to US and most guidelines cite the high accuracy and other advantages of CT. This approach is the gold standard for both the diagnosis and the staging of patients with ALCD due to its excellent sensitivity and specificity [bib_ref] Graded compression ultrasonography and computed tomography in acute colonic diverticulitis: meta-analysis of..., Laméris [/bib_ref] [bib_ref] Acute left colonic diverticulitis-compared performance of computed tomography and watersoluble contrast enema:..., Ambrosetti [/bib_ref]. CT scan can also rule out other diagnoses such as ovarian pathology, or leaking aortic or iliac aneurysm. CT findings in patients with ALCD may include diverticulosis with associated colon wall thickening, fat stranding, phlegmon, extraluminal gas, abscess formation, or intra-abdominal free fluid. CT imaging can go beyond accurate diagnosis of ALCD. CT criteria may also be used to determine the grade of severity and may drive treatment planning of patients [bib_ref] A proposal for a CT driven classification of left colon acute diverticulitis, Sartelli [/bib_ref]. US is a real-time dynamic examination with wide availability and easy accessibility [bib_ref] Sigmoid diverticulitis: US findings, Mazzei [/bib_ref]. Its limitations include operator dependency, poor assessment in obese patients, and difficulty in the detection of free gas and deeply located abscesses [bib_ref] Ultrasound of colon diverticulitis, Puylaert [/bib_ref]. A systematic review and meta-analysis of studies [bib_ref] Toward an evidence-based step-up approach in diagnosing diverticulitis, Andeweg [/bib_ref] that reported diagnostic accuracy of the clinical diagnosis and diagnostic modalities in patients with suspected diverticulitis was published in 2014. Summary sensitivity estimates for US were 90% (95% CI 76-98%) versus 95% (95% CI 91-97%) for CT (p = 0.86). Summary specificity estimates for US were 90% (95% CI 86-94%) versus 96% (95% CI 90-100%) for CT (p = 0.04). Although CT is the most sensitive imaging investigation for patients with suspected acute diverticulitis, a step-up approach with CT performed after an inconclusive or negative US has been proposed as safe and alternative approach for patients with suspected acute diverticulitis [bib_ref] Toward an evidence-based step-up approach in diagnosing diverticulitis, Andeweg [/bib_ref] [bib_ref] OPTIMA study group: imaging strategies for detection of urgent conditions in patients..., Laméris [/bib_ref]. Magnetic resonance imaging, which is not constrained by the operator dependency limitation of compared to US [bib_ref] Prospective evaluation of the value of magnetic resonance imaging in suspected acute..., Heverhagen [/bib_ref] [bib_ref] Prospective evaluation of the value of magnetic resonance imaging in suspected acute..., Halpenny [/bib_ref] , until now is currently difficult to perform at in the emergency department. Are immunocompromised patients with ALCD at risk for failure of standard, non-operative treatment? We suggest that immunocompromised patients with ALCD be considered at high risk for failure of standard, non-operative treatment (weak recommendation based on very low-quality evidence, 2D). Immunocompromised patients are at increased risk for complicated ALCD [bib_ref] Diverticulitis in transplant patients and patients on chronic corticosteroid therapy: a systematic..., Hwang [/bib_ref] [bib_ref] Acute diverticulitis with colon perforation in renal transplantation, Valle [/bib_ref] [bib_ref] Severe diverticulitis after heart, lung, and heart-lung transplantation, Qasabian [/bib_ref] [bib_ref] Complicated diverticulitis following renal transplantation, Lederman [/bib_ref]. Immunocompromised patients may fail standard, non-operative treatment. As such, most of these patients require urgent surgical intervention, and this is associated with a significantly higher mortality rate [bib_ref] Controversies in the surgical management of sigmoid diverticulitis, Bordeianou [/bib_ref]. A recent study by Biondo et al. [bib_ref] Outcomes of colonic diverticulitis according to the reason of immunosuppression, Biondo [/bib_ref] analyzed the relationship between the different causes of immunosuppression (IMS) and ALCD. Immunocompromised patients were divided in 5 groups according to the causes of IMS: group I, chronic corticosteroid therapy; group II, transplant patients; group III, malignant neoplasm disease; group IV, chronic renal failure; and group V, other immunosuppressant treatments. The rate of emergency surgery was high (39.3%), and it was needed more frequently in group I (chronic corticosteroid therapy). In this study, postoperative mortality was of 31.6% and recurrence rate after successful non-operative management occurred in 30 patients (27.8%). ## Should antibiotics be recommended in immunocompetent patients with uncomplicated acute diverticulitis? In immunocompetent patients with uncomplicated diverticulitis without signs of systemic inflammation, we recommend to not prescribe antibiotic therapy (strong recommendation based on high-quality evidence, 1A). In patients requiring antibiotic therapy, we recommend oral administration whenever possible, primarily, because an early switch from intravenous to oral therapy may facilitate a shorter inpatient length of stay (strong recommendation based on moderate-quality evidence, 1B). The definition of uncomplicated acute diverticulitis is often vague and poorly defined. Uncomplicated acute diverticulitis is defined as localized diverticular inflammation without any abscess or perforation. A universally accepted classification divides intra-abdominal infections (IAIs) into complicated and uncomplicated [bib_ref] The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines..., Sartelli [/bib_ref]. In uncomplicated IAIs, the infection only involves a single organ and does not extend to the peritoneum, while in complicated IAIs, the infectious process extends beyond the organ, causing either localized or diffuse peritonitis [bib_ref] The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines..., Sartelli [/bib_ref]. For a better definition of acute diverticulitis in these guidelines, we use the term complicated and uncomplicated according to the classification of IAIs. Uncomplicated acute diverticulitis is an anatomically confined inflammatory process. CT findings include diverticula, thickening of the wall, and increased density of the pericolic fat. Patients with uncomplicated diverticulitis usually have an indolent course with a low incidence of subsequent complications. The utility of antibiotics in acute uncomplicated acute diverticulitis has been a point of controversy. In recent years, several studies demonstrated that antimicrobial treatment was not superior to withholding antibiotic therapy, in terms of clinical resolution, in patients with mild unperforated diverticulitis [bib_ref] Antibiotics for uncomplicated diverticulitis, Shabanzadeh [/bib_ref]. The current consensus is that uncomplicated acute diverticulitis may be a self-limiting condition in which local host defenses can manage the inflammation without antibiotics in immunocompetent patients. In this context, antibiotics are not necessary in the treatment of uncomplicated disease. A multicenter randomized trial was published in 2012 by Chabok et al. involving ten surgical departments in Sweden and one in Iceland recruiting 623 patients with computed tomography-confirmed acute uncomplicated left-sided diverticulitis [bib_ref] Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis, Chabok [/bib_ref]. Patients were randomized to treatment with (314 patients) or without (309 patients) antibiotics. Antibiotic treatment for acute uncomplicated diverticulitis neither accelerated recovery nor prevented complications or recurrence. Therefore, antibiotics should be reserved for the treatment of complicated diverticulitis. A prospective, single-arm, study overviewed [bib_ref] Symptomatic treatment for uncomplicated acute diverticulitis: a prospective cohort study, Mali [/bib_ref] the safety and efficacy of symptomatic (non-antibiotic) treatment for CT-proven uncomplicated acute diverticulitis during a 30-day follow-up period. Overall, 161 patients were included in the study, and 153 (95%) completed the 30-day follow-up. A total of 14 (9%) patients had pericolic gas. Altogether, 140 (87%) patients were treated as outpatients, and 4 (3%) of them were admitted to the hospital during the follow-up. The primary outcome measure of the study was to find the incidence of complicated diverticulitis. None of the patients developed complicated diverticulitis or required surgery, but 2 days (median) after inclusion, antibiotics were given to 14 (9%, 6 orally, 8 intravenously) patients. A recent Dutch randomized controlled trail of observational versus systemic antibiotic treatment (DIABOLO trial) [bib_ref] Symptomatic treatment for uncomplicated acute diverticulitis: a prospective cohort study, Mali [/bib_ref] for a first episode of CT-proven ALCD Hinchey stages 1a and 1b confirmed that observational treatment without antibiotics did not prolong recovery and could be considered appropriate in these patients. This study included 22 clinical sites involving 528 patients; Hinchey modified stages 1a (confined pericolic inflammation or phlegmon) to 1b (pericolic or mesocolic abscess) and Ambrosetti's "mild/moderate" diverticulitis stage confirmed within 24 h by CT were included. Patients with previous diverticulitis, higher Hinchey stages, or "severe" diverticulitis on Ambrosetti's classification were excluded. The antibiotic treatment was a 10-day course of IV amoxicillin-clavulanic acid, 1200 mg four times daily for at least 48 h. After 48 h, the administration route could be switched to per os, 625 mg three times daily. For observational treatment, patients had to meet the criteria of tolerating a normal diet, temperature less than 100.4°F, a pain score below 4 on a visual analogue scale (using only acetaminophen for pain control), and the ability to support self at the same level as before illness. If the patient deteriorated, CT was repeated and antibiotic treatment was started if the temperature rose above 102.2°F, blood cultures were positive, or the patient was septic. No significant differences between the observation and antibiotic treatment groups were found for secondary endpoints: complicated diverticulitis (3.8% vs. 2.6%, respectively; p = 0.377), ongoing diverticulitis (7.3% vs. 4.1%, respectively; p = 0.183), recurrent diverticulitis (3.4% vs. 3.0%, respectively; p = 0.494), sigmoid resection (3.8% vs. 2.3%, respectively; p = 0.323), readmission (17.6% vs. 12.0%, respectively; p = 0.148), adverse events (48.5% vs. 54.5%, respectively; p = 0.221), and mortality (1.1% vs. 0.4%, respectively; p = 0.432). Hospital stay was significantly shorter in the observation group (2 vs. 3 days; p = 0.006). However, even if no significant differences between Hinchey stages 1a and 1b diverticulitis were found, the vast majority of patients included had a diagnosis of Hinchey stage 1a ALCD (90.1% in the observational and 94% in the antibiotic-treated group) with only a small percentage of patients with Hinchey stage 1 stage 1b diverticulitis. Based on these results, the authors concluded that antibiotics can be safely omitted in patients with a first episode of uncomplicated (Hinchey 1a) ALCD. Similar results were found for Hinchey 1b diverticulitis. However, since the trial lacked power to detect smaller subgroup effects and there are no other reports in literature, the authors concluded that observational treatment should be limited to Hinchey 1a cases [bib_ref] Randomized clinical trial of observational versus antibiotic treatment for a first episode..., Daniels [/bib_ref]. More recently, the long-term effects of omitting antibiotics in uncomplicated ALCD were assessed after 24 months' follow-up of the DIABOLO trial [bib_ref] Randomized clinical trial of observational versus antibiotic treatment for a first episode..., Daniels [/bib_ref]. Complete case analyses showed no difference in rates of recurrent diverticulitis (15.4% in the observational group vs. 14.9% in the antibiotic group; p = 0.885), complicated diverticulitis (4.8% vs. 3.3%; p = 0.403), and sigmoid resection (9.0% vs. 5.0%; p = 0.085). Young patients (< 50 years) and patients with a pain score at presentation of 8 or higher on a visual analogue pain scale were at risk for complicated or recurrent diverticulitis. In this multivariable analysis, treatment type (with or without antibiotics) was not an independent predictor for complicated or recurrent diverticulitis [bib_ref] Long-term effects of omitting antibiotics in uncomplicated acute diverticulitis, Van Dijk [/bib_ref]. Although the above studies have shown there is limited evidence that antibiotics should be routinely administered to patients with uncomplicated diverticulitis, it is understood that disease severity varies in uncomplicated diverticulitis and that further studies are needed to better risk-stratify these patients in order to determine the appropriate treatment course. The high mortality associated with sepsis requires clinicians to maintain a high index of clinical suspicion, in the conditions that predispose to sepsis in high-risk patients [bib_ref] WSES guidelines for management of intra-abdominalinfections, Sartelli [/bib_ref]. The expert panel suggests antibiotic therapy covering Gram-negative bacilli and anaerobes in patients with radiological documented uncomplicated acute diverticulitis associated with systemic manifestations of infection or in high-risk patients such as immunocompromised patients, elderly patients, and those with comorbidities. If antibiotic therapy is necessary, oral administration of antibiotics may be equally as effective as intravenous administration. An expeditious switch from intravenous to oral may allow a rapid patient discharge. A randomized controlled trial (RCT) of oral versus intravenous therapy for clinically diagnosed acute uncomplicated diverticulitis was published in 2009 [bib_ref] Randomized controlled trial of oral vs intravenous therapy for the clinically diagnosed..., Ridgway [/bib_ref]. Oral and intravenous regimens utilizing ciprofloxacin and metronidazole were compared. There were 41 patients in the oral arm and 38 in the IV arm (n = 79). No patients had to be converted to intravenous antibiotics from the oral group. There was a complete resolution of symptoms in both groups. No studies have examined the value of dietary restriction or bed rest. Could patients with uncomplicated ALCD be treated as outpatient? We suggest management in an outpatient setting for patients with uncomplicated ALCD and no comorbidities. We suggest re-evaluation within 7 days. If the clinical condition deteriorates, re-evaluation should be carried out earlier (weak recommendation based on moderatequality evidence, 2B). Patients with uncomplicated acute diverticulitis symptoms without significant comorbidities, who are able to take fluids orally and manage themselves at home, can be treated as outpatients. They should be re-evaluated within 7 days from the time of the diagnosis. However, if the clinical condition deteriorates, re-evaluation should be carried out earlier. Patients with significant comorbidities and unable to take fluids orally should be treated in hospital with intravenous fluids. Etzioni et al. [bib_ref] Outpatient treatment of acute diverticulitis: rates and predictors of failure, Etzioni [/bib_ref] in 2010 published a retrospective analysis, demonstrating that outpatient treatment was effective for the vast majority (94%) of patients suffering from acute diverticulitis. A systematic review on outpatient management of acute uncomplicated acute diverticulitis was recently published [bib_ref] Systematic review: outpatient management of acute uncomplicated diverticulitis, Jackson [/bib_ref]. Jackson et al. concluded that current evidence suggested that a more progressive, ambulatory-based approach to the majority of cases of acute uncomplicated acute diverticulitis was justified. Rodríguez-Cerrillo et al. [bib_ref] Treatment of elderly patients with uncomplicated diverticulitis, even with comorbidity, at home, Rodrìguez-Cerrillo [/bib_ref] have recently shown that also elderly patients with comorbidities can be safely treated at home avoiding hospital admission. The DIVER trial [bib_ref] Outpatient versus hospitalization management for uncomplicated diverticulitis: a prospective, multicenter randomized clinical..., Biondo [/bib_ref] has demonstrated that outpatient treatment may be safe and effective in selected patients with uncomplicated acute diverticulitis and can reduce the costs without negatively influencing the quality of life of these patients. This multicenter, RCT included patients older than 18 years with acute uncomplicated diverticulitis. All the patients underwent abdominal CT. The first dose of antibiotic was given intravenously to all patients in the emergency department, and then, patients were either admitted to hospital or discharged. Among a total of 132 patients, four patients in those admitted to hospital and three patients in those discharged to home management developed treatment failure (there were no differences between the groups (p = 0.62)). The overall health care cost per episode was 3 times less in the outpatient treated group, with significant costs savings of €1124.70 per patient. No differences were observed between the groups in terms of quality of life. A systematic review including 21 studies (11 prospective, 9 retrospective, and only 1 randomized trial) with 1781 patients who had outpatient management of ALCD was recently published [bib_ref] Is the outpatient management of acute diverticulitis safe and effective? A systematic..., Cirocchi [/bib_ref]. The meta-analysis concluded that outpatient management is safe, and the overall failure rate in an outpatient setting was 4.3% (95% CI 2.6-6.3%). Location of diverticulitis is not a selection criterion for an outpatient strategy (p = 0.512). The other subgroup analyses did not report any factors that influence the rate of failure: previous episodes of acute diverticulitis (p = 0.163), comorbidities (p = 0.187), pericolic gas (p = 0.653), intra-abdominal abscess (p = 0.326), treatment according to a registered protocol (p = 0.078), type of follow-up (p = 0.700), type of antibiotic treatment (p = 0.647), or diabetes (p = 0.610). In patients who failed outpatient treatment, the majority had prolonged antibiotic therapy and only few had percutaneous drainage for an abscess (0.13%) or surgical intervention for perforation (0.06%). However, these results should be interpreted with some caution because of the low quality of available data. The data reported suggested that outpatient management is safe if associated with an accurate selection of patients (40%); no subgroup analysis demonstrated significant differences between groups (including comorbidities, previous episode and diabetes). The main limitations of the findings of the present review concern their applicability in common clinical practice as it was impossible to identify strict criteria of failure. Another review about outpatient management of ALCD was published in 2017 [bib_ref] Out-patient management of mild or uncomplicated diverticulitis: a systematic review, Balasubramanian [/bib_ref]. The search yielded 192 publications. Of these, 10 studies met the inclusion criteria including 1 RCT, 6 clinical controlled trials, and 3 case series. There was no difference in failure rates of medical treatment (6.5 vs. 4.6%, p = 0.32) or in recurrence rates (13.0 vs. 12.1%, p = 0.81) between those receiving ambulatory care and inpatient care for uncomplicated diverticulitis. Ambulatory treatment was associated with an estimated daily cost savings of between €600 and €1,900 per patient treated. Metaanalysis of data was not possible due to heterogeneity in study designs and inclusion criteria. What is the best treatment for patients with acute diverticulitis with CT findings of pericolic gas? In patients with CT findings of pericolic extraluminal gas, we suggest a trial of non-operative treatment with antibiotic therapy (weak recommendation based on lowquality evidence, 2C). High mortality associated with sepsis requires maintaining a high index of clinical suspicion for deterioration and more aggressive management. WSES expert panel recommends antibiotic therapy in patients with pericolic extraluminal gas [bib_ref] A proposal for a CT driven classification of left colon acute diverticulitis, Sartelli [/bib_ref]. A sub-analysis of the DIA-BOLO trial was recently published [bib_ref] Conservative treatment in diverticulitis patients with pericolicextraluminal air and the role of..., Bolkenstein [/bib_ref]. All patients with Hinchey 1a diverticulitis and with isolated pericolic gas on CT were identified. Pericolic gas was defined as gas located < 5 cm from the affected segment of colon. The primary outcome of the study was failure of non-operative management that was defined as need for percutaneous abscess drainage or emergency surgery within 30 days after presentation. A multivariate logistic regression analyses of clinical, radiological, and laboratorial parameters with respect to treatment failure was performed. A total of 109 patients were included. Fifty-two (48%) patients were treated with antibiotics. Nine (8%) patients failed nonoperative management, seven (13%) in the antibiotic treatment group and two (4%) in the non-antibiotic group (p = 0.083). Only increased CRP level at presentation was an independent predictor for treatment failure. The authors concluded that non-operative treatment in diverticulitis patients with isolated pericolic gas is a suitable treatment strategy. However, due to the low event rate, it remains uncertain whether antibiotic treatment is necessary in patients with isolated pericolic gas. What is the best treatment for patients with a small diverticular abscess (< 4-5 cm)? What is the best treatment for patients with large diverticular abscess? For patients with a small (< 4-5 cm) diverticular abscess, we suggest an initial trial of non-operative treatment with antibiotics alone (weak recommendation based on low-quality evidence, 2C). We suggest to treat patients with large abscesses with percutaneous drainage combined with antibiotic treatment; whenever percutaneous drainage of the abscess is not feasible or not available, we suggest to initially treat patients with large abscesses with antibiotic therapy alone, clinical conditions permitting. Alternatively, an operative intervention is required (weak recommendation based on low-quality evidence, 2C). Approximately 15-20% of patients admitted with acute diverticulitis have an abscess on CT scan [bib_ref] Danish national guidelines for treatment of diverticular disease, Andersen [/bib_ref]. The treatment of abscess always requires antibiotic therapy. If the abscess is limited in size, systemic antibiotic therapy alone is considered safe and effective in removing the abscess and solving acute inflammation with a pooled failure rate of 20% and a mortality rate of 0.6% [bib_ref] Treatment of patients with acute colonic diverticulitis complicated by abscess formation: a..., Gregersen [/bib_ref]. When abscess diameter is larger, antibiotics could fail to reach the adequate concentration inside the abscess leading to an increased failure rate. The size of 4-5 cm may be a reasonable limit between antibiotic treatment alone, versus percutaneous drainage combined with antibiotic treatment in the management of diverticular abscesses [bib_ref] Long-term outcome of mesocolic and pelvic diverticular abscesses of the left colon:..., Ambrosetti [/bib_ref] [bib_ref] Percutaneous CT scan guided drainage versus antibiotherapy alone for Hinchey II diverticulitis:..., Brandt [/bib_ref] [bib_ref] Impact of CT-guided drainage in the treatment of diverticular abscesses: size matters, Siewert [/bib_ref] [bib_ref] The long-term results of percutaneous drainage of diverticular abscess, Singh [/bib_ref] [bib_ref] Factors affecting the successful management of intra-abdominal abscesses with antibiotics and the..., Kumar [/bib_ref]. When the patient's clinical conditions allow it and percutaneous drainage is not feasible, antibiotic therapy alone can be considered. However, careful clinical monitoring is mandatory. A high suspicion for surgical control of the septic source should be maintained and a surgical treatment should be performed if the patient shows a worsening of inflammatory signs or the abscess does not reduce with medical therapy. There are currently no randomized studies available on the best treatment of intra-abdominal abscess from acute diverticulitis, and current recommendations are based only on observational studies. A retrospective study comparing outcomes of selected patients treated with initial antibiotics alone versus percutaneous drainage was published in 2015 by Elagili et al. [bib_ref] Antibiotics alone instead of percutaneous drainage as initial treatment of large diverticular..., Elagili [/bib_ref]. All patients with diverticular abscess ≥ 3 cm in diameter treated in a single institution in 1994-2012 with percutaneous drainage or antibiotics alone followed by surgery were identified from an institutional diverticular disease database. Groups were compared based on patient and disease characteristics, treatment failures, and postoperative outcomes. Thirtytwo patients were treated with antibiotics alone because of either technically impossible percutaneous drainage or surgeon preference, while 114 underwent percutaneous drainage. Urgent surgery was required in 8 patients with persistent symptoms during treatment with antibiotics alone (25%) and in 21 patients (18%) after initial percutaneous drainage (p = 0.21). Patients treated with antibiotics had a significantly smaller abscess diameter (5.9 vs. 7.1 cm, p = 0.001) and shorter interval from initial treatment to sigmoidectomy (mean 50 vs. 80 days, p = 0.02). Postoperative complications following antibiotics alone were significantly less severe than after percutaneous drainage based on the Clavien-Dindo classification (p = 0.04). In patients displaying an appropriate clinical improvement, the drainage catheter can be removed when the output has ceased or decreased substantially. In doubtful cases, a CT scan can be performed with water-soluble contrast via the percutaneous drainage catheter prior to drain removal. If no identifiable cavity remains, the catheter should be removed. If resolution of the abscess is not reached and the patient has no clinical improvement, further drainage or catheter repositioning might be indicated and may eventually necessitate surgery. Should an early colonic evaluation be planned in patients treated non-operatively for a diverticular abscess? Should an early colonic evaluation be recommended for patients with a CT-proved uncomplicated acute diverticulitis treated nonoperatively? In patients with diverticular abscesses treated nonoperatively, we suggest to plan an early colonic evaluation (4-6 weeks) (weak recommendation based on lowquality evidence, 2C). In patients with CT-proven uncomplicated diverticulitis treated non-operatively, we do not recommend routine colonic evaluation (weak recommendation based on moderate-quality evidence, 2B). Colonic localized abscess is an uncommon, but possible, presentation of an occult colon malignancy, and it may mimic complicated diverticular disease [bib_ref] Perforated colonic cancer presenting as intra-abdominal abscess, Tsai [/bib_ref] [bib_ref] Perforated colorectal cancer: an important differential diagnosis in all presumed diverticular abscesses, Yeo [/bib_ref]. It has been demonstrated that the risk of malignancy after a CT-proven uncomplicated diverticulitis is low and, in the absence of other indications, routine colonoscopy may not be necessary. A systematic review investigating the rate of colorectal cancer (CRC) found by colonoscopy after an episode of uncomplicated diverticulitis was published in 2014 [bib_ref] Routine colonoscopy is not required in uncomplicated diverticulitis: a systematic review, De Vries [/bib_ref]. Nine studies met the inclusion criteria and included a total number of 2490 patients with uncomplicated diverticulitis. Subsequent colonoscopy after an episode of uncomplicated diverticulitis was performed in 1468 patients (59%). Seventeen patients were diagnosed with CRC, having a prevalence of 1.16% (95% confidence interval 0.72-1.9% for CRC). Hyperplastic polyps were seen in 156 patients (10.6%), lowgrade adenoma in 90 patients (6.1%), and advanced adenoma in 32 patients (2.2%). The results of this review demonstrate that unless colonoscopy is regarded for screening in individuals aged 50 years and older, routine colonoscopy in the absence of other clinical signs of CRC is not required in patients following an episode of acute uncomplicated diverticulitis. Another systematic review and meta-analysis on the role of routine colonic evaluation after radiologically confirmed acute diverticulitis was published in 2014 [bib_ref] Systematic review and metaanalysis of the role of routine colonic evaluation after..., Sharma [/bib_ref]. Eleven studies from 7 countries were included in the analysis. Among 1970 patients, cancer was only found in 22 (0.01%) cases. The risk of malignancy after a radiologically proven episode of acute uncomplicated diverticulitis was low. Patients with complicated diverticulitis had a significant risk of CRC at subsequent colonic evaluation. A retrospective study of 633 patients with acute diverticulitis diagnosed by CT was published in 2014 [bib_ref] Risk of colon cancer after computed tomography-diagnosed acute diverticulitis: is routine colonoscopy..., Sallinen [/bib_ref]. Of the 663 patients, 97 patients underwent emergency resection, while 536 patients were treated non-operatively, 394 of whom subsequently underwent colonoscopy. The findings showed 17 cancers (2.7%) in patients with an initial diagnosis of acute diverticulitis. As shown by CT, 16 cancer patients (94%) had an abscess, while one patient had pericolic extraluminal gas but no abscess. Of the patients with an abscess, 11.4% had cancer mimicking acute diverticulitis. No cancer was found in the patients with uncomplicated diverticulitis. What is the role of non-operative treatment in patients with CT findings of distant gas without diffuse intra-abdominal fluid? In patients with CT findings of distant free gas without diffuse intra-abdominal fluid, we suggest a non-operative treatment in selected patients only if a close follow-up can be performed (weak recommendation based on very low-quality evidence, 2D). Although most patients hospitalized for acute diverticulitis can be managed by non-operative treatment, up to 25% may require urgent operative intervention [bib_ref] Practice parameters for the treatment of sigmoid diverticulitis, Feingold [/bib_ref]. Patients with diffuse peritonitis are typically critically ill patients and require prompt fluid resuscitation, antibiotic administration, and surgery. While the absolute prevalence of perforated diverticulitis complicated by generalized peritonitis is low, it is associated with significant postoperative mortality, regardless of selected surgical strategy. Despite CT findings of distant free gas (a known predictor of failure of non-operative treatment [bib_ref] A proposal for a CT driven classification of left colon acute diverticulitis, Sartelli [/bib_ref] , Dharmarajan et al. [bib_ref] The efficacy of nonoperative management of acute complicated diverticulitis, Dharmarajan [/bib_ref] described a high success rate for nonoperative management in patients with acute diverticulitis and a pneumoperitoneum, excluding those with hemodynamic instability. Sallinen et al. [bib_ref] Nonoperative management of perforated diverticulitis with extraluminal air is safe and effective..., Sallinen [/bib_ref] reported results of non-operative management in patients with CT verified extraluminal gas. The study showed that nonoperative treatment was feasible therapy only for hemodynamically stable patients with pericolic extraluminal gas or with small amount of distant intraperitoneal gas in the absence of clinical diffuse peritonitis or fluid in the fossa Douglas. Occurrence of large amount of distant intraperitoneal gas or distant retroperitoneal gas even in the absence of clinical generalized peritonitis was associated with high failure rate (57-60%) of nonoperative management. Moreover, nearly 60% patients with distant intraperitoneal gas were primarily treated by surgery. Highly selected group of patients at this stage may be treated by conservative treatment. However, it may be associated with a significant failure rate and a careful clinical and CT monitoring is mandatory [bib_ref] The value of inflammation markers and body temperature in acute diverticulitis, Van De Wall [/bib_ref]. Suggested intervention for patients at this stage should be surgical resection and anastomosis with or without stoma in stable patients without comorbidities, and Hartmann's procedure (HP) in unstable patients or in patients with multiple comorbidities [bib_ref] A proposal for a CT driven classification of left colon acute diverticulitis, Sartelli [/bib_ref]. Should laparoscopic lavage and drainage be recommended in patients with diffuse peritonitis due to diverticular perforation? We suggest performing laparoscopic peritoneal lavage and drainage only in very selected patients with generalized peritonitis. It is not considered as the first line treatment in patients with peritonitis from acute colonic diverticulitis (weak recommendation based on highquality evidence, 2A). A minimally invasive approach using laparoscopic peritoneal lavage and drainage has been debated in recent years as an alternative to colonic resection [bib_ref] Laparoscopic peritoneal lavage for Hinchey III diverticulitis: is it as effective as..., Rossi [/bib_ref]. It can potentially avoid a stoma in patients with diffuse peritonitis. It consists of the laparoscopic aspiration of pus followed by abdominal lavage and the placement of abdominal drains, which remain for many days after the procedure. In 2013, a Dutch retrospective analysis of 38 patients [bib_ref] Dutch diverticular disease collaborative study G. early experience with laparoscopic lavage for..., Swank [/bib_ref] treated by laparoscopic lavage was published highlighting some doubts about this procedure to treat critically ill patients. In seven patients, this approach did not control abdominal sepsis, two patients died of multiple organ failure and five ones required further surgical interventions (three Hartmann resection, one diverting stoma, and one perforation closure). One of these died from aspiration, and the remaining four experienced prolonged and complicated hospital stay. Multiple comorbidities, IMS, a high CRP level, and/or a high Mannheim Peritonitis Index were also predictors of a high risk of failure. The authors concluded that patient selection was of utmost importance and identification of an overt sigmoid perforation is of critical importance. Great debate is still open on this topic, mainly due to the discrepancy and sometime disappointing results of the latest prospective trials such as SCANDIV, Ladies, and DILALA trials [bib_ref] Laparoscopic lavage is feasible and safe for the treatment of perforated diverticulitis..., Angenete [/bib_ref] [bib_ref] Laparoscopic lavage vs primary resection for acute perforated diverticulitis: the SCANDIV randomized..., Schultz [/bib_ref] [bib_ref] Laparoscopic peritoneal lavage or sigmoidectomy for perforated diverticulitis with purulent peritonitis: a..., Vennix [/bib_ref] In 2014, the first results from the RCT DILALA were published [bib_ref] Laparoscopic lavage is feasible and safe for the treatment of perforated diverticulitis..., Angenete [/bib_ref]. Initial diagnostic laparoscopy showing Hinchey III disease was followed by randomization between laparoscopic lavage and colon resection and stoma. Morbidity and mortality after laparoscopic lavage did not differ when compared with the Hartmann procedure. Laparoscopic lavage resulted in shorter operating time, shorter time in the recovery unit, and shorter hospital stay with the avoidance of a stoma. In this trial, laparoscopic lavage as treatment for patients with perforated diverticulitis Hinchey III disease was feasible and safe in the short-term. In 2015, the results of SCAN-DIV study were published [bib_ref] Laparoscopic lavage vs primary resection for acute perforated diverticulitis: the SCANDIV randomized..., Schultz [/bib_ref]. Among patients with likely perforated diverticulitis and undergoing emergency surgery, the use of laparoscopic lavage vs. primary resection did not reduce severe postoperative complications and led to worse outcomes in secondary endpoints. These findings do not support laparoscopic lavage for treatment of perforated diverticulitis. In the same year, the result of LADIES study was published. This showed that laparoscopic lavage was not superior to sigmoidectomy for the treatment of purulent perforated diverticulitis [bib_ref] Laparoscopic peritoneal lavage or sigmoidectomy for perforated diverticulitis with purulent peritonitis: a..., Vennix [/bib_ref]. After their publication, the results of the three studies were summarized in six different meta-analyses, with similar findings [bib_ref] Laparoscopic lavage versus resection in perforated diverticulitis with purulent peritonitis: a meta-analysis..., Ceresoli [/bib_ref] [bib_ref] Laparoscopic lavage versus primary resection for acute perforated diverticulitis: review and meta-analysis, Penna [/bib_ref] [bib_ref] Laparoscopic lavage in the management of perforated diverticulitis: a contemporary meta-analysis, Galbraith [/bib_ref] [bib_ref] Laparoscopic lavage versus surgical resection for acute diverticulitis with generalised peritonitis: a..., Cirocchi [/bib_ref] [bib_ref] Laparoscopic lavage is superior to colon resection for perforated purulent diverticulitis-a meta-analysis, Angenete [/bib_ref] [bib_ref] Laparoscopic peritoneal lavage or surgical resection for acute perforated sigmoid diverticulitis: a..., Shaikh [/bib_ref]. When compared with emergency surgery with resection, laparoscopic lavage in Hinchey III acute diverticulitis shows a comparable mortality but is associated with a failure rate with a significantly augmented need for reoperation due to the failure of the treatment and to intra-abdominal abscess formation. Long-term results were similar, with no difference in morbidity and mortality. Several controversies remain about laparoscopic lavage and drainage. It may be an acceptable alternative in selected patients [bib_ref] The evolving role of laparoscopic lavage and drainage, Biffl [/bib_ref] ; however, it cannot be considered the first line treatment in patients with diverticular peritonitis. Should primary anastomosis with or without protecting stoma be preferred instead of Hartmann's procedure in patients with diffuse peritonitis from diverticular perforation? We recommend Hartmann's procedure (HP) for managing diffuse peritonitis in critically ill patients and in selected patients with multiple comorbidities (strong recommendation based on low-quality evidence, 2B). In clinically stable patients with no comorbidities, we suggest primary resection with anastomosis with or without a diverting stoma (weak recommendation based on low-quality evidence, 2B). HP has been considered the procedure of choice in patients with generalized peritonitis and remains a safe technique for emergency colectomy in diverticular peritonitis, and is especially useful in critically ill patients and in patients with multiple comorbidities. However, restoration of bowel continuity after a HP is associated with significant morbidity and resource utilization [bib_ref] Current management of diverticulitis, Mccafferty [/bib_ref]. As a result, many of these patients do not undergo reversal surgery and remain with a permanent stoma [bib_ref] Reversal of Hartmann's procedure following acute diverticulitis: is timing everything?, Fleming [/bib_ref]. Common use of the HP in treating diverticular perforation worldwide is confirmed by a recent Australian study analyzing administrative data of patients with acute diverticulitis admitted, from 2009 to 2013, in eight tertiary referral centers with specialist colorectal services [bib_ref] Operative intervention rates for acute diverticulitis: a multicentre state-wide study, Hong [/bib_ref]. The HP was the most commonly performed emergency operation, accounting for 72% of resections. Another population-based retrospective cohort study using administrative discharge data, conducted in Ontario, Canada, was published in 2014 [bib_ref] Evolving practice patterns in the management of acute colonic diverticulitis: a population-based..., Li [/bib_ref]. Among 18, 543 patients hospitalized with a first episode of diverticulitis, from 2002 to 2012, 3873 underwent emergency surgery. The use of laparoscopy increased (9 to 18%, p < 0.001), whereas the use of the HP remained unchanged (64%), and like in the Australian study, was the most frequently used operative approach in patients with complicated acute diverticulitis. In recent years, some authors have reported the role of primary resection and anastomosis with or without a diverting stoma, in the treatment of acute diverticulitis, even in the presence of diffuse peritonitis [bib_ref] Impact of primary resection on the outcome of patients with perforated diverticulitis, Chandra [/bib_ref]. The decision regarding the surgical choice in patients with diffuse peritonitis is generally left to the judgment of the surgeon, who takes into account the clinical condition and the comorbidities of the patient. Studies comparing mortality and morbidity of the HP versus primary anastomosis did not show any significant differences. However, most studies had relevant selection biases, as demonstrated by four systematic reviews [bib_ref] Primary anastomosis or Hartmann's procedure for patients with diverticular peritonitis? A systematic..., Salem [/bib_ref] [bib_ref] Resection and primary anastomosis in acute complicated diverticulitis, a systematic review of..., Abbas [/bib_ref] [bib_ref] Treatment of Hinchey stage III-IV diverticulitis: a systematic review and meta-analysis, Cirocchi [/bib_ref]. A study evaluating all patients with acute diverticulitis undergoing emergent primary anastomosis with diverting loop ileostomy and HP was recently published using the ACS-NSQIP Colectomy Procedure Targeted Database from 2012 to 2016 [bib_ref] Hartmann's procedure vs primary anastomosis with diverting loop ileostomy for acute diverticulitis:..., Lee [/bib_ref]. Out of 130,963 patients, 2729 patients were included. The median age was 64 years, and 48.5% were male; the majority of patients underwent a HP, and only 208 (7.6%) underwent primary anastomosis with diverting loop ileostomy. Patients undergoing a HP had more comorbidities [e.g., COPD (9.8% vs. 4.8%, p = 0.017)], were more functionally dependent [6.3% vs. 2.4%, p = 0.025], and were more unwell [e.g., septic shock (11.1% vs. 5.3%, p = 0.015)] compared to primary anastomosis with diverting loop ileostomy patients. The mortality rates for the patients undergoing a HP versus primary anastomosis with diverting loop ileostomy were 7.6% and 2.9%, respectively (p = 0.011). The morbidity rates were 55.4% and 48.6%, respectively (p = 0.056). In multivariable analyses, compared to the HP, primary anastomosis with diverting loop ileostomy did not result in increased rates of mortality (OR = 0.21, 95% CI 0.03-1.58, p = 0.129) or morbidity (OR = 0.96, 95% CI 0.63-1.45, p = 0.834). The authors concluded that primary anastomosis with diverting loop ileostomy appears to be at least a safe alternative to the HP for select patient populations needing emergent surgical management of acute diverticulitis. A comparison of primary resection and anastomosis with or without defunctioning stoma to the HP as the optimal operative strategy for patients presenting with Hinchey stage III-IV was published by Constantinides et al. [bib_ref] Operative strategies for diverticular peritonitis: a decision analysis between primary resection and..., Constantinides [/bib_ref]. A total of 135 primary resection and anastomosis, 126 primary anastomosis with defunctioning stoma, and 6619 HPs were considered in the study. Morbidity and mortality were 55% and 30% for primary resection and anastomosis, 40% and 25% for primary anastomosis with defunctioning stoma, and 35% and 20% for the HP. Stomas remained permanent in 27% of HPs and in 8% of primary anastomoses with defunctioning stoma. The authors concluded that primary anastomosis with defunctioning stoma may be the optimal strategy for selected patients with diverticular peritonitis and may represent a good compromise between postoperative adverse events, long-term quality of life, and risk of permanent stoma. A small randomized trial of primary anastomosis with ileostomy versus a HP in patients with diffuse diverticular peritonitis was published by Oberkofler et al. in 2012 [bib_ref] A multicenter randomized clinical trial of primary anastomosis or Hartmann's procedure for..., Oberkofler [/bib_ref]. Sixtytwo patients with acute left-sided colonic perforation (Hinchey III and IV) from 4 centers were randomized to Hartmann procedure (n = 30) and to primary anastomoses with diverting ileostomy (n = 32). A planned stoma reversal operation was performed after 3 months in both groups. The study reported no difference in initial mortality and morbidity (mortality 13% vs. 9% and morbidity 67% vs. 75% in the HP vs. primary anastomosis), but a reduction in length of stay, lower costs, fewer serious complications, and greater stoma reversal rates in the primary anastomosis group. A multicenter RCT conducted between June 2008 and May 2012, the DIVERTI (Primary vs. Secondary Anastomosis for Hinchey Stage III-IV Diverticulitis) trial [bib_ref] Hartmann's procedure or primary anastomosis for generalized peritonitis due to perforated diverticulitis:..., Bridoux [/bib_ref] , was published in 2017. All 102 patients enrolled were comparable for age (p = 0.4453), sex (p = 0.2347), Hinchey stage III vs. IV (p = 0.2347), and Mannheim Peritonitis Index (p = 0.0606). Overall mortality did not differ significantly between the HP (7.7%) and primary anastomosis (4%) (p = 0.4233) groups. Morbidity for both resection and stoma reversal operations was comparable (39% in the HP arm vs. 44% in the primary anastomosis arm; p = 0.4233). At 18 months, 96% of primary anastomosis patients and 65% of the HP patients had a stoma reversal (p = 0.0001). Although mortality was similar in both arms, the rate of stoma reversal was significantly higher in the primary anastomosis arm. This trial provides additional evidence in favor of primary anastomosis with diverting ileostomy over the HP in patients with diverticular peritonitis. In 2019, the results of the LADIES study [bib_ref] Hartmann's procedure versus sigmoidectomy with primary anastomosis for perforated diverticulitis with purulent..., Lambrichts [/bib_ref] demonstrated that in hemodynamically stable, immunocompetent patients younger than 85 years, primary anastomosis is preferable to the HP as a treatment for perforated diverticulitis (Hinchey III or Hinchey IV disease). Patients aged between 18 and 85 years who presented with clinical signs of general peritonitis and suspected perforated diverticulitis were eligible for inclusion if plain abdominal radiography or CT scan showed diffuse free gas or fluid. Patients with Hinchey I or II diverticulitis were not eligible for inclusion. Patients were allocated (1:1) to the HP or sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy. Recently, a systematic review of the existing literature about surgical management of Hinchey III and IV diverticulitis was published [bib_ref] Primary resection anastomosis versus Hartmann's procedure in Hinchey III and IV diverticulitis, Halim [/bib_ref]. A total of 25 studies involving 3546 patients were included in this study. The overall mortality in patients undergoing a HP was 10.8% across the observational studies and 9.4% in the RCTs. The mortality rate in patients undergoing a primary anastomosis was lower than that in the HP group, at 8.2% in the observational studies and 4.3% in the RCTs. A comparison of primary anastomosis with the HP demonstrated a 40% lower mortality rate in the primary anastomosis group than in the HP group (OR 0.60, 95% CI 0.38-0.95, p = 0.03), when analyzing the observational studies. However, meta-analysis of the RCTs did not demonstrate any difference in mortality. Wound infection rates between the two groups were comparable. Should laparoscopic resection be preferred to open resection in patients with diffuse peritonitis due to perforated diverticulitis? In patients with diffuse peritonitis due to perforated diverticulitis, we suggest to perform an emergency laparoscopic sigmoidectomy only if technical skills and equipment are available (weak recommendation based on low-quality evidence, 2C). Laparoscopic sigmoidectomy for diverticulitis had initially been confined to the elective setting. However, in physiologically stable patients, laparoscopic sigmoidectomy may be feasible in the setting of purulent and fecal diverticular peritonitis. In 2015, a systematic review on laparoscopic sigmoidectomy for diverticulitis in the emergency setting was published [bib_ref] Emergency laparoscopic sigmoidectomy for perforated diverticulitis with generalised peritonitis: a systematic review, Vennix [/bib_ref]. The review included 4 case series and one cohort study (total of 104 patients) out of 1706 references. A HP was performed in 84 patients, and primary anastomosis was fashioned in 20 patients. The mean operating time varied between 115 and 200 min. The conversion to open surgery rate varied between 0 and 19%. The mean length of hospital stay ranged between 6 and 16 days. Surgical re-intervention was necessary in 2 patients. In 20 patients operated upon without defunctioning ileostomy, no anastomotic leakage was reported. Three patients died during the postoperative period. Stoma reversal after HP was performed in 60 out of 79 evaluable patients (76%). These guidelines are limited by the low-quality evidence that showed that emergency laparoscopic sigmoidectomy for the treatment of perforated diverticulitis with generalized peritonitis is feasible. These studies occurred in selected patients and in experienced units and are not generalizable to all centers. High-quality prospective or randomized studies are needed to demonstrate benefits of emergency laparoscopic sigmoidectomy compared to open sigmoidectomy for perforated diverticulitis. Should damage control surgery with staged laparotomies be recommended in patients with acute peritonitis due to diverticular perforation? We suggest damage control surgery (DCS) with staged laparotomies in selected unstable patients with diffuse peritonitis due to diverticular perforation (weak recommendation based on low-quality evidence, 2C). A damage control surgical strategy may be useful for patients in physiological extremis from abdominal sepsis [bib_ref] Damage control surgery for abdominal emergencies, Weber [/bib_ref]. The initial surgery focuses on control of the sepsis, and a subsequent operation deals with the anatomical restoration of the gastrointestinal tract, after a period of physiological resuscitation. This strategy facilitates both the control of the severe sepsis control as well as potentially improving the rate of primary anastomosis [bib_ref] Damage control surgery for perforated diverticulitis with diffuse peritonitis: saves lives and..., Tartaglia [/bib_ref]. Generalized diverticular peritonitis is a life-threatening condition requiring prompt emergency operation. To improve outcomes and reduce the rate of colostomy formation, a new algorithm for damage control operation, lavage, limited resection or closure of perforation, and second look surgery to restore intestinal continuity was developed in recent years [bib_ref] Damage control surgery with abdominal vacuum and delayed bowel reconstruction in patients..., Kafka-Ritsch [/bib_ref] [bib_ref] Damage control with abdominal vacuum therapy (VAC) to manage perforated diverticulitis with..., Perathoner [/bib_ref]. Some patients may be physiologically deranged. These patients, who are hemodynamically unstable, are not optimal candidates for immediate complex operative interventions. After initial surgery, which should be limited to source control, e.g., primary closure of the perforation/local resection of the diseased bowel, the patient is taken to the intensive care unit (ICU) for physiologic optimization. However, this strategy will also delay bowel anastomosis to a period of physiological stability [bib_ref] Deferred primary anastomosis versus diversion in patients with severe secondary peritonitis managed..., Ordóñez [/bib_ref] potentially changing the intraoperative physiological milieu, potentially favoring a primary anastomosis, and avoiding the formation of a stoma altogether. In the setting of acute diverticulitis, several reports (with low level of evidence) were published. In 2010, a prospective observational study was published by Kafka-Ritsch et al. [bib_ref] Damage control surgery with abdominal vacuum and delayed bowel reconstruction in patients..., Kafka-Ritsch [/bib_ref]. A total of 51 patients (28 females 55%) with a median age of 69 (range 28-87) years, with perforated diverticulitis Hinchey III (n = 40, 78%) or Hinchey IV (n = 11, 22%), were prospectively enrolled in the study. Patients were initially managed with limited resection, lavage, and temporary abdominal closure followed by second, reconstructive operation 24-48 h later, which are supervised by a colorectal surgeon. Bowel continuity was restored in 38 (84%) patients, of which four were protected by a loop ileostomy. Five anastomotic leaks (13%) were encountered requiring loop ileostomy in two patients and a HP in remaining three patients. The overall mortality rate was 9.8%, and 35 of 46 surviving patients (76%) left the hospital with reconstructed colon continuity. Fascial closure was achieved in all patients. Sohn et al. performed a case-control study comparing traditional strategy versus damage control: there were no differences in morbidity and mortality, but there was a significant reduction of stoma creation in the damage control group [bib_ref] Damage control strategy for the treatment of perforated diverticulitis with generalized peritonitis, Sohn [/bib_ref]. Despite promising experiences, little robust or largescale data are available, and the open abdomen and damage control strategy are not without risk: for example, such procedures are associated with the formation of entero-atmospheric fistula and high costs, among other issues. Guidelines recommend this strategy only in critically ill patients who cannot withstand major surgery. Although there is now a biologic rationale for such an intervention as well as non-standardized and erratic clinical utilization, this remains a novel therapy with potential side effects and clinical equipoise. The WSES recommends to use an open abdomen approach in selected significantly physiologically deranged patients with ongoing sepsis [bib_ref] Management of intra-abdominal infections: recommendations by the WSES 2016 consensus conference, Sartelli [/bib_ref]. The Closed Or Open after Laparotomy (COOL) study constitutes a prospective RCT that will randomly allocate eligible surgical patients intraoperatively to either formal closure of the fascia or use of the open abdomen with application of with active negative peritoneal pressure therapy. This trial will be powered to demonstrate a mortality difference in this highly lethal and morbid condition to ensure critically ill patients are receiving the best care possible and not being harmed by inappropriate therapies based on opinion only [bib_ref] Closed or open after laparotomy (COOL) after source control for severe complicated..., Kirkpatrick [/bib_ref]. What factors should be considered in planning elective resection in cases of acute diverticulitis treated non-operatively? We suggest evaluating patient-related factors and not number of previous episodes of diverticulitis in planning elective sigmoid resection (weak recommendation based on very low-quality evidence, 2D). After an episode of ALCD treated conservatively, we suggest planning of an elective sigmoid resection in high-risk patients, such as immunocompromised patients (weak recommendation based on very low-quality evidence, 2D). Recurrence of acute diverticulitis is lower than previously thought. Historically, it has been reported that about one third of all patients with acute diverticulitis will have a recurrent attack, often within 1 year [bib_ref] Practice parameters for sigmoid diverticulitis, Rafferty [/bib_ref] [bib_ref] Long-term follow-up after an initial episode of diverticulitis: what are the predictors..., Hall [/bib_ref]. However, the recurrence after an uncomplicated episode of diverticulitis appears much lower: with a recent prospective study reported a recurrence of only 1.7% over 5 years of follow-up [bib_ref] Role of acute diverticulitis in the development of complicated colonic diverticular disease..., Humes [/bib_ref] [bib_ref] Prospective, five-year follow up study of patients with symptomatic uncomplicated diverticular disease, Salem [/bib_ref]. After a follow-up of 4 years, El Sayed et al. [bib_ref] Risk of recurrent disease and surgery following an admission for acute diverticulitis, El-Sayed [/bib_ref] , in an English study of over 65,000 patients managed nonoperatively for their first episode of diverticulitis, found the recurrence rate to be around 11.2%. Emergency and elective colectomy rates were 0.9 and 0.75%, respectively. Female gender, young age, smoking, obesity, and complicated initial disease were risk factors for readmission and emergency surgery. The study also pointed out that some factors associated with recurrence are modifiable; weight reduction and smoking cessation can be championed. In 2014, a systematic review of studies reviewing the diagnosis and management of chronic and recurrent diverticulitis (from studies published between January 2000 to March 2013) was published [bib_ref] Surgery for diverticulitis in the 21st century: a systematic review, Regenbogen [/bib_ref]. The 68 studies included were almost exclusively observational and had limited certainty of treatment effect. The authors found that complicated recurrence after recovery from an uncomplicated episode of diverticulitis was rare (< 5%) and that age at onset younger than 50 years and 2 or more recurrences did not increase the risk of complications. The authors concluded that the indication for elective colectomy following 2 episodes of diverticulitis is no longer accepted. Indication to colectomy should be made based on consideration of the risks of recurrent diverticulitis, the morbidity of surgery, ongoing symptoms, the complexity of disease, and operative risk. A recent open-label randomized multicenter trial (DIR-ECT trial) randomized 109 patients from 24 teaching and two academic hospitals in the Netherlands presenting with recurrent and persisting abdominal complaints after an episode of diverticulitis to receive surgical treatment or non-operative management [bib_ref] Surgery versus conservative management for recurrent and ongoing left-sided diverticulitis (DIRECT trial):..., Van De Wall [/bib_ref]. After a brief follow-up of 6 months, elective sigmoidectomy resulted in a better quality of life (assessed by many specific questionnaires) compared to non-operative management. However, the results of the study may be affected by the heterogeneity of patients enrolled (patients with both recurrent diverticulitis and patients with persistent abdominal complaints). Currently, the decision to perform an elective resection after one or more episodes of AD should be undertaken on a case-by-case basis, taking into account risk factors, complications, age, and severity of episodes as well as the patient's personal circumstances and comorbidities (e.g., immunosuppressed patients) [bib_ref] Indications for elective sigmoid resection in diverticular disease, Klarenbeek [/bib_ref]. What is the optimal antibiotic therapy for patients with diffuse peritonitis due to diverticular perforation? What is the optimal duration of antibiotic therapy after surgical source control in diffuse peritonitis due to diverticular perforation? We suggest to choose the empirically designed antibiotic regimen on the basis of the underlying clinical condition of the patient, the pathogens presumed to be involved, and the risk factors for major antimicrobial resistance patterns (strong recommendation based on moderatequality evidence, 1B). We suggest a 4-day period of postoperative antibiotic therapy in complicated ALCD if source control has been adequate (weak recommendation based on moderatequality evidence, 2B). Antibiotic therapy plays an important role in the management of complicated acute diverticulitis. Typically, it is an empiric antibiotic treatment. The regimen should depend on the severity of infection, the pathogens presumed to be involved, and the risk factors indicative of major resistance patterns [bib_ref] Outcomes of colonic diverticulitis according to the reason of immunosuppression, Biondo [/bib_ref]. Several recommendations have been recently published in literature [bib_ref] Outcomes of colonic diverticulitis according to the reason of immunosuppression, Biondo [/bib_ref]. However, consideration of local epidemiological data and resistance profiles is essential for antibiotic selection. Considering intestinal microbiota of large bowel acute diverticulitis requires antibiotic coverage for Gram-positive and Gram-negative bacteria, as well as for anaerobes. Most of the complicated acute diverticulitis is mainly a community-acquired infection. The main resistance threat in IAIs is posed by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, which are becoming increasingly common in community-acquired infections worldwide [bib_ref] Prospective evaluation of the value of magnetic resonance imaging in suspected acute..., Halpenny [/bib_ref]. The most significant risk factors for ESBLproducing pathogens include prior exposure to antibiotics and comorbidities requiring concurrent antibiotic therapy [bib_ref] Outcomes of colonic diverticulitis according to the reason of immunosuppression, Biondo [/bib_ref]. Anti-ESBL-producer coverage should be warranted for patients with these risk factors. Discontinuation of antibiotic treatment should be at 4 days from source control as this has been demonstrated as non-inferior to longer therapy based on the STOP IT trial [bib_ref] Trial of short-course antimicrobial therapy for intraabdominal infection, Sawyer [/bib_ref]. The recent prospective trial by Sawyer et al. demonstrated that in patients with complicated IAIs undergoing an adequate source-control procedure, the outcomes after approximately 4 days fixed-duration antibiotic therapy were similar to those after a longer course of antibiotics that extended until after the resolution of physiological abnormalities [bib_ref] Trial of short-course antimicrobial therapy for intraabdominal infection, Sawyer [/bib_ref].Patients who have signs of sepsis beyond 5 to 7 days of adequate antibiotic treatment warrant aggressive diagnostic investigation in search of a reservoir of infection. Which are the principles of the treatment of acute right-sided colonic diverticulitis? Although studies have shown that the percentage of complications requiring surgery is higher in patients with ALCD than in patients with ARCD, the principles of diagnosis and treatment of patients with ARCD are similar to those with ALCD. We suggest that all the statements for ALCD also apply to ARCD. Acute colonic diverticulitis is a common condition affecting the adult population. Traditionally, the sigmoid colon is considered the most commonly involved part, and ARCD is much rarer [bib_ref] Right-sided colonic diverticulitis: clinical features, sonographic appearances, and management, Chiu [/bib_ref]. However, in some regions of the world, ARCD outnumber ALCD [bib_ref] Right-sided colonic diverticulitis: clinical features, sonographic appearances, and management, Chiu [/bib_ref]. The ARCD differs from the ALCD in some aspects. The former is usually solitary [bib_ref] Ultrasound of colon diverticulitis, Puylaert [/bib_ref] [bib_ref] Boutross-Tadross O. Diverticular disease of the right colon, Radhi [/bib_ref] , and has a low rate of complicated diverticulitis [bib_ref] Efficacy of conservative management in patients with right colonic diverticulitis, Ha [/bib_ref]. ARCD generally occurs in middle-aged men, and its incidence does not increase with age. Especially the ARCD located in the cecum, it is difficult to distinguish ARCD from acute appendicitis because of their similar symptoms and signs. CT scanning appears to be the best overall imaging modality in the diagnosis of possible ARCD [bib_ref] Right-sided sigmoid diverticular perforation, Little [/bib_ref] [bib_ref] Medical approach to right colon diverticulitis with perforation, Espinosa [/bib_ref]. However, US is more economic than CT and poses no radiation, which may be particularly important since the patients having right-sided diverticulitis are relatively younger. US features, including diverticular wall thickening, surrounding echogenic fat, and intra-diverticular echogenic material, can provide clear information for making correct preoperative diagnosis. However, US is operator dependent. Ambiguous US studies may be complemented with a contrast-enhanced CT [bib_ref] Comparative study of the clinical features and treatment for right and left..., Kim [/bib_ref]. Currently, the management of ARCD is not well defined, and no unique guidelines have been proposed. Although previous studies have shown that the percentage of complications requiring surgery is higher in patients with ALCD than in patients with ARCD [bib_ref] Solitarycaecal diverticulitis. Recognition and management, Al-Hilaly [/bib_ref] , the principles of diagnosis and treatment of ARCD are very similar to those of ALCD. As a treatment option, non-operative methods should be preferred, in cases without diffuse peritonitis although differentiating benign and malignant cases pre-operatively is often difficult [bib_ref] Prospective randomized clinical trial of uncomplicated right-sided colonic diverticulitis: antibiotics versus no..., Kim [/bib_ref]. Surgical treatment is usually used in the treatment of complicated cases [bib_ref] Right-sided colonic diverticulitis: clinical features, sonographic appearances, and management, Chiu [/bib_ref] [bib_ref] Effectiveness of conservative approach in right colon diverticulitis, Destek [/bib_ref] [bib_ref] Management of colonic diverticulitis tailored to location and severity: comparison of the..., Chung [/bib_ref]. Resection of the inflamed colon with primary anastomosis can be performed by laparoscopy in experienced centers [bib_ref] Surgical therapy in rightsided diverticulitis, Hildebrand [/bib_ref]. # Conclusions ALCD is a common problem encountered by Western surgeons in the acute setting. The sigmoid is usually the most commonly involved colonic segment, while ARCD is much rarer. An international multidisciplinary panel of experts from the World Society of Emergency Surgery (WSES) updated its guidelines on the management of acute left-sided colonic (ALCD) diverticulitis according to the most recent available literature. The update includes recent changes introduced in the management of ALCD. The new update contains a section on ARCD, which is more prevalent than ALCD in some regions of the world.	None	https://wjes.biomedcentral.com/track/pdf/10.1186/s13017-020-00313-4	None
78697e891ce55505b5890f8c609c1867eca1e895	pubmed	Guidelines for diagnosis and treatment in neurology – Lyme neuroborreliosis	Guidelines for diagnosis and treatment in neurology – Lyme neuroborreliosis ## Scope and purpose ## Reasons for selecting the guideline topic Lyme borreliosis is the most common tick-borne infectious disease in Europe. The Borrelia enter the skin during the blood sucking process of the hard-bodied tick Ixodes ricinus. There they are either inactivated by the innate (congenital) immune system or a local infection occurs. Disease develops in a small proportion of infected patients. Inflammation of the skin frequently occurs, typically as erythema migrans. As the disease progresses, the Borrelia can disseminate and infect various organs such as the skin, nervous system, joints and heart. The nervous system is involved in 3-15% of all patients with Lyme borreliosis. This usually manifests as meningoradiculitis. The late or chronic form of the disease rarely occurs but can lead to encephalomyelitis with an unfavourable prognosis. In very rare cases vasculitis of the arteries to the brain develops with consecutive strokes. If antibiotic treatment is not available or its onset is considerably delayed, serious neurological residuals can persist. ## Guideline objective This guideline on neuroborreliosis aims to provide: - Recommendations for confirming a clinical diagnosis; clarifying, in particular, which clinical constellation warrants CSF testing - Recommendations for stage-appropriate diagnostic testing: serological detection of IgG Borrelia antibodies using a 2-step ELISA/immunoblot process - Recommendations on determining Borrelia-specific intrathecal antibody synthesis (Borreliaspecific CSF/serum antibody index) - Meaningful use of molecular-diagnostic testing and culture tests - Recommendations on diagnostic certainty (possible, probably, confirmed neuroborreliosis) - Treatment of early-and late-stage neuroborreliosis - Recommendations on monitoring treatment - Recommendations on treating persisting atypical or non-specific symptoms after antibiotic treatment - Prevention of Lyme borreliosis - Recommendations on the follow-up observation of the tick bite - Supplying information to patients (Appendix 6 in Attachment 1) - The guideline does not include information on diseases caused by Borrelia recurrentis (relapsing fever) - Matters pertaining to co-infections linked to tick-borne diseases are not within the scope of this guideline ## Patient target group - Children and adults suffering from neuroborreliosis or suspected of having neuroborreliosis - Patients presenting to a physician for diagnosis and treatment of neuroborreliosis - Patients presenting to a physician with neurological symptoms that indicate neuroborreliosis - Patients whose symptoms persist after antibiotic treatment for neuroborreliosis and who need a differential diagnosis - Patients presenting to a physician with questions about neuroborreliosis - Patients presenting to a physician for a tick bite ## Area of care - In-and out-patient care Target user group/target audience - Information for physicians in private practices and clinics involved in treating neuroborreliosis (see Section 2, Composition of the guideline group: participation of interest groups) ## Formulation of key questions The key questions for the literature survey were formulated at an initial meeting with formal consensus by the consensus group. They were developed with respect to patients, interventions, comparative interventions (comparatives) and patient-relevant endpoints (outcomes) in accordance with the PICO process. The meeting was chaired by an independent moderator from the AWMF in Frankfurt am Main on 11 February 2014. ## A) definition of neuroborreliosis (pico): In infectiology, the microbiological detection of pathogens is considered the "gold standard" for defining an infectious disease. Since detecting the pathogen in CSF is not sensitive enough with respect to neuroborreliosis (10-30% sensitivity), diagnostic criteria have been agreed on which; this definition differentiates between a "possible", "probable" and "confirmed" case of neuroborreliosis (Section 3.11 of the guideline text). Discussion on the above procedure: - "Seronegative cases" (controversial) are not taken into account in clinical definitions: Decision: These should be taken into account in the descriptive review and discussed as part of the recommendations under the aspect of their transferability to extended patient groups. To find relevant guidelines, a literature survey was carried out in the electronic database MEDLINE (via Ovid) and in the databases of four guideline networks (National Guideline Clearinghouse (www.guideline.gov), International Guideline Library of the Guidelines International Network (www.g-i-n.net/library/interational-guidelines-library), the National Institute for Health and Care Excellence (NICE, www.nice.org.uk/guidance/published?type=guidelines), and the Association of Scientific Medical Societies (AWMF, www.awmf.org/leitlinien/leitlinien-suche.html). All guidelines published in these databases between 1999 and 2014 and published in German or English have been included (see Appendix for search strategy). First a literature survey was carried out of the relevant guidelines. A total of 177 guidelines were found, of which only 8 met the inclusion criteria. Six guidelines were issued by scientific societies; the remaining two guidelines were issued by self-help organisations and patient associations. The "Appraisal of Guidelines for Research and Evaluation II" questionnaire (AGREE II) was used to assess and rate the methodological quality of the guidelines. Assessments were carried out in a total of 6 domains based on predefined assessment criteria (scope of application, participation of interest groups, stringency of guideline development, clarity of design, applicability and editorial independence). These domains were used to calculate an overall percentage rating (%). A guideline receiving an overall rating of <50% is considered to be of low methodological quality. The domain "Methodological precision of guideline development" is also relevant, as methodological aspects of evidence-based research (systematic literature survey, selection of literature) play a particularly important role in this area. A guideline receiving a rating of <50% in this domain was also considered to be of low methodological quality. A total of 177 entries were screened in the various databases. After excluding irrelevant entries, 8 guidelines remained. Their full texts were evaluated using the AGREE II tool. An assessment of the non-excluded guidelines was independently carried out by two experts; their evaluations are presented in. Three of these guidelines had an overall rating ≥50%. None of the guidelines included under the aspect "methodological precision" had a value ≥50%. Because the quality of the included guidelines was questionable at best, recommendations from these guidelines were not adopted without further review and our own literature survey was conducted. ## Systematic literature survey (dersch et al. 2015a) A systematic literature survey was conducted in order to assess the pharmacological processes for treating neuroborreliosis. This was followed by an evaluation and summary of existing literature. The search strategy and methodology of this systematic review were reviewed and published in advance as part of a peer review process. The literature was to be summarised and evaluated separately for adults and children. Diagnoses had to be made on the basis of internationally agreed case definitions (see above). Studies had to report data on drug therapy for patients with neuroborreliosis and include a control group. ## Treating neuroborreliosis in adults (dersch et al. 2015a) ## Selecting evidence A survey of the literature found a total of 5,779 entries after duplicates were removed. Irrelevant entries were eliminated by screening the titles and abstracts of each entry. This left 119 texts that were examined in their entirety. A further 86 entries were excluded on the basis of being irrelevant. Of the remaining 33 studies, 17 studies had only one treatment arm so no data could be extracted for statistical comparisons. A total of 16 studies had two or more treatment arms and thus data could be extracted for a meta-analysis. Of these 16 trials, eight were randomised controlled trials (RCTs). is a flow chart showing the studies that were included (PRISMA statement). The characteristics of the RCTs are shown in. [formula] Attachment [/formula] ## Evaluation of the evidence The quality of the individual RCTs was investigated and evaluated using the risk-of-bias tool from the Cochrane Collaboration (www.handbook.cochrane.org). The quality of the non-randomised studies (cohort studies) was measured using the ACROBAT-NRSI tool of the Cochrane Collaboration (www.riskofbias.info). The entire body of evidence was evaluated using the GRADE methodology (Grading of Recommendations Assessment, Development and Evaluation). The data extraction and risk of bias were carried out by two independent experts. For a meta-analysis of the existing studies, pooled effect estimates were calculated for the treatment effects using a "fixed effects model" based on the Mantel-Haenszel method. There were no studies on the treatment of neuroborreliosis in which antibiotic treatment was compared to a placebo. ## Creation of evidence tables The GRADE methodology was used by two experts to independently evaluate the quality of the evidence with regard to the individual comparisons. The evaluation of the individual comparisons is summarised in evidence tables. Two unblinded studies, concerns regarding the allocation and selective reporting Small groups, the 'optimal information size' was not reached, wide confidence interval The 'optimal information size' was not reached, wide confidence interval Critical risk of bias (interventions not clearly described, baseline confounding, no blinding), meta-analysis is therefore not justified 2. Low heterogeneity (various interventions, various treatment durations), relevance for effect estimate unclear 3. The 'optimal information size' was not reached, wide confidence intervals ## Treating neuroborreliosis in children (dersch et al. 2016a) The body of evidence on treating neuroborreliosis in childhood was also compiled from clinical studies and evaluated in a systematic review. The methodology is based on the systematic review mentioned above on treating neuroborreliosis in adulthood. ## Systematic literature survey Inclusion and exclusion criteria were defined and published in advance. The patients in the individual studies had to be <18 years old. The diagnosis had to be transparent in the individual studies. There are no established case definitions for diagnosing neuroborreliosis in childhood. Therefore, the diagnostic criteria of neuroborreliosis in adulthood were used as inclusion criteria for the individual studies in the systematic review (cf. guideline Section 3.11). For a metaanalysis of the existing studies, pooled effect estimates were calculated for the treatment effects using a "fixed effects model" based the Mantel-Haenszel method. A survey of the literature identified a total of 5,779 entries after duplicates were removed. Irrelevant entries were eliminated by screening the titles and abstracts of each entry. This left 44 texts that were examined in their entirety. A further 38 entries were excluded on the basis of being irrelevant. A total of six studies met the inclusion criteria including two RCTs, a prospective cohort study and three retrospective cohort studies.is a flow chart showing the included studies (PRISMA statement). The study characteristics of the included studies are shown in. ## Selecting evidence The selected studies and the results of the evidence analysis are shown in(see below) and in Section 5.5 of the guideline text. ## Creation of evidence tables The assessment of the individual comparisons is summarised in evidence tables ( Baseline confounding, selected patients, no blinding, unclear description of interventions, meta-analysis therefore not justified 2. ## Heterogeneous interventions, interventions not clearly described 3. The 'optimal information size' was not reached, wide confidence intervals Small group size, the 'optimal information size' was not reached 3. ## Heterogenous interventions ## Prognosis of neuroborreliosis (dersch et al. 2016b) A systematic review investigated the prevalence and spectrum of residual symptoms following neuroborreliosis with the aim of making evidence-based statements on the prognosis and progression of neuroborreliosis. Residual symptoms refer here to neurological symptoms that were present before therapy as disease symptoms and which remain after therapy. ## Systematic literature survey A literature survey was conducted in three electronic databases (MEDLINE, EMBASE and Central) using a previously published, broad-based search strategy. The search strategy was the same as in the literature surveys described above for the treatment of neuroborreliosis, however it also contained studies that did not include a control group (studies with only one treatment arm). The diagnosis had to be made on the basis of internationally established case definitions (cf. Section 3.11. of the guideline). . ## Selecting evidence Data on residual symptoms were extracted from the individual studies as reported by the original authors. The data on the spectrum of residual symptoms were combined into categories to allow a meaningful comparison (e.g. data on "facial nerve palsy" and "aducens nerve palsy" were placed into the category "cranial nerve palsy"). It was also recorded how the diagnosis of neuroborreliosis was made in the individual studies. Thus, the patient cohorts of the individual studies were categorised based on the case definitions of neuroborreliosis. : Included studies on residual symptoms following neuroborreliosis ## Prevalence of residual symptoms The prevalence of residual symptoms across all available studies was compiled in a meta-analysis. Since the heterogeneity of study populations was assumed to be high, a "random effects model" was used to calculate the meta-analysis for the prevalence of residual symptoms. The meta-analysis showed a prevalence of residual symptoms after treatment of 28% (95% CI 23-34%) across all studies. The prevalence of residual symptoms differed depending on the case definition used. In studies that included patients without a diagnosis confirmed by CSF testing ("possible neuroborreliosis"), residual symptoms were statistically significantly more frequent than in studies that included patients with a neuroborreliosis diagnosis confirmed by CSF testing ("probable" and "confirmed" neuroborreliosis) (31% vs. 24%, p=0.0048). ## Spectrum of the residual symptoms The spectrum of residual symptoms was reported for a total of 687 patients in studies where the diagnosis was confirmed by CSF testing and for 624 patients in studies without confirmation by CSF testing. The results of the review are presented in Section 4. ## Formulation of the recommendations and structured consensus building formal consensus building: process and implementation An initial draft of the guideline was developed by Prof. S. Rauer following consensus on the key issues and based on the results of the systematic literature survey. The draft was agreed on in the expert group using a modified Delphi procedure and subsequently brought to a vote in the consensus group using the nominal group technique. Four consensus conferences were held that were independently moderated by the AWMF. The nominal group technique contained the following steps: [formula] - [/formula] ## Consideration of benefits, side effects, relevant outcomes The systematic review found that there is no reliable data on placebo-controlled treatment. At the same time, there are analysable studies comparing the efficacy and side effects of different classes of antibiotics. These are described in Section 5 of the guideline. The relevant studies are summarised in Appendixes 3, 4 and 5 of the guideline (Attachment 1). Appendix 8 of the guideline (Attachment 1) presents an evaluation of the evidence of these studies using the GRADE methodology. ## Formulation of the recommendations and the grading of evidence and/or recommendations In infectiology the microbiological detection of pathogens by culture, microscopy or PCR is the diagnostic gold standard. Accepted case definitions are used in the diagnosis of neuroborreliosis (cf. Section 3.11. of the guideline) since there is no reliable gold standard because pathogen detection in cerebrospinal fluid has a very low sensitivity rate (10-30%). Thus, for methodological reasons, controlled studies on diagnostic testing procedures can only be conducted to a very limited degree. Evidence grading is provided in the background for all treatment recommendations based on the systematic reviews Evidence grading: studies on therapy interventions Ia Evidence from a meta-analysis of at least three randomised controlled trials (RCTs) Ib Evidence from at least one randomised controlled trial or a meta-analysis of fewer than three RCTs IIa Evidence from at least one methodologically sound controlled study without randomisation IIb Evidence from at least one methodologically sound, quasi-experimental descriptive study III Evidence from a methodologically sound, non-experimental observational study, such as comparative studies, correlational studies and case studies IV Evidence from reports by expert committees or expert opinions and/or the clinical experience of recognised authorities Uniform formulations are used in order to standardise the guideline recommendations. The following grading applies: Strong recommendation: "shall" ↑↑ Recommendation: "should" ↑ Open recommendation: "can be considered" ↔ Recommendation against an intervention: "should not" ↓ Strong recommendations against an intervention: "shall not" ↓↓ The grading of the recommendations was determined within the framework of formal consensus conferences. In addition to the quality of the underlying evidence, the following criteria were explicitly taken into account: - Consistency in the study results, directness of evidence, precision of the effect estimates (see GRADE profile) - ## Stating and countering potential conflicts of interest explanation and review of interests The potential conflicts of interest were documented in a structured AWMF form by all persons working on the guideline (members of the steering committee, expert group, consensus group). The potential conflicts of interest were assessed by a panel of expert reviewers appointed by the DGN who worked anonymously, pursued the highest degree of objectivity, were committed to confidentiality and had declared their own interests with respect to the DGN. This evaluation is summarised in a table in an appendix to this report (Attachment 3). ## Statement by the dgn experts -panels on assessing conflicts of interest: The fact that the guideline coordinator Prof. Dr. S. Rauer is co-founder and co-owner of ravo Diagnostika GmbH Freiburg was seen from the start as a conflict of interest. The company develops, produces and markets serological tests for determining Borrelia-specific antibodies as part of routine diagnostic testing. For this reason, S. Rauer was generally not entitled to vote as part of the consensus process. The DGN's vote was cast by PD Dr Stephan Kastenbauer, who was appointed deputy coordinator for this task by the DGN. Prof. A. Krause, member of the steering committee, declared several interests that did not relate to the topic of this guideline. However, there was not sufficient transparency with regard to the interdependencies and ramifications (subsidiaries) of the pharmaceutical companies involved. Thus, an unconscious bias in the decisions, e.g. with regard to antibiotic treatment, cannot be ruled out. Prof. A. Krause did not participate in voting on pharmacological treatment, in particular, antibiotic therapy. Formal reasons for conflicts of interest: Dr. Walter Berghoff, German Borreliosis Society (DBG), (member of the consensus group): Imprecise information stated on the interest form, for example, no income was declared from topic-related expert services provided to courts etc. Ute Fischer, Borreliosis and FSME Association Germany (BFBD), (member of the consensus group): non-fiction author, particularly the Borreliosis Yearbook series. Imprecise information stated on the interest form, for example, no income was declared from publications. The risk of bias through potential conflicts of interest were countered through: - Interdisciplinary, pluralistic composition of the guideline group with the involvement of representatives with different viewpoints - Systematic survey and assessment of the evidence by the German Cochrane Centre - Structured consensus building moderated by an independent guideline advisor from the AWMF ## Overall assessment of those involved The group of authors comprises 33 members, seven of whom are in the steering group. According to the interest criteria, 28 members (five in the steering group) are free of conflicts of interest or only have minor topic-related conflicts of interest. This means that the criterion of having 50% members without conflicts of interest is met by the group as a whole and by the steering group. Conflicts of interest cannot be ruled out for three members; in the case of two members, as a result of insufficient information given, or doubts about the completeness of the declaration form; in the case of an author (member of the steering group), non-participation in the voting on antibiotic treatment is deemed appropriate. There are potentially serious conflicts of interest for two members (both in the steering group, including the lead coordinator). Their possible influence is neutralised 1) through twice as many unencumbered members of the steering group, 2) through a second coordinator, 3) through abstention of voting by the lead coordinator, 4) through an overwhelming majority of members of the author group without conflicts of interest. In summary, the measures to limit possible conflicts of interest are deemed sufficient to ensure the independence of the decision-making used to prepare this guideline according to the criteria of the DGN and AMWF. The group of authors is well-balanced. ## Distribution and implementation ## Concept for distribution and implementation Websites of the AWMF and DGN; translation into English and publication in an international journal with focus on evidence-based medicine; presentation of the guideline at congresses. ## Supporting materials for applying the guideline ## Applying the guideline recommendations Since the recommended diagnostic testing and treatment can be performed both on an in-patient and out-patient basis depending on the nature of the symptoms, and the recommended antibiotics can be administered both orally and intravenously, few organisational problems are likely to arise when implementing the recommendations. As the recommended antibiotics are available in generic form, cost bearers should have no issues in applying the guideline. ## Validity period and updating procedures The guideline is valid for 3 years from the publication date (12 April 2018); 6 months before the expiry date, a literature survey shall be conducted with respect to existing systematic reviews and systematically evaluated for the subsequent period. The correspondingly updated manuscript will be discussed as part of a new consensus procedure, and the key recommendations will be reviewed with respect to their relevance to the current situation. Prof. Dr. S. Rauer and Dr. R. Dersch are responsible for updating the guideline in consultation with the DGN Guideline Commission.	None	None	Lyme borreliosis is the most common tick-borne infectious disease in Europe. A neurological manifestation occurs in 3–15% of infections and can manifest as polyradiculitis, meningitis and (rarely) encephalomyelitis. This S3 guideline is directed at physicians in private practices and clinics who treat Lyme neuroborreliosis in children and adults. Twenty AWMF member societies, the Robert Koch Institute, the German Borreliosis Society and three patient organisations participated in its development. A systematic review and assessment of the literature was conducted by the German Cochrane Centre, Freiburg (Cochrane Germany). The main objectives of this guideline are to define the disease and to give recommendations for the confirmation of a clinically suspected diagnosis by laboratory testing, antibiotic therapy, differential diagnostic testing and prevention.
516f991c314f134163aac3b6009c6ad9f118d096	pubmed	Joint statement for the diagnosis, management, and prevention of chronic obstructive pulmonary disease for Gulf Cooperation Council countries and Middle East–North Africa region, 2017	Joint statement for the diagnosis, management, and prevention of chronic obstructive pulmonary disease for Gulf Cooperation Council countries and Middle East–North Africa region, 2017 Smoking and subsequent development of COPD is an ever-increasing epidemic in Arabian Gulf and Middle East countries, with no signs of decline. The important fact to be highlighted is that this COPD epidemic of increasing incidence and prevalence is mostly unrecognized by patients, due to the common attribution of symptoms to "smoker's cough", and the underdiagnosis and undertreatment by physicians because the common signs and symptoms masquerade as asthma. Consequently, there are long-term adverse effects of missing the diagnosis. The purpose of this review article is to focus upon the status of COPD in Arabian Gulf and Middle East countries, stressing the increasing burden of smoking and COPD, to emphasize the specific factors leading to rise in prevalence of COPD, to bring to light the underdiagnosis and undermanagement of COPD, and to treat COPD in conformity with standard guidelines with local and regional modifications. This review ends with suggestions and recommendations to the health department to formulate policies and to generate awareness among the general public about the side effects of smoking and consequences of COPD. # Introduction The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines define COPD as a common preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities caused by significant exposure to noxious particles or gases.COPD is responsible for substantial morbidity and mortality globally. The Global Burden of Disease project in 2001 identified COPD as the sixth-leading cause of death in the developing or underdeveloped world, culminating in 4.9% of total deaths.As per World Health Organization (WHO) estimates in 2004,more than 60 million people are suffering from COPD and approximately 3 million people died directly or indirectly due to COPD. By 2030, COPD will become the third-leading cause of death worldwide according to a WHO prediction. A recent US study identified COPD as the fourth-leading cause of chronic morbidity and mortality, and incidence and prevalence continuously on the rise. [bib_ref] Chronic obstructive pulmonary disease: an overview, Devine [/bib_ref] Despite the fact that around 90% of COPD-related deaths occur The prevalence of smoking and COPD has risen significantly in Gulf Cooperative Council (GCC) countries and the Middle East-North Africa (MENA) region, due to the lack of knowledge of the risks of smoking and COPD. It is worth noting that in the GCC-MENA region, COPD is largely underdiagnosed/wrongly diagnosed and hence inappropriately treated. Diagnosis of COPD is delayed until it is moderately or severely advanced, due to lack of standardized procedures to diagnose COPD, overreliance on clinicoradiological parameters by clinicians for diagnosis, low general public awareness, indifferent attitudes in physicians and the general public about smoking and COPD, high prevalence of smoking (active and passive) and environmental pollution, nonimplementation of health regulations for smoking cessation, and the dictum that "everything that wheezes is asthma" leading to misdiagnosis of COPD as asthma. ## Smoking prevalence and smoking habits A pandemic of smoking and COPD is sweeping across the Middle East and MENA region. The recently conducted BREATHE study revealed that the adjusted smoking rate in the general population of MENA countries was estimated to be 31.2% (ranging from 15.3% in Morocco to 53.9% in Lebanon). The smoking rate in men ranged from 29.7% in Morocco to 61% in Turkey, whereas in women it ranged from 1.4% in Morocco to 47.3% in Lebanon. Overall, the highest rates were detected in Jordan, Lebanon, Syria, and Turkey. [bib_ref] Smoking habits in the Middle East and North Africa: results of the..., Khattab [/bib_ref] Many people in the GCC-MENA region consider smoking cigarettes and water pipes a socializing activity. In this region, tobacco is consumed in different forms, eg, water pipe (narghile/hookah) and medwakh (a pipe used to smoke dokha, a tobacco mixed with herbs and spices "dokha" in Arabic means "dizziness"), and the lack of health regulations to prohibit smoking and shisha in clubs, coffeehouses, and other public places is a major contributor to first and secondhand smoke. [bib_ref] Are narghile smokers different from cigarette smokers?, Riachy [/bib_ref] Water-pipe smoking is highly prevalent in women and the young, due to less cultural stigma associated with water-pipe smoking. It is important to note that the nicotine exposure from daily water-pipe use is considered equivalent to 20 cigarettes/day, [bib_ref] Waterpipe smoking and nicotine exposure: a review of the current evidence, Neergaard [/bib_ref] and it has been found that water-pipe and medwakh smokers have dependence on nicotine and are unable to quit, despite repeated attempts. There is a clear misconception that the water pipe is harmless compared to cigarettes, because the smoke is filtered and the noxious smoking particles absorbed and dissolved in water. [bib_ref] Patterns of waterpipe use and dependence: implications for intervention development, Maziak [/bib_ref] We discuss regional smoking patterns and burden in later sections. ## Other risk factors for copd relevant to gcc-mena The development of COPD and its progression is multifactorial, including complex interplay of genetic/risk factors and environmental exposure. Considering the huge proportion of expatriates in the UAE population, this statement holds further true; however, most of the genetic factors that could be potential contributors to the development of COPD in the GCC-MENA region are unknown, due to a lack of phenotypic and genetic research studies on COPD. ## Environmental factors Outdoor air pollution, occupational exposure to dust and fumes, biomass-smoke inhalation, first-and secondhand smoke, and previous tuberculosis are important environmental factors associated with COPD in the GCC-MENA region. Although tobacco smoking is the most common and important cause for COPD development, the populationattributable fraction of smoking as an etiological cause of COPD ranges from 9.7% to 97.9%. A Swedish cohort observed that the population-attributable fraction of smoking as a cause of COPD was present in 76.2%, [bib_ref] Seven-year cumulative incidence of COPD in an agestratified general population sample, Lindberg [/bib_ref] suggesting that there are other factors contributing to COPD development. ## Outdoor air pollution Outdoor pollution coming mainly from emission of gases/ fumes and pollutants from vehicular and industrial emission is an important public health problem in the fast-developed GCC-MENA region. In a community-based study, higher traffic density was found to be significantly associated with lower forced expiratory volume in 1 second (FEV ## ) and International Journal of COPD 2017:12 submit your manuscript \| www.dovepress.com Dovepress Dovepress 2871 GCC-MENa joint statement on COPD diagnosis and management forced vital capacity (FVC) values in women. [bib_ref] Traffic exposure and lung function in adults: the Atherosclerosis Risk in Communities..., Kan [/bib_ref] In a recent survey, Dubai Municipality found that the city ranked very high in vehicular pollution in the developed world, using an on-road vehicle emission-measurement device (measuring percentage scores for levels of harmful pollutants, including hydrocarbons, CO, nitrogen oxides, and CO 2 ). Dubai's statistical data showed that the number of motor vehicles had increased by an annual average of about 12% in Dubai every year, significantly contributing to air pollution. Frequent dust storms may also lead to acute exacerbation of COPD. ## Rapid industrialization and urbanization Very rapid construction of multistory buildings in the last 2 decades with the significant risk of exposure to harmful construction dust to laborers and nearby residents could have significantly contributed to the development of COPD, especially in the young. ## Indoor air pollution Indoor air pollutants contributing to COPD development are tobacco smoke, by-products of combustion of coal/wood/ barbeque, such as nitrogen dioxide, carbon monoxide, volatile organic compounds, and biological allergens. [bib_ref] Chronic obstructive pulmonary disease and associated healthcare resource consumption in the Middle..., Polatli [/bib_ref] Among these, tobacco and biomass-smoke (wood, crop residue, barbeque) 13,14 exposure contributes to the development of COPD. A recent meta-analysis showed biomass-smoke exposure to be a significant risk factor for developing COPD. [bib_ref] Risk of COPD from exposure to biomass smoke: a metaanalysis, Hu [/bib_ref] However, in view of the rapid urbanization and no or minimal use of biomass fuel, indoor air pollution would not be a significant contributing factor for the young, but could definitely be a contributory factor to COPD in the elderly when biomass fuel was the main source of cooking. In the GCC-MENA region, traditional Arabian incense (bakhour) is a common source of indoor smoke, and has consistently been found to be associated with worsening of asthma and wheezing bronchitis, especially in children, in many studies. Unfortunately, there are no studies available to establish bakhour as a contributory or worsening cause of COPD; however, scientifically speaking, slow and incomplete combustion of bakhour produces continuous smokecontaining pollutants (toxic gases and chemical particles), including polycyclic aromatic hydrocarbons, CO, benzene, and isoprene, that accumulate easily in indoor environments if ventilation is inadequate or in crowded places, [bib_ref] Incense smoke: clinical, structural and molecular effects on airway disease, Lin [/bib_ref] and could be a potential indoor risk factor for COPD in the MENA region. One study with the objective of characterization of particles and gases emitted from Arabian incense revealed that carbon monoxide and oxides of nitrogen concentration in time-weighted averages exceeded current governmentregulation values and emissions from environmental tobacco smoke. Charcoal emissions were the main contributor to high CO and NOx concentrations. A significant cellinflammatory response was observed to smoke components formed from incense burning. Our hazard evaluation suggests that incense burning contributes to indoor air pollution, and could be harmful to human health by worsening asthma and COPD. 17 ## Rationale for gcc-mena joint statement To produce this joint statement on COPD in the GCC-MENA region, we searched PubMed, Google Scholar, ResearchGate, Medline, SciSearch, Journal Citation Reports, Science Edition, Embase, Scopus, Directory of Open Access Journals, OAIster, and other research portals extensively for articles published on the burden of COPD in the MENA region, and found that there is scarce material available from the GCC-MENA region. BREATHE was the largest regional study done, with eleven countries participating, focusing on the epidemiology/pathogenesis/standardization of diagnosis/ treatment and preventive strategies and covering all other important aspects of this chronic, debilitating, multisystem, inflammatory disease and considering the widely varied sociocultural, demographic, and ethnic background/factors in this part of the world, with its majority of immigrant populations from low/middle socioeconomic class and their different attitudes/beliefs, patterns of smoking, and compliance with treatment. [bib_ref] Chronic obstructive pulmonary disease in the adult population within the Middle East..., El Hasnaoui [/bib_ref] We decided to uncover various issues, with particular emphasis on local and regional factors covering all aspects of COPD in this GCC-MENA positional statement, and we recommend that all regional health authorities implement strict policies for the prevention/diagnosis and treatment of this debilitating disease in the GCC-MENA region as per standard evidence-based management strategies with regional modification to reduce the incidence of smoking and consequent COPD and to provide best standardized care to all COPD patients. ## Incidence and prevalence of copd in gcc-mena region More than 3 million people died of COPD in 2012, which is equal to 6% of all deaths globally that year. As per WHO estimates, 65 million people have moderately severe COPD. Estimates show that COPD in 2030 will be the third-leading cause of death worldwide.More than 90% of COPD-related ## 2872 Mahboub et al deaths occur in low-and middle-income countries. The primary cause of COPD is tobacco smoking (through tobacco use or secondhand smoke). COPD now affects men and women almost equally, due to increased use of tobacco and related products among women in high-income countries. COPD is not curable, but treatment can slow the progression of the disease. A systemic meta-analysis of spirometry-based studies (n=123 studies) across the world showed growing prevalence of COPD globally, and produced the following results: - Global prevalence increased from [bib_ref] Seven-year cumulative incidence of COPD in an agestratified general population sample, Lindberg [/bib_ref] ## Burden of copd in mena region There is a scarcity of studies in Africa, Southeast Asia, and the EMR. [bib_ref] Global and regional estimates of COPD prevalence: systemic review and meta-analysis, Adeloye [/bib_ref] For the purpose of this review, PubMed was searched for articles published on the burden of COPD in the MENA region/EMR. Twelve studies were short-listed to assess the burden of COPD in the MENA region. BREATHE was the largest regional study done, with eleven countries participating. [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] It estimated the prevalence of COPD to be 3.6% in the MENA region, ranging from 1.9% in the UAE to 6.1% in Syria. [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] Al Zaabi et al estimated spirometry-based postbronchodilator prevalence to be 3.7% in the UAE.Another study in Dubai estimated COPD prevalence to be much higher -at 12.9%. [bib_ref] Case-finding of chronic obstructive pulmonary disease with questionnaire, peak flow measurements and..., Mahboub [/bib_ref] This difference in COPD prevalence can be explained, as the latter study resorted to prebronchodilator definition, which does not differentiate a substantial group of asthma patients from COPD, and hence overestimated the prevalence. Recent studies in Saudi Arabia have revealed COPD prevalence of 2.4%-14.2%. [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] [bib_ref] Prevalence of chronic obstructive pulmonary disease among smokers attending primary healthcare clinics..., Ghobain [/bib_ref] [bib_ref] The prevalence of chronic obstructive pulmonary disease in Riyadh, Saudi Arabia: a..., Ghobain [/bib_ref] The study with high estimated prevalence was conducted in high-risk patients (smokers presenting to primary health clinics) instead of the general population, hence overestimating the results. [bib_ref] Prevalence of chronic obstructive pulmonary disease among smokers attending primary healthcare clinics..., Ghobain [/bib_ref] This difference was also noted in Jordan, with COPD prevalence being 5.4% (BREATHE study in general population) vs 8.2% in a study done in male smokers by Al Omari et al. [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] [bib_ref] Prevalence of chronic obstructive pulmonary disease among adult male cigarettes smokers: a..., Omari [/bib_ref] One recent Egyptian study conducted on a high-risk population categorized study subjects based on risk factors for COPD (smokers, occupational exposure, and biomass fuel-combustion exposure), and estimated threefold-higher prevalence of COPD (9.6% vs 3.5% in BREATHE). [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] [bib_ref] Prevalence and predictors of chronic obstructive pulmonary disease among high-risk Egyptians, Said [/bib_ref] Another spirometry-based study in Egypt estimated the prevalence of COPD to be 6.6%. [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] [bib_ref] Prevalence of chronic obstructive pulmonary disease (COPD) in Qena Governorate, Badway [/bib_ref] Similarly, COPD prevalence in Lebanon was 5.3% in a questionnaire-based BREATHE study, while it was 9.7% in another study using postbronchodilator definition of COPD. [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] [bib_ref] Chronic obstructive pulmonary disease prevalence in Lebanon: a cross-sectional descriptive study, Waked [/bib_ref] It is obvious that spirometry-based studies produce higher prevalence than questionnaire-based studies. Burden of Lung Disease (BOLD) studies were conducted in the countries in the GCC-MENA region. Based on BOLD protocol-estimated prevalence of COPD in Tunisia, Saudi Arabia, and Morocco of 7.8%, 4.2%, and 12.6%, respectively, BREATHE COPD-prevalence estimates were 3.7%, 2.4%, and 2.2%, respectively. [bib_ref] The prevalence of chronic obstructive pulmonary disease in Riyadh, Saudi Arabia: a..., Ghobain [/bib_ref] [bib_ref] Prevalence of COPD and tobacco smoking in Tunisia: results from the BOLD..., Daldoul [/bib_ref] [bib_ref] Prevalence of chronic obstructive pulmonary disease in Fez, Morocco: results from the..., El Rhazi [/bib_ref] Underreporting of mild symptoms, smoking prevalence (especially in females), criteria for diagnosis of COPD in BREATHE, and differences in methodology could partially account for this difference. Estimated sex-and age-based prevalence of COPD also showed varied results. All studies reviewed demonstrated either statistically significant increased prevalence in males over females [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] [bib_ref] The prevalence of chronic obstructive pulmonary disease in Riyadh, Saudi Arabia: a..., Ghobain [/bib_ref] [bib_ref] Chronic obstructive pulmonary disease prevalence in Lebanon: a cross-sectional descriptive study, Waked [/bib_ref] or no difference. [bib_ref] Case-finding of chronic obstructive pulmonary disease with questionnaire, peak flow measurements and..., Mahboub [/bib_ref] [bib_ref] Prevalence of chronic obstructive pulmonary disease (COPD) in Qena Governorate, Badway [/bib_ref] This inconsistency can be explained by the wide variation in smoking prevalence in females within the region, differences in cultural background, and differences in exposure to other risk factors, eg, biomass fuel. Older age in some studies showed higher prevalence of COPD. [bib_ref] Prevalence of chronic obstructive pulmonary disease (COPD) in Qena Governorate, Badway [/bib_ref] [bib_ref] Prevalence of chronic obstructive pulmonary disease in Fez, Morocco: results from the..., El Rhazi [/bib_ref] GOLD stage II (moderate) COPD was found to have the highest prevalence in a majority of the studies that staged the population. [bib_ref] Prevalence of chronic obstructive pulmonary disease in Fez, Morocco: results from the..., El Rhazi [/bib_ref] # Discussion ## What is common? There is substantial variation in COPD trends, both globally and regionally. Smoking is the single commonest and most important risk factor for COPD. A comparison was made of the various studies done worldwide with those of the MENA region to assess the relationship between prevalence of smoking and prevalence of COPD. There were differences in the study groups, methodology, and definitions used, as already mentioned. In 2015, over 1.1 billion people smoked tobacco. Although it is declining worldwide and in many countries, the prevalence of tobacco smoking appears to be increasing in the WHO EMR and the African region.The BOLD study (from 14 countries worldwide) estimated smoking prevalence of 57.1% and COPD (stage 2 or higher) of 8.1%. [bib_ref] Case-finding options for COPD: results from the Burden of Obstructive Lung Disease..., Jithoo [/bib_ref] Similarly, PLATINO (from five Latin countries) estimated average smoking prevalence was 56.8%, with average COPD prevalence of 9.04%. [bib_ref] Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study):..., Menezes [/bib_ref] International Journal of COPD 2017:12 submit your manuscript \| www.dovepress.com ## Dovepress ## Dovepress ## 2873 GCC-MENa joint statement on COPD diagnosis and management The Continuing to Confront COPD survey (updated version) from 13 countries estimated prevalence of smoking and COPD at 65% and 8.2%, respectively. 35 BREATHE (inspired by this survey) estimated smoking prevalence of 31.2% and COPD of 3.6% in the MENA region. [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] For the sake of comparison, smoking prevalence is almost double in the West compared to the MENA region, with COPD prevalence following the same trend. Needless to say, this is only a rough estimate to support the previously well-established fact that smoking is the commonest risk factor for COPD, with prevalence increasing proportionally. ## What is different? Comparison of studies There is concern that the incidence and prevalence of COPD have been underestimated in the region, owing to overreliance on clinical diagnosis, with most of the time diagnoses not being based on spirometry or international guidelines. [bib_ref] COPD: an underdiagnosed disease at hospital environment, Kart [/bib_ref] Spirometry vs questionnaire-based BOLD and PLATINO were both spirometry-based studies. Spirometry-based studies from the MENA region reviewed totaled eleven. The first study ever in the region was that of Al Zaabi et al in 2011, and results were comparable to the largest questionnaire-based BREATHE study in the MENA region. [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] Three studies were based on the BOLD protocol: Al Ghobain et al in Saudi Arabia, [bib_ref] The prevalence of chronic obstructive pulmonary disease in Riyadh, Saudi Arabia: a..., Ghobain [/bib_ref] Daldoul et al in Tunisia, [bib_ref] Prevalence of COPD and tobacco smoking in Tunisia: results from the BOLD..., Daldoul [/bib_ref] and El Rhazi et al in Morocco. [bib_ref] Prevalence of chronic obstructive pulmonary disease in Fez, Morocco: results from the..., El Rhazi [/bib_ref] The other studies have already been described herein. ## Differences in study groups Within the MENA region, significant variation in study groups can explain differences in COPD prevalence determined from the studies. For example, three studies were done in Saudi Arabia using different methodology, including smoking population, BREATHE study questionnaire, and BOLD protocol, which found COPD prevalence to be 14.2%, 2.4%, and 4.2%, respectively. ## Comparison of risk factors Cigarette smoking is the most important risk factor in the development and progression of COPD. However, a substantial number of COPD cases occur in the absence of smoking, especially among young adults and women and in developing countries. The population-attributable fraction of smoking as a cause of COPD was found to be less than 80% in a review by an ad hoc subcommittee of the American Thoracic Society, which revealed that a substantial burden of disease was attributable to nonsmoking and environmental risk factors. [bib_ref] An official American Thoracic Society public policy statement: novel risk factors and..., Eisner [/bib_ref] Specific genetic syndromes are causally related to the development of COPD. Traffic and other outdoor pollution, secondhand smoke, biomass smoke, and occupational exposure are associated with COPD. Chronic uncontrolled asthma and sequelae of untreated chronic tuberculosis are associated with irreversible changes in lung parenchyma and airway remodeling with loss of lung function, but there is still uncertainty about whether there are important phenotypic differences compared with COPD, as is typically seen in clinical settings. [bib_ref] An official American Thoracic Society public policy statement: novel risk factors and..., Eisner [/bib_ref] tobacco smoking As per WHO estimates in 2000, the rate of mortality from smoking in the adult population (age .30 years) was 19% in industrialized countries and 9% in developing countries. [bib_ref] Estimates of global mortality attributable to smoking in 2000, Ezzati [/bib_ref] Khattab et al estimated adjusted smoking prevalence to be 31.2% in the MENA region. [bib_ref] Smoking habits in the Middle East and North Africa: results of the..., Khattab [/bib_ref] Highest rates were observed in Jordan, Lebanon, Syria, and Turkey. Significant variation was observed in the MENA region for estimated smoking prevalence between countries, ranging from 15.3% in Morocco to 53.9% in Lebanon. Sex prevalence for smoking ranged from 29.7% in Morocco to 61% in Turkey in men and 1.4% in Morocco to 47.3% in Lebanon in women. Sex differences could be attributed to women having limited access to public places, religious and cultural beliefs, and social stigma. However, an increasing trend of smoking in women may be seen, due to increased marketing of cigarettes, social status, more professionally active women, and Westernization in the region. [bib_ref] Smoking habits in the Middle East and North Africa: results of the..., Khattab [/bib_ref] Smoking in the MENA region (particularly water-pipe smoking) is part of the culture. Lack of rules and regulations to ban smoking in public places contributes to the high prevalence of smoking in the region. [bib_ref] Chronic obstructive pulmonary disease in Middle East and UAE: an unrecognized underestimated..., Zaabi [/bib_ref] Water-pipe smoking deserves special mention in this region, as it may increase the risk of COPD, lung carcinoma, and other chronic respiratory problems. [bib_ref] Tobacco smoking using a waterpipe: a re-emerging strain in a global epidemic, Maziak [/bib_ref] [bib_ref] The effects of water pipe tobacco smoking on health outcomes: a systematic..., Akl [/bib_ref] [bib_ref] Chinese water-pipe smoking and the risk of COPD, She [/bib_ref] Alzaabi et al screened 62,086 subjects in BREATHE, and found that water-pipe use was reported by 2,173 (3.5%, 95% CI 3.4%-3.6%), of whom 934 (43%) smoked both water pipes and cigarettes. The majority of water-pipe users were men (82%) and aged 40-49 years (53.7%). Over 90% of users smoked their water pipe for $1 hour per day. [bib_ref] The effects of water pipe tobacco smoking on health outcomes: a systematic..., Akl [/bib_ref] The prevalence of water-pipe use is high in the EMR. A national survey in Kuwait showed that 57% of men and 69% of women had used a water pipe at least once. Waterpipe use is also common in Egypt, where 22% of 6,762 men ## 2874 Mahboub et al from two rural villages reported current or past use. [bib_ref] Prevalence and predictors of chronic obstructive pulmonary disease among high-risk Egyptians, Said [/bib_ref] Recent data from the EMR show that substantial numbers of adolescents and young adults are now smoking water pipes. In Syria, for example, about half of university students report having used a water pipe, and about a quarter of males currently use it. The picture is similar in Lebanon, where of 1,964 Beirut university students, 30.6% of men and 23.4% of women reported current, weekly water-pipe use in 2001. Across several EMR countries, about 10%-18% of those aged 13-15 years use tobacco products other than cigarettes, most likely water pipes. [bib_ref] Tobacco smoking using a waterpipe: a re-emerging strain in a global epidemic, Maziak [/bib_ref] A systematic review of water-pipe use on health outcomes published in 2016 showed chronic bronchitis and COPD were significantly associated (P,0.05) with water-pipe use. [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] [bib_ref] Chinese water-pipe smoking and the risk of COPD, She [/bib_ref] [bib_ref] A systematic review of effects of waterpipe smoking on cardiovascular and respiratory..., Haddad [/bib_ref] [bib_ref] Waterpipe smoking and dependence are associated with chronic bronchitis: a case-control study..., Salameh [/bib_ref] [bib_ref] Impact of active and passive smoking as risk factors for asthma and..., Mohammad [/bib_ref] Water-pipe use was significantly (P,0.05) associated with COPD in one study, [bib_ref] Prevalence of chronic obstructive pulmonary disease (COPD) in Qena Governorate, Badway [/bib_ref] and was a significant (P,0.05) risk for developing COPD in another study. [bib_ref] Chinese water-pipe smoking and the risk of COPD, She [/bib_ref] A large study in UAE nationals found smoking prevalence to be commonest in younger groups, with an increasing trend in medwakh use among the young. [bib_ref] Tobacco smoking using medwakh is an emerging health problem: evidence from a..., Al-Houqani [/bib_ref] Passive smoking was also found to be an important risk factor for COPD in developed and developing countries. [bib_ref] An official American Thoracic Society public policy statement: novel risk factors and..., Eisner [/bib_ref] [bib_ref] Exposure to outdoor air pollution and chronic bronchitis in adults: a case-control..., Salameh [/bib_ref] Factors other than smoking The prevalence of COPD among nonsmokers is estimated to be 3%-15%, further validating the role of other risk factors. [bib_ref] Case-finding options for COPD: results from the Burden of Obstructive Lung Disease..., Jithoo [/bib_ref] [bib_ref] Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study):..., Menezes [/bib_ref] [bib_ref] An official American Thoracic Society public policy statement: novel risk factors and..., Eisner [/bib_ref] A cross-sectional study in Lebanon revealed 3.4% of nonsmokers had COPD (GOLD stage I) and 11.75% chronic bronchitis. Lower prevalence in nonsmokers in the MENA region compared to other areas of the world could be attributed to a younger demographic in developing countries. [bib_ref] Correlates of COPD and chronic bronchitis in nonsmokers: data from a cross-sectional..., Waked [/bib_ref] The Tunisian BOLD study estimated a prevalence of 4.7% (GOLD stage I) among nonsmokers (45% of COPD in the study were nonsmokers). [bib_ref] COPD in nonsmokers: reports from the Tunisian population-based Burden of Obstructive Lung..., Denguezli [/bib_ref] Outdoor pollution and urbanization There is strong evidence of an association between outdoor pollution and decreased pulmonary function growth during childhood and adolescence, though there are few studies that have defined COPD by spirometry. 51-53 SAPALDIA-cohort analysis examined the association between 11-year change in air quality and lung-function decline among 8,047 adult subjects (4,742 had complete follow-up), with significant decline with higher PM 10 , a measure of particulate matter in the air. [bib_ref] Reduced exposure to PM 10 and attenuated age-related decline in lung function, Downs [/bib_ref] The AHSMOG study examined survey-based definitions of chronic bronchitis or emphysema only. [bib_ref] Chronic obstructive pulmonary disease symptom effects of long-term cumulative exposure to ambient..., Euler [/bib_ref] [bib_ref] Long-term particulate and other pollutants and lung function in nonsmokers, Abbey [/bib_ref] The German SALIA study in women showed higher PM 10 was related to an increased risk of COPD (GOLD stage I criteria). [bib_ref] Long-term air pollution exposure and living close to busy roads are associated..., Schikowski [/bib_ref] There is also evidence of biological plausibility, in that exposure to air pollutants, such as particulate matter, O 3 , and NO 2 , can produce deleterious effects on the airway, irreversible loss of pulmonary function over time, and COPD. [bib_ref] COPD and long-term exposure to traffic-related air pollution: a cohort study, Andersen [/bib_ref] A case-control study in Lebanon found a statistically significant association between outdoor pollution and chronic bronchitis. It concluded that living close to a busy road/power plant was linked to chronic bronchitis. Dubai was found to ranked highest in the developed world using a pollutant score on account of two variables: volume of cars and emission from each vehicle. [bib_ref] Chronic obstructive pulmonary disease in Middle East and UAE: an unrecognized underestimated..., Zaabi [/bib_ref] Rapid urbanization and motorization are responsible for this situation. COPD prevalence was found to be higher in urban dwellers (60% of all cases) in 2010 in a meta-analysis of WHO world regions. 20 ## Biomass fuel In developing countries, a significant proportion of COPD cases occur among never-or nonsmokers, especially in women cooking with open-fire stoves. The fuel used in these stoves is collectively known as biomass (wood, animal dung, and crop residue). These stoves emit high levels of toxic air pollutants similar to those present in tobacco smoke, with exposure mostly occurring over the entire life span.Approximately half the world's population still uses solid fuels for cooking, and this biomass-fuel usage is even higher in rural areas (up to 80%). Particulate-matter concentrations greatly exceed most governmental standards for outdoor air. [bib_ref] An official American Thoracic Society public policy statement: novel risk factors and..., Eisner [/bib_ref] Several case-control and cross-sectional studies, mostly from developing countries, have found a consistent direct correlation between cooking with biomass fuel and respiratory symptoms, chronic bronchitis, and chronic airflow obstruction, with evidence of an exposure-response relationship, eg, hours of cooking per day and number of years cooking with biomass. [bib_ref] Chronic bronchitis and cor pulmonale in Nepal, Pandey [/bib_ref] [bib_ref] Domestic biomass fuel combustion and chronic bronchitis in two rural Bolivian villages, Albalak [/bib_ref] [bib_ref] An analysis of effect of common domestic fuels on respiratory function, Behera [/bib_ref] [bib_ref] Respiratory symptoms in Indian women using domestic cooking fuels, Behera [/bib_ref] [bib_ref] Ventilatory function in nonsmoking rural Indian women using different cooking fuels, Behera [/bib_ref] [bib_ref] Prevalence of chronic bronchitis and associated risk factors in a rural area..., Cetinkaya [/bib_ref] [bib_ref] Risk factors for chronic obstructive lung disease in Saudi Arabia, Dossing [/bib_ref] [bib_ref] Obstructive airway diseases in women exposed to biomass smoke, Ekici [/bib_ref] [bib_ref] Chronic pulmonary disease in rural women exposed to biomass fumes, Kiraz [/bib_ref] [bib_ref] Domestic smoke pollution and chronic bronchitis in a rural community of the..., Pandey [/bib_ref] [bib_ref] Exposure to biomass smoke and chronic airway disease in Mexican women: a..., Pérez-Padilla [/bib_ref] [bib_ref] The effect of biomass burning on respiratory symptoms and lung function in..., Regalado [/bib_ref] [bib_ref] Indoor air pollution from biomass fuels and respiratory health of the exposed..., Shrestha [/bib_ref] [bib_ref] Prevalence and risk factors for chronic bronchitis in Pelotas, RS, Brazil: a..., Menezes [/bib_ref] [bib_ref] Effect of indoor air pollution on the respiratory system of women using..., Dutt [/bib_ref] [bib_ref] Cooking fuel smoke and respiratory symptoms among women in low-income areas in..., Ellegard [/bib_ref] [bib_ref] Biomass fuels are the probable risk factor for chronic obstructive pulmonary disease..., Liu [/bib_ref] [bib_ref] Woodsmoke exposure and risk for obstructive airways disease among women, Dennis [/bib_ref] [bib_ref] Wood smoke exposure and risk of chronic obstructive pulmonary disease, Orozco-Levi [/bib_ref] A study from Colombia found that biomass-stove use for $10 years was associated with a greater risk of COPD (GOLD stage I). [bib_ref] Prevalence of COPD in five Colombian cities situated at low, medium, and..., Caballero [/bib_ref] Exposure to woodsmoke (barbeques, cooking stoves) was shown to increase the risk of chronic bronchitis in smokers (current or past) in a study in the US. [bib_ref] Chronic obstructive pulmonary disease in the adult population within the Middle East..., El Hasnaoui [/bib_ref] In the MENA region, a study in the UAE showed that among COPD patients, biomass exposure was higher (33%) than other risk factors, including cigarette smoking (12% current, 12% past).An Egyptian study showed a COPD (GOLD stage I) prevalence of 11.2% in women exposed to biomass fuel; 86.2% of the total females in the exposed group were nonsmokers. [bib_ref] Prevalence and predictors of chronic obstructive pulmonary disease among high-risk Egyptians, Said [/bib_ref] Other exposure (occupational, arabian incense) Consistent direct associations have been observed between exposure to workplace pollutants and COPD in multiple high-quality epidemiological studies. [bib_ref] An official American Thoracic Society public policy statement: novel risk factors and..., Eisner [/bib_ref] Prevalence of exposure to bakhour is high in the MENA region, particularly the Arabian Gulf. It has been found to be an exacerbating factor in asthma not proven to be associated with COPD.Genetic factors α 1 -Antitrypsin deficiency (AATD) accounts for 1%-2% of COPD cases, especially in the young. [bib_ref] Chronic obstructive pulmonary disease in Middle East and UAE: an unrecognized underestimated..., Zaabi [/bib_ref] There are very limited data available in the region to estimate the prevalence of AATD. One study in Saudi Arabia concluded higher-thanexpected prevalence of the AATD allele in the Saudi population. Genetics has an important role to play in the prevalence of COPD, and more studies need to be conducted. [bib_ref] Prevalence of α-1-antitrypsin gene mutations in Saudi Arabia, Aljarallah [/bib_ref] asthma and tuberculosis Many studies have the identified presence of irreversible airway obstruction in asthmatics, including nonsmokers, with evidence that longer asthma duration may lead to more severe chronic airway obstruction, due to accelerated loss of pulmonary function. [bib_ref] Asthma and irreversible airflow obstruction, Brown [/bib_ref] [bib_ref] Nonreversible airflow obstruction in life-long nonsmokers with moderate to severe asthma, Ulrik [/bib_ref] [bib_ref] Duration of asthma and physiologic outcomes in elderly nonsmokers, Cassino [/bib_ref] [bib_ref] The relationship between age and duration of asthma and the presence of..., Connolly [/bib_ref] Because airway obstruction and remodeling can lead directly to COPD, it is likely that asthma, with or without additional risk factors, can later develop into COPD. It remains uncertain, however, whether asthma patients with irreversible airway obstruction are phenotypically and pathologically similar to "typical" COPD patients or if they represent a separate subset of patients. There is limited but suggestive evidence of an association between tuberculosis and chronic airflow obstruction. The evidence is inadequate to show a causal relationship between tuberculosis and COPD worldwide and in the MENA region. ## Sex Across all WHO regions, COPD is more prevalent in men (14.3%) than women (7.6%), suggesting a higher-risk profile among men, with similar results seen in the MENA region: men (5.2%) vs women (1.8%). [bib_ref] Global and regional estimates of COPD prevalence: systemic review and meta-analysis, Adeloye [/bib_ref] [bib_ref] Distribution of COPD-related symptoms in the Middle East and North Africa: results..., Tageldin [/bib_ref] Recently, with increased tobacco consumption among women and higher risk of exposure to indoor pollution (biomass fuel used for cooking and heating) in low-and middle-income countries, sex differences in the disease may be reduced.For example, in the revised Continuing to Confront COPD survey of North America and Europe done in 2013, women (7.1%) had a higher prevalence of COPD than men (6.2%) in the US only. The other countries showed similar patterns, with higher prevalence in men. [bib_ref] Continuing to Confront COPD international patient survey: methods, COPD prevalence, and disease..., Landis [/bib_ref] Burden of COPD in terms of cost and health care-resource consumption COPD causes burdens in terms of mortality, morbidity, high health care costs, disability, and impaired quality of life. [bib_ref] Chronic obstructive pulmonary disease and associated healthcare resource consumption in the Middle..., Polatli [/bib_ref] The European Union (EU) reported that the direct cost from COPD was over €38.6 billion in 2005, representing about 3% of total health care expenditure. [bib_ref] Epidemiology and costs of chronic obstructive pulmonary disease, Chapman [/bib_ref] In 2010, the US government spent nearly $49.9 billion on COPD, including $29.5 billion spent on direct health care compared to $38 billion spent in 2005, with direct health care costs being $22 billion. Direct costs per patient in 2005 were $2,700-$5,900. [bib_ref] Assessment of the economic burden of COPD in the U.S.: a review..., Foster [/bib_ref] The burden in low-and middle-income countries has been comparatively high, owing to relatively low COPD awareness, challenges with COPD diagnosis, and increased exposure to additional risk factors, like combustion of biomass fuel. [bib_ref] The burden of COPD in Africa: a literature review and prospective survey..., Mehrotra [/bib_ref] With increasing smoking prevalence in the MENA region, especially in the young, and increased life expectancy, the burden of resource consumption of COPD is likely to increase. The results of the BREATHE study were as follows (monetary quantification was not possible, due to wide variation in the region in terms of structure of health care provision). - Physician consultation was the most frequent cause of health care-resource use, followed by emergency visits and hospitalizations, with similar hierarchy seen in developed countries. 91-96 - Health care consumption showed proportional increase with GOLD severity. - Frequency of symptoms, exacerbations, and higher COPD-assessment test (CAT) scores resulted in higher burden in terms of resource consumption. Group D in CAT had the highest expenditure, with a sixfold increase in hospitalization and emergency visits. Exacerbation of COPD was the major reason for physician consultation, hospitalization, and emergency visits. This puts emphasis on having individualized approaches in high-risk patients to optimize management of COPD and prevent exacerbations. - The presence of comorbidities (mainly cardiovascular and diabetes) showed increased hospitalizations (P,0.0001) and hence increased consumption of resources, consistent with other studies. 97,98 - Variation was observed within the MENA region, which could be explained by differences in health care systems, eg, availability of health care facilities to the general population and reimbursement processes. 99 ## Diagnosis and assessment of copd The diagnosis of COPD should be considered in any patient who is complaining of dyspnea, cough, and sputum production, and who has a history of exposure to risk factors. [bib_ref] Symptom variability in patients with severe COPD: a pan-European cross-sectional study, Kessler [/bib_ref] ## Clinical presentation Characteristic symptoms of COPD Dyspnea This is simply described as air hunger or increased effort to breathe. It is usually chronic, progressive, and increases with exertion. [bib_ref] Distinguishable types of dyspnea in patients with shortness of breath, Simon [/bib_ref] Dyspnea is the most characteristic symptom of COPD, and it represents a major cause of disability and anxiety associated with COPD. ## Cough Chronic cough is the first COPD symptom to develop, initially intermittent, then it becomes every day. It may be productive or unproductive. 104 ## Sputum production Commonly, small amounts of tenacious sputum are associated with coughing. The term "chronic bronchitis" refers to regular sputum production for $3 months in 2 consecutive years with an absence of other conditions that could explain it.Wheezing and chest tightness Wheezes and chest tightness are aspecific symptoms that can be variably present in COPD patients. ## Other symptoms Severe COPD may present with symptoms of cor pulmonale (ankle swelling), fatigue, weight loss, anorexia, anxiety, and depression. [bib_ref] Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible..., Schols [/bib_ref] These symptoms have an important prognostic value, [bib_ref] Weight loss is a reversible factor in the prognosis of chronic obstructive..., Schols [/bib_ref] and can also be an indicator for other diseases (eg, tuberculosis, lung cancer), and thus should always be investigated. ## Medical history A detailed medical history is required in order to assess: - exposure to risk factors (smoking, occupational or environmental exposures); - asthma, allergy, sinusitis, or nasal polyps; respiratory infections in childhood; other respiratory diseases; - family history of smoking, COPD, or other chronic respiratory disease; - pattern of symptom development (COPD typically develops in adult life, and most patients develop progressive dyspnea over years, with chronic cough and sputum production); - history of exacerbations or previous hospitalizations for respiratory disorder; - presence of comorbidities, such as heart disease, osteoporosis, musculoskeletal disorders, and malignancies that may also contribute to limitation of activity; 108 - impact of the disease on the patient's life, including social and economic impact. ## Physical examination Physical signs as expiratory and inspiratory wheezes, coarse crepitations, and signs of hyperinflation may be present if lung function is significantly impaired. The absence of physical signs does not exclude the diagnosis. [bib_ref] Physician perceptions and management of COPD, Kesten [/bib_ref] [bib_ref] Alteration in breathing pattern with progression of chronic obstructive pulmonary disease, Loveridge [/bib_ref] Spirometry Spirometry is considered the most objective and reproducible test to detect airflow limitation. The test measures the volume of air forcibly exhaled from the point of maximal inspiration (FVC), the volume of air exhaled during the first second of this maneuver (FEV 1 ), and the ratio of these two measurements (FEV 1 :FVC). Measurements are compared to reference values based on age, sex, height, and race. [bib_ref] Interpretative strategies for lung function tests, Pellegrino [/bib_ref] Spirometry of a normal subject is shown in [fig_ref] Figure 1: Spirometry showing normal [/fig_ref] , and that of a COPD patient showing an obstructive pattern in [fig_ref] Figure 1: Spirometry showing normal [/fig_ref]. An obstructive pattern is defined by FEV 1 :FVC ratio below the fifth percentile of a predicted value, and the shape of the flow-volume curve is concave. ## Assessment of copd COPD is a complex disease, and hence the objectives of COPD assessment are to determine the severity of disease, risk of exacerbations, and hospital admissions, and its impact on the patient's health status, quality of life, and risk of death. Knowledge of the previous combined parameters will guide optimum individualized therapy. The following aspects must be considered in COPD assessment: patient symptoms, spirometric abnormality, exacerbation risk, and presence/absence of comorbidities. ## Assessment of symptoms A simple measure of breathlessness using the modified Medical Research Council (mMRC) dyspnea scale was previously considered adequate for assessment of symptoms. [bib_ref] Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure..., Bestall [/bib_ref] [bib_ref] Dyspnea is a better predictor of 5-year survival than airway obstruction in..., Nishimura [/bib_ref] However, since COPD has multiple symptomatic effects, [bib_ref] Health status measurement in chronic obstructive pulmonary disease, Jones [/bib_ref] it is recommended to use more sophisticated tests with comprehensive symptom assessment. Questionnaires like the CAT (http://www.catestonline.org) and clinical COPD questionnaire (CCQ; http://www.ccq.nl) are practical and suitable for this purpose. However, because use of the mMRC is still widespread, an mMRC score $2 is still included as a cutoff point for separating "less breathlessness" from "more breathlessness". [bib_ref] Creating scenarios of the impact of COPD and their relationship to COPD..., Jones [/bib_ref] [bib_ref] Comparisons of health status scores with MRC grades in COPD: implications for..., Jones [/bib_ref] CAT This is an eight-item unidimensional measure of health-status impairment in COPD. [bib_ref] COPD assessment test: rationale, development, validation and performance, Jones [/bib_ref] It was developed to be applied worldwide, and validated translations are available in many languages. The score ranges from 0 to 40, and CAT scores correlate very closely with the St George's Respiratory Questionnaire. [bib_ref] Development, validity and responsiveness of the clinical COPD questionnaire, Van Der Molen [/bib_ref] CCQ This is a ten-item self-administered subjective questionnaire developed to measure clinical control in patients with COPD. [bib_ref] Reliability and validity of the clinical COPD questionnaire and chronic respiratory questionnaire, Reda [/bib_ref] [bib_ref] Standardization of spirometry, Miller [/bib_ref] Although the concept of "control" in COPD remains controversial, the CCQ is short and easy to administer. It is reliable, available in many languages, and has been well validated. ## Assessment of airflow limitation Spirometry should be performed using techniques that meet recommended published standards after the administration of an adequate dose of a short-acting inhaled bronchodilator. [bib_ref] International variations in the prevalence of COPD (the BOLD study): a population..., Buist [/bib_ref] Spirometric measurements should be evaluated by comparison of the results with appropriate reference values based on standard demographic nomograms. The presence of postbronchodilator FEV 1 /FVC ,0.7 confirms airflow obstruction in the patient. ## Assessment of exacerbation risk An exacerbation of COPD is defined as an acute worsening of underlying respiratory symptoms that result in requirement of additional therapy. [bib_ref] What is (and what is not) a COPD exacerbation: thoughts from the..., Hurst [/bib_ref] The best predictor of frequent exacerbations (two or more exacerbations per year or one or more leading to hospital admission) is the presence of frequent exacerbations in the past. Low frequency is defined as one (or zero) exacerbation per year or no hospital admission. [bib_ref] Susceptibility to exacerbation in chronic obstructive pulmonary disease, Hurst [/bib_ref] The risk of exacerbations increases significantly in severe and very severe disease. COPD exacerbations are associated with deterioration in health status, increased decline in lung function, and increased risk of death. 124 ## Assessment of comorbidities Other diseases related to smoking and aging may coexist with COPD, [bib_ref] Patterns of comorbidities in newly diagnosed COPD and asthma in primary care, Soriano [/bib_ref] and COPD itself may lead to multiple systemic effects, including but not limited to cardiovascular disease, skeletal muscle dysfunction, metabolic syndrome, osteoporosis, depression, and lung cancer. [bib_ref] Ventilatory function and chronic mucus hypersecretion as predictors of death from lung..., Lange [/bib_ref] [bib_ref] Higher risk of lung cancer in chronic obstructive pulmonary disease: a prospective,..., Skillrud [/bib_ref] Comorbidities should be looked for routinely and treated appropriately in any patient with COPD. ## Combined copd assessment The combined assessment of COPD helps to categorize patients into one of four groups [fig_ref] Figure 2: Refined ABCD assessment tool [/fig_ref] , which helps guide therapy. To classify patients into a specific group, we perform the following steps. ## Symptom assessment If the patient has fewer symptoms (CAT ,10) or less breathlessness (mMRC grade 0-1), then he/she belongs in the boxes on the left. If the patient has more symptoms (CAT $10) and/or more breathlessness (mMRC grade $2); then they belong in the boxes on the right. ## Risk-of-exacerbation assessment To detect if the patient has high or low risk, we choose the higher risk of the following three methods: - Assess the number of exacerbations the patient has had within the previous 12 months (zero or one indicate low risk [lower part of box], while two or more exacerbations indicate high risk [upper part of box]). - Determine whether the patient has had one or more hospitalization in the previous year for a COPD exacerbation, indicating high risk (upper part of box). - The latest GOLD 2017 document refines the ABCD assessment tool by separating spirometry grades from the "ABCD" groups. ## Further clinical phenotyping The Spanish guidelines for COPD (GesEPOC) recognize the importance of characterizing patients by clinical phenotype, helping to customize treatment according to the characteristics of each patient, and identifying clinical phenotypes that may help to identify group of patients with different mortality and treatment responses. [bib_ref] Clinical COPD phenotypes identified by cluster analysis: validation with mortality, Burgel [/bib_ref] [bib_ref] Spanish COPD guidelines (GesEPOC): pharmacological treatment of stable COPD, Miravitlles [/bib_ref] [bib_ref] Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD)..., Garcia-Aymerich [/bib_ref] GesEPOC identify four phenotypes, and these are of value in deciding which anti-inflammatory treatments should be given to patients: nonexacerbators, mixed COPD (asthma phenotype), exacerbators with chronic bronchitis phenotype, and exacerbators with emphysema phenotype. ## Asthma-copd overlap syndrome (acos) Those patients who are characterized by persistent airflow limitation with several features, usually associated with asthma and several features usually associated with COPD. Asthma-COPD overlap syndrome (ACOS) is therefore identified in clinical practice by the features that it shares with both asthma and COPD. [bib_ref] What is asthma-COPD overlap syndrome (ACOS)? Towards a consensus definition from a..., Sin [/bib_ref] Recently suggested criteria for the diagnosis of ACOS follow [fig_ref] Table 2: Criteria for diagnosis of asthma-COPD overlap syndrome Note [/fig_ref]. ## Role of eosinophils The prevalence of eosinophilic inflammation in COPD patients is unknown. We do not know whether patients ## 2879 GCC-MENa joint statement on COPD diagnosis and management with sputum or blood eosinophilia represent a stable COPD phenotype over time. Prospective clinical trials are required to determine a cutoff threshold for blood eosinophils that predicts future exacerbation risk in COPD patients with an exacerbation history and to clarify the blood-eosinophil cutoff value that can be used in clinical practice. The most commonly reported value in the literature is 2%; however, there have been many other cutoff values reported. [bib_ref] Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD, Pavord [/bib_ref] The ACOS committee generally felt that a 2% threshold lacked sufficient specificity to diagnose eosinophilic airway inflammation. Until more evidence is available, the committee endorses a higher threshold of peripheral blood-eosinophil count of $300 cells/μL to increase the specificity of the biomarkers to diagnose eosinophilic airway inflammation as a minor criterion for ACOS. [bib_ref] Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone..., Pascoe [/bib_ref] [bib_ref] Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis, Bafadhel [/bib_ref] It has been found that many physicians in GCC-MENA follow the clinical phenotype approach of COPD treatment, and there is evidence that this approach has the potential to reduce the risk of exacerbation and assessment of different medium-and long-term mortality; however, large multicenter trials are needed to validate the evidence fully. ## Additional investigations Imaging Radiological signs that may suggest COPD include signs of lung hyperinflation (flattened diaphragm and increase in retrosternal airspace volume), hyperlucency of the lungs, and rapid tapering of vascular markings [fig_ref] Table 3: Differential diagnosis of COPD [/fig_ref]. However, radiological assessment in COPD patients, either chest X-ray or computed tomography (CT), may be helpful to exclude other diagnoses or to detect associated comorbidities (pulmonary fibrosis, pleural diseases, and cardiomegaly). Chest CT scans are recommended prior to lung-volume-reduction surgery in emphysema. [bib_ref] A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema, Fishman [/bib_ref] lung volume and diffusion capacity Body plethysmography may document increased residual volume and increased total lung capacity, which indicates air trapping and pulmonary hyperinflation. Measurement of lung CO-diffusion capacity provides information on the functional impact of emphysema in COPD. Pulse oximetry and arterial blood-gas measurement Pulse oximetry should be used to assess all stable patients with FEV 1 ,35% predicted, clinical signs suggestive of respiratory failure, or right-side heart failure. If peripheral saturation is ,92%, arterial blood gases should be done and action taken accordingly. [bib_ref] How accurate are pulse oximeters in patients with acute exacerbations of chronic..., Kelly [/bib_ref] Screening for α 1 -antitrypsin deficiency Younger patients (,45 years) with lower-lobe emphysema should be screened. A serum concentration of AAT below 15%-20% of the normal value is highly suggestive of homozygous AATD. ## Exercise testing Objectively measured exercise impairment assessed by a reduction in self-paced walking distance 137 or during incremental exercise testing in a laboratory 138 is a powerful indicator of health-status impairment and predictor of prognosis. [bib_ref] Health status measurement in chronic obstructive pulmonary disease, Jones [/bib_ref] Walking tests can be useful for assessing disability, and are used to assess the effectiveness of pulmonary rehabilitation. ## Composite scores Several variables may be combined in a composite score to try to identify disease severity. One of these scores is the BODE (body-mass index, obstruction, dyspnea, exercise) index, which has been found to be a better predictor of subsequent survival than any component alone. 140 ## Pharmacological management of copd The GOLD 2017 management strategy recommends a combined assessment of COPD based on symptoms and exacerbations to categorize patients into clinical phenotypes (groups A-D). These groups have distinct pharmacological treatment recommendations covering initial management and a stepwise approach to follow-up treatment. We have used the principles of GOLD 2017 to make pharmacological treatment recommendations using a format that will hopefully be easy to follow for the practicing clinician. ## 2880 Mahboub et al GOLD recognizes that some of its pharmacological treatment algorithms are only partly based on evidence. Most of our recommendations are similar to GOLD, but we highlight recommendations that differ and key areas where more evidence is needed. The evidence for the various pharmacological treatments for COPD is firstly summarized, followed by recommendations for initial and follow-up treatment. ## Clinical evidence for pharmacological treatment Long-acting muscarinic antagonists (LAMAs) improve symptoms, lung function, and exercise performance and reduce exacerbation rates. [bib_ref] A 4-year trial of tiotropium in chronic obstructive pulmonary disease, Tashkin [/bib_ref] [bib_ref] Once-daily NVA237 improves exercise tolerance from the first dose in patients with..., Beeh [/bib_ref] Long-acting β 2 -agonists (LABAs) also address these parameters, but have less effect on exacerbations than LAMAs. [bib_ref] Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease, Calverley [/bib_ref] [bib_ref] Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease..., Decramer [/bib_ref] [bib_ref] Tiotropium versus salmeterol for the prevention of exacerbations of COPD, Vogelmeier [/bib_ref] Long-acting bronchodilators provide a convenient treatment option, with prolonged duration of action compared to short-acting bronchodilators. Dual-bronchodilator combination inhalers containing both a LAMA and LABA have a greater effect on lung function and symptoms than long-acting bronchodilator monotherapies. [bib_ref] New combination bronchodilators for chronic obstructive pulmonary disease: current evidence and future..., Singh [/bib_ref] LAMA-LABA combinations have a greater impact on exacerbations than long-acting bronchodilator monotherapies, [bib_ref] Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled..., Bateman [/bib_ref] although only one study has been performed in COPD patients with a history of exacerbations. [bib_ref] Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149..., Wedzicha [/bib_ref] Inhaled corticosteroid (ICS)-LABA combinations improve lung function and symptoms, and several clinical trials in COPD patients with exacerbation history have shown an effect on exacerbation prevention: recent studies have shown an approximately 25% exacerbation-rate reduction due to the ICS component. [bib_ref] Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease, Calverley [/bib_ref] [bib_ref] Extrafine beclomethasone/ formoterol in severe COPD patients with history of exacerbations, Wedzicha [/bib_ref] [bib_ref] Extrafine beclometasone diproprionate/formoterol fumarate: a review of its effects in chronic obstructive..., Singh [/bib_ref] Long-term use of ICS is associated with side effects, including pneumonia, [bib_ref] Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease, Calverley [/bib_ref] [bib_ref] Extrafine beclomethasone/ formoterol in severe COPD patients with history of exacerbations, Wedzicha [/bib_ref] [bib_ref] Extrafine beclometasone diproprionate/formoterol fumarate: a review of its effects in chronic obstructive..., Singh [/bib_ref] bone fractures, 151 cataracts, 152 diabetes, [bib_ref] Inhaled corticosteroids and the risks of diabetes onset and progression, Suissa [/bib_ref] and mycobacterial infection. [bib_ref] Use of inhaled corticosteroids and the risk of tuberculosis, Lee [/bib_ref] Pneumonia has been highlighted as a clinical concern, but the rate of these events is low and appears to be greater in certain subgroups, such as older patients and those with low body-mass index, low FEV 1 , and a history of pneumonia. [bib_ref] Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone..., Crim [/bib_ref] [bib_ref] Incident pneumonia and mortality in patients with chronic obstructive pulmonary disease: a..., Festic [/bib_ref] Overall, the benefits of ICS-LABA combinations on exacerbation prevention outweigh the risks. One clinical trial (the FLAME study) has compared ICS-LABA with LABA-LAMA in COPD patients with an exacerbation history. There was a greater impact of LABA-LAMA on exacerbations. [bib_ref] Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD, Wedzicha [/bib_ref] More studies are needed to confirm this finding in wider patient populations, and with different drugs within these classes. Triple therapy refers to the combination of ICS plus LABA plus LAMA, either in a single combination or as separate inhalers. Triple therapy improves lung function and symptoms and reduces exacerbations compared to LAMA monotherapy or ICS-LABA treatment. [bib_ref] Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic..., Welte [/bib_ref] [bib_ref] Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β 2 -agonist..., Singh [/bib_ref] There are currently insufficient data on the comparison of triple therapy and LAMA-LABA treatment. Roflumilast (AstraZeneca, Cambridge, UK) is a PDE4 inhibitor that has anti-inflammatory effects, reducing exacerbations in COPD patients with FEV 1 ,50%, a history of exacerbations, and chronic bronchitis. [bib_ref] Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary..., Martinez [/bib_ref] Long-term macrolide-antibiotic use reduces exacerbation rates, but it is unclear whether this is due to antibacterial or antiinflammatory activity. [bib_ref] Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily..., Han [/bib_ref] There are risks of increased bacterial resistance with long-term macrolide use, and the clinical phenotype of patients most likely to respond has not been conclusively described. The evidence for the use of mucolytics to prevent exacerbations is inconsistent. ## Initial pharmacological treatment COPD patients at initial diagnosis should be categorized as either "frequent exacerbators", suffering two or more exacerbations (requiring oral steroids and/or antibiotics) or one hospitalization in the last year, or those with low exacerbation frequency ("infrequent exacerbators"), experiencing one (or zero) exacerbation in the previous year. Symptoms should be assessed using mMRC score or CAT score. Initial pharmacological treatment is described in [fig_ref] Figure 3: Initial pharmacological treatment for new patient [/fig_ref] , and key points are summarized in . ## Infrequent exacerbators COPD patients with low exacerbation frequency should initially receive long-acting bronchodilator treatment without the need for ICS. Patients should be started on a LAMA. Some patients with a very high degree of symptoms at initial presentation can be started with a LAMA-LABA combination inhaler, although the exact clinical characteristics favoring this approach have not been defined. ## Frequent exacerbators Frequent exacerbators should commence on either a LAMA-LABA or an ICS-LABA combination, both of which address symptoms and exacerbations. GOLD also proposes these options, but favors LAMA-LABA, due to the risk of pneumonia associated with ICS and the results of the FLAME trial. GOLD advocates an individualized approach to COPD treatment, and identifies characteristics that favor ICS-LABA treatment response, such as the presence of asthma features or higher blood-eosinophil counts. We recommend an individual approach to decide the most appropriate treatment (ICS-LABA or LAMA-LABA), based on factors already described that predict ICS benefit or risk. COPD patients with a low symptom burden (CAT score ,10 or mMRC score 0-1) may be managed initially with a lower level of treatment than already described. For infrequent exacerbators, a short-acting BA and/or shortacting MA can be used initially, although often such patients need to step up to long-acting bronchodilator treatment. Frequent exacerbators with a low symptom burden may be managed initially with a LAMA. ## Pharmacological treatment at follow-up At follow-up, escalation of treatment should be based on whether the patient requires further treatment for symptoms only, or symptoms and exacerbations; it is uncommon for patients to suffer exacerbations without the need to treat symptoms. Follow-up pharmacological treatment is described in [fig_ref] Figure 4: Follow-up treatment of COPD patients [/fig_ref] , and key points are summarized in . ## Treatment of symptoms only The need to treat symptoms further should be based on an individual assessment of dyspnea, exercise capacity, and quality of life. Follow-up treatment of symptoms alone (without exacerbations) may require the addition of further long-acting bronchodilator treatment; there is no need to add an ICS. Patients treated with LAMA monotherapy can be escalated to a LAMA-LABA combination, while those treated with ICS-LABA can be escalated to triple therapy (ICS-LABA-LAMA). For patients with significant symptoms despite LAMA-LABA treatment, nonpharmacological approaches should be readdressed (eg, pulmonary rehabilitation, check for comorbidities), as well as checking inhaler technique and compliance. ## Treatment of symptoms and exacerbations Clinical trials have shown a benefit for various combination treatments (ie, triple therapy, ICS-LABA, and LABA-LAMA) in patients with a history of one or more exacerbations in the last year. [bib_ref] Waterpipe smoking and nicotine exposure: a review of the current evidence, Neergaard [/bib_ref] [bib_ref] Patterns of waterpipe use and dependence: implications for intervention development, Maziak [/bib_ref] [bib_ref] Seven-year cumulative incidence of COPD in an agestratified general population sample, Lindberg [/bib_ref] [bib_ref] Hazard assessment of United Arab Emirates (UAE) incense smoke, Cohen [/bib_ref] The natural history of exacerbations is that a proportion of patients with one exacerbation in the previous year will experience none the following year. [bib_ref] Susceptibility to exacerbation in chronic obstructive pulmonary disease, Hurst [/bib_ref] We recommend that escalation of treatment is appropriate for patients with one exacerbation/year for each of the previous 2 years or two or more exacerbations (or one hospitalization) in the previous year. Patients suffering with symptoms and exacerbations at follow-up can receive either an additional bronchodilator Notes: Patients with few symptoms (Cat ,10 or mMrC 0-1) may be managed with a short-acting bronchodilator. Patients with high symptom burden may be initially treated with laMa/laBa. Patients with fewer symptoms (Cat ,10 or mMrC 0-1) may initially be treated with laMa.ICS-laBa combination would be preferred in aCOS patients. Abbreviations: mMRC, modified Medical Research Council (dyspnea scale); CAT, COPD-assessment test; laMa, long-acting muscarinic antagonist; laBa, long-acting β 2 -agonist; ICS, inhaled corticosteroid; aCOS, asthma-COPD overlap syndrome. Key principles of initial pharmacological management Identify patients with frequent exacerbations* Frequent exacerbators may start with either laMa-laBa or ICS-laBa Factors favoring ICS-laBa include high blood-eosinophil count and asthma features Patients with low exacerbation frequency usually commence on laMa Note: two exacerbations requiring oral steroids and/or antibiotics or one hospitalization in the previous year. Abbreviations: laMa, long-acting muscarinic antagonist; laBa, long-acting β 2agonist; ICS, inhaled corticosteroid. ## Stepping down treatment There are some situations in clinical practice where a step down in treatment should be considered. These are where an ICS-LABA combination has been inappropriately prescribed to a patient suffering with symptoms who has never experienced an exacerbation, for whom ICS withdrawal should be considered, and where the treatment of a patient has been escalated, but there has been either no or little clinical benefit, in which case a step down or switching of treatment should be considered. ## Differences between drugs of the same class The recommendations provided assume that the drugs within each class have similar effects. For the main drug classes recommended (LAMA, ICS-LABA, and LAMA-LABA), clinical trial data show generally similar effects of drugs (within a class) in terms of clinical efficacy, although direct comparisons in the same study are often lacking. On a practical level, the major differences between drugs within a class are the inhaler device and the need for once-or twice-daily delivery. It is important to check that the patient can use the inhaler device selected, and that the dosing regime is appropriate for the patient. Twice-daily dosing may be more suitable for patients with nighttime/ early-morning symptoms, although an advantage for twicedaily vs once-daily dosing in this regard has not been definitively proven. ## Blood eosinophils Post hoc analysis of clinical trials in COPD patients with an exacerbation history has demonstrated that higher bloodeosinophil counts predict an increased effect of ICS on exacerbation-rate reduction. [bib_ref] Blood eosinophils: a biomarker of response to extrafine beclomethasone/formoterol in chronic obstructive..., Siddiqui [/bib_ref] [bib_ref] Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone..., Pascoe [/bib_ref] This observation has now been confirmed in a prospective randomized controlled trial (Vestbo et al, unpublished data, 2017). The blood-eosinophil cutoff values that should be used in clinical practice to predict a beneficial effect of ICS have yet to be defined. ## Nonpharmacological management of copd As discussed earlier and in view of COPD being a systemic disease, comprehensive management of COPD includes nonpharmacological management incorporating various modalities to support already-declined lung functions, improve quality of life, and prevent morbidity and mortality consequent to COPD. ## Self-management education Education is an important component of the nonpharmacological aspect of COPD. Topics covered in education programs include smoking cessation, detailed knowledge about COPD, general and specific approaches to therapy and other aspects of COPD, strategies to minimize symptoms, primarily dyspnea, and initial management of exacerbations.It is important to recognize that patient education alone does not change behavior or motivate patients, but if done appropriately can increase ability to cope with the stress of illness and improve health status. Self-help groups and group discussion may also help in encouraging COPD patients to follow a healthy lifestyle. ## Pulmonary rehabilitation GOLD 2017 guidelines stress that pulmonary rehabilitation should be a keystone in the management plan of COPD patients, underscoring its importance and effectiveness. Pulmonary rehabilitation is defined as a comprehensive intervention based on a thorough assessment of the COPD patient and delivering such interventions as exercise, behavior, and education to improve the quality of life of COPD patients. The American Thoracic Society -European Respiratory Society joint statement states that all symptomatic patients, particularly those with systemic manifestations of COPD, benefit from rehabilitation, while the GOLD 2017 statement recommends it for patients with high symptoms burden and risk of exacerbation (groups B-D). These patients should be encouraged to participate in well-structured rehabilitation programs, taking into account individual patients' characteristics and comorbidities. [bib_ref] European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation, Spruit [/bib_ref] [bib_ref] Pulmonary rehabilitation exercise prescription in chronic obstructive pulmonary disease: review of selected..., Garvey [/bib_ref] Patients planned for lung-volume-reduction surgery should also be included both preoperatively and postoperatively. [bib_ref] The effects of pulmonary rehabilitation in the National Emphysema Treatment Trial, Ries [/bib_ref] Evidence-based best practice for rehabilitation programs includes structured and supervised exercise training, smoking cessation, nutrition therapy, and self-management skills. ## 2883 GCC-MENa joint statement on COPD diagnosis and management Adherence and cooperation are needed for rehabilitation programs, and patients who have active heart disease or are limited due to joint or orthopedic illness may be unable to join a program. Should active smokers be participating in such programs, whether they are motivated to adhere continues to be a field of investigation. Clearly, degree of FEV 1 is not a contraindication, as the American College of Chest Physicians recommends rehabilitation for those with FEV 1 ,50%. [bib_ref] Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice..., Qaseem [/bib_ref] Pulmonary rehabilitation benefits include improving quality of life, body strength, and exercise tolerance. It also reduces exacerbation rate, and this in turn will affect the health care burden of COPD. However, the most interesting and debatable issue is rehabilitation's impact on mortality, a question not resolved, yet with some indication that pulmonary rehabilitation may improve COPD mortality. [bib_ref] Respiratory rehabilitation after acute exacerbation of COPD may reduce risk for readmission..., Puhan [/bib_ref] ## Exercise training A combination of constant-load or interval training with strength training of upper-and lower-extremity muscle groups and goals of endurance training to 60%-80% of symptom-limited maximum work or heart rate is preferred, [bib_ref] Comparison of effects of strength and endurance training in patients with chronic..., Ortega [/bib_ref] [bib_ref] Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and..., Garber [/bib_ref] or to Borg dyspnea or fatigue score of 4-6. [bib_ref] Dyspnea ratings for prescribing exercise intensity in patients with COPD, Horowitz [/bib_ref] Exercise training should be done after full optimization of LAMA-LABA therapy. ## Smoking cessation First and foremost in nonpharmacological management of COPD is that it includes smoking cessation. Data are currently clear that stopping smoking is important, as it decreases or halts decline in FEV 1 . In fact, the Lung Health Study revealed an improvement in lung function within a year or so of quitting smoking, and such data also push physicians to help patients to stop rather than reduce cigarette-smoke intake. [bib_ref] Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease: the..., Scanlon [/bib_ref] A Finnish study has shown a survival benefit among those who stop smoking, regardless of COPD stage. [bib_ref] Pulmonary function, smoking cessation and 30-year mortality in middle aged Finnish men, Pelkonen [/bib_ref] Clearly, most attention has been focused on nicotine-replacement therapy, particularly combination-delivery systems (nicotine patch and nasal spray most preferred). There is also nicotine gum, lozenges, and inhalers. Research has shown nonpharmacologic approaches, such as behavioral counseling or hypnosis, especially when combined with nicotine patches, to be rewarding. [bib_ref] Hypnosis for smoking cessation: a randomized trial, Carmody [/bib_ref] Nonnicotine therapy may include bupropion (Impax Laboratories, Inc., Hayward, CA, USA) and venlafaxine (Pfizer), which help in increasing quit rates. Electronic cigarettes' role in smoking cessation is uncertain, and they are not US Food and Drug Administration-approved. A few studies have formally evaluated nicotine craving when using electronic cigarettes, with mixed results. Although patients support the use of electronic cigarettes in smoking cessation, more structured studies on safety and efficacy should be done to determine whether these products can play a role in smoking cessation. [bib_ref] Electronic cigarettes: do they have a role in smoking cessation?, Odum [/bib_ref] Vaccination Influenza vaccination is recommended for all patients with COPD. The pneumococcal vaccines PCV13 and PPSV23 are recommended for all patients .65 years of age. PPSV23 is also recommended for younger COPD patients with significant comorbidities, including heart and lung disease. [bib_ref] Use of 13-valent pneumococcal conjugate vaccine and 23-valent vaccine among adults aged..., Tomczyk [/bib_ref] ## Nutritional support Nutritional supplementation is recommended for malnourished COPD patients. There are positive effects on body weight, fat mass, and fat-free mass when nutritional supplementation is provided and when used during exercise training, and demonstrated significant improvements in 6-minute walk test, respiratory muscle strength, and health status. [bib_ref] Nutritional supplementation for stable COPD, Ferreira [/bib_ref] ## Oxygen therapy Long-term oxygen therapy is indicated for stable patients who have PaO 2 #55 mmHg or SaO 2 #88% with or without hypercapnia confirmed twice over a 3-weeks period, or those with PaO 2 of 55-60 mmHg or SaO 2 of 88%, evidence of pulmonary artery hypertension, and peripheral edema suggesting of congestive heart failure or polycythemia. Patients should be reevaluated after 2-3 months, with repeat arterial blood gas or SaO 2 test done to assess need for continued oxygen therapy. ## Ventilatory support Long-term or nocturnal noninvasive ventilation may be considered in selected COPD patients, especially those with pronounced daytime hypercapnia and history of recurrent/ recent hospitalization, although review data are not sufficient to support or refute this recommendation. [bib_ref] Nocturnal non-invasive positive pressure for stable COPD, Struik [/bib_ref] Interventional pulmonology/endoscopic lung-volume reduction In selected COPD patients with heterogeneous emphysema and significant overinflation refractory to optimized medical treatment, endoscopic lung-volume reduction by placement of endobronchial valves and coils could be considered after thorough evaluation of the individual patient and at highly specialized centers. [bib_ref] Lung volume reduction surgery for diffuse emphysema, Tiong [/bib_ref] ## Surgical intervention In carefully selected COPD patients with large bulla with compressive effects or risk of spontaneous rupture surgical, ## 2884 Mahboub et al bullectomy may be considered to relive the compressive effects of bullae. Some thoracic surgery centers in the GCC region are doing such surgeries after complete evaluation. Lung-volume-reduction surgery is another option in selected COPD patients. However, these modalities should be considered only after detailed assessment of patients, including extent and pattern of emphysema on high-resolution CT scan, presence of fissure integrity, absent collateral ventilation, and centers with high expertise. ## Lung transplant This is an option for very severe advanced COPD refractory to maximal pharmacological and nonpharmacological therapy, and following are the criteria for considering lung transplant: COPD patient with progressive disease, not a candidate for endoscopic or surgical lung-volume reduction, BODE index score of 5-6, PaCO 2 .50 mmHg and/or PaO 2 ,60 mmHg, and FEV 1 ,25% predicted. [bib_ref] A consensus document for the selection of lung transplant candidates -2014: an..., Weill [/bib_ref] Other variables to be considered include more than three severe exacerbations in last year, exacerbation with hypercapnic respiratory failure, and pulmonary artery hypertension. ## Joint committee recommendations and suggestions to curtail copd in gcc-mena region Accurate information about the prevalence and types of tobacco use is essential to deliver effective public health policy. Implementation of effective public health strategies, including education and awareness of the general public, strict health regulations aimed at smoking reduction, and managing and preventing COPD, is very important. The main obstacle to this is the lack of data related to prevalence and burden of COPD with consequent prohibition in governmental health-planning strategies to curb COPD incidence and prevalence. There is a great deal of room for improvement in COPD care in the GCC-MENA region, and current trends suggest the following developments are possible and highly desirable. - More accurate data on illness, exacerbations, natural history, cost and deaths related to COPD, particularly in areas where no data are available, will provide a stronger foundation for fighting against COPD. - Studies of the effectiveness of current prevention, education, medication, rehabilitation, and terminal care will help to spread best practice and drive higher standards of COPD care. - New therapeutic modalities will inhibit the decline in lung function and improve the overall quality of life of COPD patients. - As smoking remains the key risk factor for COPD, measures that will reduce the burden of disease include more effective smoking-cessation interventions and techniques to encourage people to quit smoking, strict surveillance of harmful occupational exposure, and protection in early childhood against harmful exposure and events that affect the lung. - Health ministries and the general public need to be made aware of the high burden of COPD in the MENA region, and these countries should implement common strategies for effective prevention, diagnosis, and treatment of this disabling and life-threatening disease. ## Research needs Comprehensive research is needed in key areas related to COPD: - As smoking rates in UAE are increasing along with the rise in other risk factors for COPD, with resultant increased COPD incidence and prevalence, there is a need to know how this will affect the course, management, and prognosis of the disease, along with effects on health care systems. - Although spirometry is a prerequisite in COPD studies, more extensive characterization of the disease than that offered by spirometry is required. Novel imaging techniques and biomarkers offer the potential to characterize subgroups or phenotypes of COPD. Cohort studies should be conducted to assess the long-term natural history of COPD and its phenotypes. ## Suggestions to health authorities Strict policies for control of sale of smoking products, prohibition of smoking near schools and public places, imposition of large penalties for violators, and increased tax prices on tobacco and related products should be implemented. Tobacco merchandisers should be obliged to distribute packages displaying graphics stating the negative effects of the smoking habit. However, it is not clear whether these measures would really cut down the prevalence of smoking and COPD morbidity and mortality. International Journal of COPD 2017:12 submit your manuscript \| www.dovepress.com ## Dovepress ## Dovepress ## 2885 GCC-MENa joint statement on COPD diagnosis and management # Conclusion A comprehensive assessment is required for the accurate diagnosis of COPD, assessment of symptoms, and risk of exacerbation. Phenotypic classification may further help. In the MENA region, studies are under way to assess the phenotypic variants of COPD and to correlate various aspects of COPD with phenotypic evaluation, which would give us better insight into the pathogenesis of COPD in the coming years. In the MENA region, most pulmonary physicians follow the standard GOLD recommendations; however with the recent availability of LAMA-LABA/ICS-LABA once daily, triple-combination LAMA-LABA-ICS, newer inhaler devices, and many pharmaceutical companies providing affordable inhalers with good efficacy, we hope that in future pharmacological management of COPD will be more in accordance with GOLD 2017. In the context of nonpharmacologic management of COPD in the MENA region, there are many shortcomings: most patients are underdiagnosed/undertreated, are diagnosed by general practitioners (GPs) or internal medicine doctors, the unavailability of spirometry for confirmation of diagnosis, noncompliance among patients, low socioeconomic-class patients and patients from various sociodemographic backgrounds with different attitudes about disease and its management, absence of well-structured pulmonary rehabilitation programs, lack of dedicated/trained staff for delivering standard rehabilitation programs in most hospitals, and unaffordability of patients for noninvasive ventilation and oxygen machines. In the last decade, there have been tremendous improvements in the care of COPD patients in the GCC region, but still the facilities for interventional pulmonology are in their infancy. In the near future, we anticipate some new upcoming state-of-the-art interventional pulmonology centers that will provide endoscopic lung-volume reduction for selected COPD patients. In the GCC region, few centers are doing surgical lung-volume reduction or bullectomy. These centers could broaden the scope of services to cater to increasing number of COPD patients who need surgical interventions. Governments should provide adequate professional training and facilities for the developments of such centers (interventional pulmonology/thoracic surgery and lung-transplant centers) in the GCC region. Studies are ongoing to evaluate the harmful chemical constituents of shisha and medwakh, and to determine their causal association with COPD. Considering the increased awareness among patients and physicians over last decade, we hope that the nonpharmacological management of COPD will improve on a par with standard evidence-based practice done in other developed countries. [fig] Figure 1: Spirometry showing normal (A) and obstructive (B) patterns. International Journal of COPD 2017:12 submit your manuscript \| www.dovepress. [/fig] [fig] Figure 2: Refined ABCD assessment tool (simpler version). Abbreviations: mMRC, modified Medical Research Council (dyspnea scale); CAT, COPD-assessment test. [/fig] [fig] Figure 3: Initial pharmacological treatment for new patient. [/fig] [fig] Figure 4: Follow-up treatment of COPD patients. Abbreviations: laMa, long-acting muscarinic antagonist; laBa, long-acting β 2 -agonist; ICS, inhaled corticosteroid.Table 5Key principles of follow-up pharmacological management treatment of symptoms (without exacerbations) requires addition of a long-acting bronchodilator treatment of symptoms and exacerbations requires addition of either a long-acting bronchodilator or inhaled corticosteroid two exacerbations in the previous year or one exacerbation/year for 2 years should be used as a threshold to escalate treatment Switching ineffective treatments should be considered Inhaler technique and compliance should be continuously monitored International Journal of COPD 2017:12 submit your manuscript \| www.dovepress.a LAMA-LABA combination or switched to an ICS-LABA combination. Patients receiving ICS-LABA or LAMA-LABA can be escalated to triple therapy or treatment can be switched from one of these combinations to the other. Switching treatment is recommended in situations where the previous pharmacological treatment provided no or little clinical benefit. For patients established on triple therapy and still suffering with exacerbations, individual clinical characteristics can be used to decide to add further treatment: chronic bronchitis (add roflumilast or mucolytics as an alternative), evidence of bacterial infection or bronchiectasis (add azithromycin [Zithromax ® ; Pfizer, New York, NY, USA]). [/fig] [fig] •: No data are available about the prevalence, incidence, or natural history of various phenotypes of COPD, and their economic burden on the UAE (studies under progress, personal communication). Our knowledge of the pathogenesis of COPD and how this can be modified is still limited. Novel molecular and genetic techniques offer promising possibilities for gaining important knowledge on disease mechanisms, which opens up possibilities for development of new drugs. [/fig] [table] Table 2: Criteria for diagnosis of asthma-COPD overlap syndrome Note: the committee recommends presence of all three major criteria and at least one minor criterion for asthma-COPD overlap syndrome. Abbreviations: FEV 1 , forced expiratory volume in 1 second; FVC, forced vital capacity; BDr, bronchodilator responsiveness. [/table] [table] Table 3: Differential diagnosis of COPD [/table]	None	https://www.dovepress.com/getfile.php?fileID=38795	Smoking and subsequent development of COPD is an ever-increasing epidemic in Arabian Gulf and Middle East countries, with no signs of decline. The important fact to be highlighted is that this COPD epidemic of increasing incidence and prevalence is mostly unrecognized by patients, due to the common attribution of symptoms to “smoker’s cough”, and the underdiagnosis and undertreatment by physicians because the common signs and symptoms masquerade as asthma. Consequently, there are long-term adverse effects of missing the diagnosis. The purpose of this review article is to focus upon the status of COPD in Arabian Gulf and Middle East countries, stressing the increasing burden of smoking and COPD, to emphasize the specific factors leading to rise in prevalence of COPD, to bring to light the underdiagnosis and undermanagement of COPD, and to treat COPD in conformity with standard guidelines with local and regional modifications. This review ends with suggestions and recommendations to the health department to formulate policies and to generate awareness among the general public about the side effects of smoking and consequences of COPD.
a63614c5a31cc40d5fa73386d05964499c9a4d08	pubmed	Supranuclear eye movements and nystagmus in children: A review of the literature and guide to clinical examination, interpretation of findings and age-appropriate norms	Supranuclear eye movements and nystagmus in children: A review of the literature and guide to clinical examination, interpretation of findings and age-appropriate norms Abnormal eye movements in children, including nystagmus, present a significant challenge to ophthalmologists and other healthcare professionals. Similarly, examination of supranuclear eye movements and nystagmus in children and interpretation of any resulting clinical signs can seem very complex. A structured assessment is often lacking although in many cases, simple clinical observations, combined with a basic understanding of the underlying neurology, can hold the key to clinical diagnosis. As the range of underlying diagnoses for children with abnormal eye movements is broad, recognising clinical patterns and understanding their neurological basis is also imperative for ongoing management. Here, we present a review and best practice guide for a structured, methodical clinical examination of supranuclear eye movements and nystagmus in children, a guide to clinical interpretation and age-appropriate norms. We also detail the more common specific clinical findings and how they should be interpreted and used to guide further management. In summary, this review will encourage clinicians to combine a structured assessment and a logical interpretation of the resulting clinical signs, in order to recognise patterns of presentation and avoid unnecessary investigations and protracted delays in diagnosis and clinical care. * J. E. Self ;,: 1234567890();,: 262 D. Osborne et al. # Introduction The function of eye movements is to bring visual stimuli to the fovea and hold them there, during head movements or movement of the stimuli themselves. Examination of these eye movements in children, in an outpatient setting, can present a clinical challenge. However, the information gained from an effective examination can help the clinician discern benign from pathological disease, localise neuropathology and non-invasively monitor a variety of neurological disorders. Hereafter, we outline methods of eye movement examination, the most important findings and their clinical implications for clinicians without access to a dedicated eye movement laboratory. Human supranuclear eye movement pathways can be conceptualised as providing solutions to the following visual demands: to compensate for large head movements (the vestibulo-ocular reflex (VOR)), to use visual information to fine-tune the VOR and to return the eyes to the central position after full excursion (the optokinetic reflex (OKR)), to track a moving visual target without moving the head (Smooth Pursuit, SP), to place a visual target onto the fovea (saccades) to maintain eccentric eye position (gaze holding) and to allow binocular co-ordinated eye movements to achieve and maintain binocular foveation (vergence movements). summarises the supranuclear eye movement control systems of greatest clinical relevance in humans. ## History taking As with all clinical assessments in children, a detailed history from the parent and child is important and can direct the clinician to certain aspects of the subsequent examination. [fig_ref] Table 2: Questions which can direct the clinician prior to examining a child with... [/fig_ref] details some of the most useful questions to be included in a thorough history from a child with an eye movement disorder. ## Clinical examination When examining supranuclear eye movements in a child, it is important to assess each separate eye movement control system in a systematic way, with an understanding of what to expect [bib_ref] Abnormal supranuclear eye movements in the child: a practical guide to examination..., Cassidy [/bib_ref]. 'Normal findings' will vary with age.summarises some of the normal clinical findings in infants and children using more freely available clinical equipment (such as the OKR drum rather than a full-field OKR stimulus). Subsequently, we describe clinical examination techniques for each system. ## Vestibulo-ocular reflex (vor) Underlying neuroanatomy A three-neuron arc, including the vestibular ganglion, vestibular nuclei and the oculomotor nuclei [fig_ref] Figure 1: The vestibulo-ocular reflex [/fig_ref] [2] operate the VOR system, which holds the eye still in space during head movements. During head motion, movement of the semi-circular canals relative to endolymph creates an afferent signal, which passes via the vestibular nerve to the ipsilateral vestibular ganglion in the internal auditory meatus. These signals are relayed to the ipsilateral vestibular nuclei (Pons and Medulla), which then transmit excitatory inputs to the contralateral oculomotor nuclei, and inhibitory inputs to the ipsilateral oculomotor nuclei (Midbrain and Pons). The oculomotor nuclei pass motor signals to the yoked extra-ocular muscles via the IIIrd, IVth and VIth cranial nerves. ## Clinical assessment of the vor A mismatch between the speed of head movement and the speed of the VOR movement (VOR gain) can be tested in older children by measuring visual acuity during slow head movements (which should not change). However, this test is rarely used in the clinic as it is not possible in preliterate children and isolated abnormalities of VOR gain are rare. 'Dolls Head Manoeuvre' (Oculocephalic Manoeuvre) or Spinning baby tests are the standard tests for VOR in the clinic. Doll's head manoeuvre The infant's head is held with both hands and rapidly, but gently, moved horizontally and vertically to test both VOR, respectively. The eyes should stay fixed in position despite the movements. The rotations can be small and should not be performed in children with cervical spine problems or downbeat nystagmus [fig_ref] Figure 2: How to perform the doll's head manoeuvre on an infant in a... [/fig_ref]. Spinning baby test The examiner stands and holds the infant at arm's length. In the case of a very young infant the back of the head is supported as shown. The examiner rotates to the right with the infant through 2-3 revolutions, whilst observing the infant's eyes. This induces a perrotatory nystagmus (driven by VOR and OKR) in the infant with fast phases to the examiners left. The rotation is then abruptly stopped inducing a post-rotatory vestibular nystagmus in the infant, with fast phases beating to the examiners right. The procedure is repeated in the opposite direction and in small infants can also be used to test vertical VOR by laying the infant flat in the examiners arms. In older children this test can be modified by the child sitting on an examiners lap and facing them while both rotate on a swivel chair. Older children can also be examined by sitting alone in a swivel chair and spun. Normal findings include a large per-rotatory nystagmus (unless the child is fixing on the examiners face) but importantly, only two to three postrotatory nystagmus beats in the opposite direction [fig_ref] Figure 3: Performing the spinning baby test in a clinical setting [/fig_ref]. Interpreting some common findings during VOR testing - Loss of the fast phase of VOR, can be a normal finding in infants before 45-weeks gestation or reflect a saccade abnormality, for example, Saccadic initiation failure (SIF). This can be seen as 'Locking up' during spinning (i.e., both eyes fixed at the limit of gaze in the opposite direction to spinning [bib_ref] Neuroradiological and eye movement correlates in children with intermittent saccade failure, Shawkat [/bib_ref]. - During doll's head testing, a catch-up saccade, when testing in one direction only, suggests a specific semicircular canal pathology. ## - In the presence of acute vertigo in older children, abnormal VOR in one direction, lack of a skew deviation and unidirectional nystagmus suggest a peripheral vestibular (e.g., vestibular neuritis) rather than central cause (e.g., stroke). - After spinning, post-rotational nystagmus lasting more than two to three beats is a sign that the VOR is not being supressed by visually guided reflexes. This is either an indication of very poor vision or a cerebellar disorder (e.g., ataxia-telangiectasia [bib_ref] Nystagmus in infancy, Casteels [/bib_ref]. ## - The VOR reflex may be decreased or absent in children with the CHARGE syndrome (a disorder characterised by coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities and ear abnormalities) [bib_ref] Vestibular areflexia as a cause of delayed motor skill development in children..., Admiraal [/bib_ref] , in type 1 ushers syndrome [bib_ref] Perform vestibular test among all small deaf children! Early detection of Usher..., Konrádsson [/bib_ref] or forms of inherited ataxia (e.g., spinocerebellar ataxia type 3, Friedreich's ataxia [bib_ref] Nystagmus in infancy, Casteels [/bib_ref]. involved. Neurological symptoms in relatives can also suggest an underlying aetiology (e.g., Spinocerebellar ataxias)Specific questions about visual behaviours-e.g., nyctalopia or photophobia Photophobia and nystagmus are common findings in disorders of cone function and albinism. High frequency nystagmus with photophobia is more common in cone dysfunction. Nyctalopia is a common symptom in rod dysfunction Does the child blink excessively or head thrust towards direction of intended gaze? Can be seen in Saccadic initiation failure (SIF) Open questioning about other visual behaviours Parents will often report a very detailed description of visual behaviours, which can direct clinical examination such as a child with chin depression and vertically 'wobbly eyes' (commonly seen in down beat nystagmus), or pushing/rubbing eyes firmly for retinal stimulation in blind babies/children Does the child experience oscillopsia? Lack of oscillopsia in the presence of involuntary eye movements such as nystagmus, suggests early-onset; constant oscillopsia suggests an acquired disorder If oscillopsia is reported, is it when stationary or when moving? Oscillopsia which is only present during head movement implies a vestibular pathology [bib_ref] A brief review of the clinical anatomy of the vestibular-ocular connections-how much..., Bronstein [/bib_ref] Are there associated speech or swallowing problems? ## Possible brainstem pathology or myasthenia gravis Are there associated coordination problems? ## Possible cerebellar pathology Is there associated hearing loss or tinnitus? ## Possible peripheral vestibular pathology Is the patient on any medications? Many medications can cause abnormalities of eye movement, most commonly anti-epileptic medication Are there any concerns about any other aspect of the child's development or health besides their eyes? Eye movement abnormalities form a part of many multisystem syndromes and can be the presenting feature A summary of human supranuclear eye movements and their evolutionary prompts [bib_ref] Abnormal supranuclear eye movements in the child: a practical guide to examination..., Cassidy [/bib_ref] [bib_ref] Fixational eye movements in the earliest stage of metazoan evolution, Bielecki [/bib_ref] [bib_ref] The evolutionary history of eye movements, Walls [/bib_ref] Evolution Evolutionary prompt Type of eye movement ## Function Balance organs (such as the semi-circular canals) evolve and mature. Maintaining retinal image stability during self-motion becomes an advantage Evolution of a retinal area of higher visual acuity (e.g., fovea) Gaze holding Tonic stimulation of extra-ocular muscles to keep the eyes in eccentric gaze ## Underlying neuroanatomy Some authors consider the pathway for OKR, tested with an OKR drum or tape in the clinic, as the same as the smooth pursuit pathway, involving striate and extra-striate cortices with descending connections via the internal capsule to the brainstem pontine nuclei, cerebellum (floccular region), vestibular nuclei and the oculomotor nuclei. Most clinicians do not have access to testing methods other than a hand-held tape or drum, therefore, the following information is directed towards findings elicited by these tests. Clinical assessment of the OKR OKR drum or tape is held at 50 cm from the child's face and rotated slowly in both horizontal and vertical directions whilst observing the child's eye movements. It is performed both monocularly and binocularly. The examiner would expect to see slow eye movements in the direction of the stimulus with a fast movement seen in the opposite direction [fig_ref] Figure 4: Using an OKR Drum in a clinical setting [/fig_ref]. Interpreting some common clinical findings during OKR testing - Lack of any OKR with drum or tape testing can be a sign of either extremely poor vision or delayed visual maturation (DVM), but may also be seen in drowsy infants. Interestingly, a full-field OKR can be elicited in some patients with DVM even where a small field OKR is absent. It has been hypothesised that using a full-field stimulus may elicit an OKR reflecting a more primitive, subcortical OKR subtype called OKNd [bib_ref] Delayed visual maturation: an update, Russell-Eggitt [/bib_ref] , however, this test is not freely available. - Vertical OKR can be demonstrated in young infants with horizontal nystagmus as a superimposed waveform if there is moderate vision. It can be used (prior to EDTs) to reassure that there is unlikely a profound visual disorder. There has been debate about whether horizontal OKR is lost, reversed or altered by shifting null zones in congenital nystagmus. By clinical observation alone, it is rare to observe robust horizontal OKR in the presence of horizontal nystagmus but where clearly demonstrable, possibly suggests that an 'idiopathic' or albinism related cause is less likely. - Quick phases of the OKR are intermittently absent in SIF (see disorders of saccades below). Similar to VOR testing, it can result in a lack of OKR or in deviation of the eyes in the direction of the slow phases because of a mismatch between the slow phase movement and the insufficient corrective saccade. Asymmetry in response to a right vs left moving OKR stimulus, when tested binocularly, indicates a unilateral cortical or pontine lesion. Asymmetry of OKR when tested in this way may occur in some patients with earlyonset poor vision in one eye. - A vertical binocular OKR response which is worse than horizontal response indicates a midbrain lesion. ## Saccades ## Underlying neuroanatomy Saccades are fast, voluntary or involuntary eye movements initiated in the visual cortex under the control of frontal oculomotor areas for voluntary saccades and the parietal cortex for reflexive saccades. The pathways then project through the internal capsule, divide into a dorsal limb which projects to the superior colliculus and a ventral limb (oculomotor pathways) which projects to the pons and midbrain nuclei. In the pons and midbrain, the neurons from the ventral limb input into a local control system for saccadic firing. This comprises excitatory burst neurons (EBNs), which fire to generate saccades, inhibitory burst neurons (IBNs), which are activated by EBNs and inhibit firing of neurons to contralateral extra-ocular muscles and pause units. IBNs tonically fire to inhibit the EBNs and therefore continuously inhibit spontaneous saccades. Horizontal saccades are mediated by the ipsilateral pons and contralateral frontal eye field (FEF) and parietal eye field (PEF); vertical saccades are generated in the midbrain. The EBNs project to the ipsilateral 6 th nerve nucleus as well as contralateral third nerve nucleus via the medial longitudinal fasciculus (MLF) [fig_ref] Figure 5: Saccades [/fig_ref]. From a clinical stand point, it is important to remember that horizontal and vertical saccades are localised separately in the ponto-medullary junction and the midbrain respectively and that the cerebellum controls the metrics for both. ## Clinical assessment of saccades Clinically, saccades can be tested in many ways according to age. The previously described spinning baby test, includes a saccadic component and can be the most informative assessment in younger infants. In older children, a brightly coloured target is presented in front of the child at a large angle (with or without a simultaneous sound in a neutral position) and eye movements are simply observed for direction, accuracy and symmetry (test monocularly if cross-fixating). The examiner should observe the presence of saccades to the right, left, up and down in both eyes. When looking for asymmetry (between vertical vs horizontal saccades and between left vs. right saccades) fixing on the bridge of the nose can aid the examiner. Interpreting some common clinical findings while testing saccades - Saccadic latency in infants is up to 1 s for the primary saccade (200 ms in adults) and gross abnormalities are usually seen in SIF. - SIF may be congenital with no recognisable pathology or associated with many underlying disorders. It is usually horizontal only and intermittent; if vertical it suggests a midbrain lesion or metabolic disorder such as Niemann-Pick disease type C or Gauchers disease type 3 [bib_ref] Neuroradiological and eye movement correlates in children with intermittent saccade failure: "ocular..., Shawkat [/bib_ref]. - Isolated dysfunction of vertical saccades is due to a midbrain lesion such as haemorrhage/Niemann-Pick disease type C. It is usually caused by lesions of the riMLF which is the centre for vertical saccadic control. As upgaze movements are double innervated, abnormalities of downward saccades are often observed first. - Lesions of the interstitial nucleus of Cajal also cause dysfunction of vertical saccades but usually in addition to a vertical gaze-evoked nystagmus (GEN). - Lesions of the posterior commissure cause dysfunction of vertical saccades which may be accompanied by convergence-retraction nystagmus and lid retraction in parinaud dorsal midbrain syndrome. Pressure on the posterior commissure from raised intracranial pressure is also thought to give rise to the 'setting-sun' sign (eye seemingly fixed in downgaze) which is unique to infants and children. - Lesions of the cerebellar oculomotor (dorsal) vermis or fastigial nucleus can cause saccadic dysmetria. Hypermetric saccades are seen in lesions of the fastigial nucleus (and Wallenberg syndrome, lateral medullary syndrome) and hypometric saccades with lesions of the dorsal vermis. - Large visual field defects may also cause hypometric saccades into the area of loss and they are also seen in resolving DVM type 1. - Isolated dysfunction (slowing ±hypometria) of horizontal saccades is due to pontine lesion of the PPRF, e.g., bleeding/glioma/Gaucher disease type 3. - Square-wave jerks are to one side of fixation only (<5°f rom fixation), last 200 ms and are most commonly seen in spino cerebellar atrophies. They are an exaggeration of normal microsaccadic fixation movements and are seen in 90% of infants at up to 3/min and are rarely of key clinical significance. - Opsoclonus is characterised by intermittent, multidirectional, back-to-back saccades and is best viewed after changing fixation or on lid closure. Ocular flutter describes the same anomaly but confined to horizontal eye movements. They share a common aetiology, which is thought to be loss of cerebellar inhibition of spontaneous saccades. Opsoclonus-myoclonus syndrome describes the combination of opsoclonus, myoclonus and ataxia and is most commonly associated with neuroblastoma, other para-neoplastic states and CNS infections [bib_ref] Childhood opsoclonus-myoclonus syndrome: diagnosis and treatment, Blaes [/bib_ref]. Ocular flutter or hypermetric saccades can be seen as opsoclonus improves. - Anti-saccades are voluntary saccades generated to the opposite direction of a target introduced into the peripheral visual field. They represent a voluntary saccade overcoming a reflexive saccade and may be misdirected (ie, implying a directional error) in children under seven, schizophrenia, ADHD and Tourette syndrome. They are rarely of clear diagnostic value in young children. - 'Voluntary nystagmus' is an infrequent but persistent cause for referral in children. It is characterised clinically by back-to-back saccades (typically horizontal), usually induced by convergence effort and often accompanied by mild lid closure. It is therefore not nystagmus (as there are no slow phases). It can be simulated in many healthy subjects and clues to the diagnosis include: miosis, lid flutter and an inability to sustain the movements for more than 30-45 s. ## Gaze holding Underlying neuroanatomy Gaze holding is controlled by a group of neural structures which differ for vertical/torsional and horizontal meridians. These distinct groups of structures are collectively termed the horizontal and vertical 'neural integrators'. The horizontal neural integrator includes the nucleus prepositus hypoglossi (Pons), vestibular nuclei (Pons and Medulla) and vestibulo-cerebellum (Cerebellum). The vertical/torsional neural integrator is the Interstitial Nucleus of Cajal (Midbrain) although an intact flocculus (Cerebellum) is also necessary. Both neural integrators have multiple neural connections and their primary role is to coordinate tonic discharge to the extra-ocular muscles in order to maintain eccentric gaze. ## Clinical assessment of gaze holding Observe the eyes in primary gaze and in vertical and horizontal eccentric gaze either by turning the patient's head, or by presenting a large stimulus in eccentric view. Abnormalities of gaze holding are usually characterised by nystagmus, due to a slow drift towards primary position and a corrective saccade into the attempted position of eccentric gaze (GEN). Examination of nystagmus is detailed below. Interpreting some common clinical findings while examining gaze holding - Typical signs of damage to the neural integrator, whether vertical, torsional or horizontal, include GEN (due to loss of eccentric gaze holding) and rebound nystagmus (nystagmus beats seen in the opposite direction to the eccentric gaze when the eye is returned to primary position). Abnormalities of VOR suppression (most commonly seen as failure of dampening postrotational vestibular nystagmus following the spinning baby test) and OKR are also commonly seen together and reflect underlying cerebellar pathology. - GEN can also be seen with the use of anti-convulsants, sedatives and other drug intoxications. - GEN in all directions implies a cerebellar lesion, particularly the flocculus and has many causes. - Isolated horizontal GEN is often caused by an isolated pontine lesion. This is because vestibulo-cerebellar disorders tend to yield additional oculomotor signs. - Purely vertical GEN is due to a lesion of the vertical/ torsional neural integrator which is the interstitial nucleus of Cajal (midbrain). ## - The presence of rebound nystagmus may indicate chronic, rather than acute cerebellar disease. ## Vergence ## Underlying neuroanatomy The neuroanatomy underlying vergence eye movements is poorly understood. Neurons within the mesenchephalic reticular formation (midbrain) and adjacent rostral superior colliculus have been identified as being related to vergence movements. These include neurons whose discharge is proportional to vergence angle (near response, NR neurons) and burst neurons. Subsets seem to exist for convergence and divergence activity but detail is currently lacking. ## Clinical assessment of vergence Vergence movements are binocular co-ordinated movements in opposite directions in order to move the point of fixation towards, or away from the subject. Convergence movements can be observed in infants using a large visual target, moved slowly towards the nose in primary gaze from approximately two months of age. They are thought to be initially driven by accommodation but after 4 months they are driven by retinal disparity which coincides with the development of fusion and stereopsis. From around 6 months, tests for fusional vergence include the 20 prismdioptre base-out prism test and studies of fusional range. The examiner should note the range of vergence movements from a near point to a distance target. Interpreting some common clinical findings while testing vergence - Vergence abnormalities are rare in children unless associated with strabismus. - Neuropathology associated with isolated anomalies of vergence is very rare. - Numerous reports and case studies have suggested that convergence spasm can occur in association with organic and non-organic disease. However, organic pathology is rarely found in an otherwise well child with isolated convergence spasm [bib_ref] Convergence spasm in conversion disorders: prevalence in psychogenic and other movement disorders..., Fekete [/bib_ref] [bib_ref] Functional convergence spasm, Ghosh [/bib_ref]. - Convergence insufficiency describes a remote near point of convergence, variable exophoria for near and reduced fusional convergence at near. It is not associated with underlying intracranial lesions and when occurring in isolation, usually in adolescents, may be treated with orthoptic exercises and prisms [bib_ref] Convergence insufficiency and its current treatment, Lavrich [/bib_ref] [bib_ref] Orthoptic treatment of convergence insufficiency, Davies [/bib_ref] [bib_ref] Convergence insufficiency and vision therapy, Mcgregor [/bib_ref]. - Convergence paralysis is characterised by complete loss of convergence and crossed diplopia. It is highly suggestive of intracranial pathology resulting from space occupying lesions of the midbrain, infection, trauma, demyelination or toxins [bib_ref] Paralysis of convergence caused by mushroom poisoning, Gilad [/bib_ref] [bib_ref] Convergence paralysis as a manifestation of polyarteritis nodosa, Wylie [/bib_ref] [bib_ref] Idiopathic convergence paralysis: a rare case, Day [/bib_ref]. It is therefore, usually associated with significant additional neurological signs and rarely encountered as an isolated phenomenon. - Divergence paralysis is rare in both paediatric or adult practice. It is characterised by complete loss of divergence, esotropia for distance and normal convergence. Bilateral sixth nerve palsy should be excluded. Causes include intracranial infection and lesions of the brainstem and periaqueductal grey matter [bib_ref] Divergence paralysis caused by acute midbrain infarction, Tsuda [/bib_ref] [bib_ref] Temporary divergence paralysis in viral meningitis, Bakker [/bib_ref] [bib_ref] Report of a case of paralysis of divergence, Zentmayer [/bib_ref]. - Divergence insufficiency is a more controversial entity and is characterised by an esotropia for distance, normal convergence and variable or reduced fusional divergence [bib_ref] Abnormal supranuclear eye movements in the child: a practical guide to examination..., Cassidy [/bib_ref]. It has been described as a continuum with divergence paralysis, in association with neuropathology including raised intracranial pressure or as a mechanical rather than neurological phenomenon [bib_ref] Divergence insufficiency and paralysis, White [/bib_ref] [bib_ref] Divergence insufficiency esotropia is a misnomer, Mittelman [/bib_ref] [bib_ref] A case of pediatric idiopathic intracranial hypertension presenting with divergence insufficiency, Kang [/bib_ref]. In the absence of an acute presentation, other supranuclear eye movement anomalies or any neurological signs, underlying neuropathology is rare. ## Smooth pursuit ## Underlying neuroanatomy The neuroanatomical pathways underpinning smooth pursuit movements have been studied extensively and many pathways and nuclei are known to play a part. The following is a simplification of the core circuit. Visual information from V1 is conveyed to area V5 (middle temporal and middle superior temporal areas) and then descends to the pontine nuclei. They are joined here by additional inputs from descending fibres from the frontal eye field (Brodman area 8). Fibres are relayed from the pontine nuclei to the flocculus and ventral paraflocculus of the cerebellum. Floccular Purkinje cells then encode eye position, velocity and to a smaller extent, acceleration. Projections then extend to the vestibular nuclei and on to the oculomotor nuclei within the brainstem [bib_ref] Cerebellar flocculus and paraflocculus Purkinje cell activity during circular pursuit in monkey, Leung [/bib_ref]. ## Clinical assessment of smooth pursuit Testing should be performed both horizontally and vertically using a large, slow moving, brightly coloured target or a slowly rotating mirror. The examiner should observe the character of the smooth pursuit movements (jerky or smooth) and identify asymmetric smooth pursuit which can be aided by focussing on the bridge of the patient's nose. An OKR drum or tape can be used if examining an uncooperative infant. Suppression of VOR and smooth pursuit are closely related oculomotor functions with similar underlying neurological substrates. Therefore, abnormalities in both systems commonly occur together. VOR suppression can be assessed by: ## Nystagmus Nystagmus is a disorder of eye movement which can be defined as 'a repetitive, to-and-fro movement of the eyes that is initiated by slow phases'. It is important to note that the pathology is the initial slow movement. This is followed by either a 'corrective' fast movement (jerk nystagmus) or a second slow movement (pendular nystagmus). It is relevant to many abnormalities of eye movement in children. Therefore, in the following section, we discuss the key clinical features to identify when nystagmus is found as part of the supranuclear eye movement examination described above. Classification of nystagmus has been inconsistent in the literature and in the following section, we use the term infantile nystagmus syndrome (INS) and fusion maldevelopment nystagmus syndrome (manifest latent nystagmus or FMNS) according to the CEMAS classification of 2001. It is important for the clinician to note that patients with INS or FMNS may have a variety of underlying ocular/systemic conditions but these descriptions have some key eye movement signs which help to exclude (often more concerning) differential diagnoses. Clinical assessment of nystagmus - Observe the child at play to identify any consistent visual behaviours such as head positions and head shaking (often, but not always, after 1 year of age), in addition to signs of systemic neurological features such as ataxia. - In addition to a routine, age-appropriate history, orthoptic examination and refraction, children's eye movements should be observed in five positions of gaze and note taken of the direction of the fast phase of nystagmus (if jerk is seen), the amplitude of the nystagmus (fine or coarse) and the effect of monocular viewing and removal of fixation. - Where MLN or FMNS is suspected, rotating the child to induce post-rotational nystagmus and then occluding each eye separately can make identification easier. The induced post-rotational nystagmus to the right or left will either add to the existing MLN or reduce it, depending on which eye is covered, yielding a clear inter-ocular difference in nystagmus intensity. - Abnormal eye movements should be observed for at least 5 min (ideally 10) to examine for reversal of nystagmus direction and any alteration in head posture. Inconsistencies in history/examination/previous clinical notes may suggest an alternating head posture often due to periodic alternating nystagmus (PAN), which itself can be congenital or aquired. - An examination of saccades/smooth pursuit/gaze holding/VOR/vergence should also be performed as described above. - An ocular examination should be performed with the best age dependant equipment available specifically looking for signs of photophobia, retinal dystrophy, retinal/choroidal hypopigmentation, iris transillumination and anterior segment anomaly e.g., cataract. - Ocular coherence tomography (OCT) of the macular should be performed where possible to identify foveal hypoplasia and other abnormalities of retinal morphology that would give an indication of retinal origin for the nystagmus. - Where possible, electro-diagnostic tests should be performed including: an electroretinogram (ERG) and a visual evoked potential (VEP) to identify retinal and post-retinal pathology such as a retinal dystrophy, or abnormal decussation at the chiasm in albinism. - Where possible, parents should be examined for the presence of subtle nystagmus, iris transillumination and foveal hypoplasia (seen in albinism phenotypes and PAX6 gene disease) and retinal dystrophies (especially where equipment is not available to fully examine the young child and/or a family history is evident). - Anomalous head postures are best viewed by asking the patient to view the smallest target they can resolve in the distance and giving them time to adopt a head posture if one is present. - Videos of head postures and nystagmus can be extremely useful especially where only fleeting glimpses of the child are possible and to aid advice from other clinicians. In the authors' practice, videos taken by parents or referring clinicians can provide the most useful part of any referral or request for advice. - Documenting nystagmus can be achieved in a variety of ways. The following diagrammatic representation is used in the authors' practice [fig_ref] Figure 6: Recording nystagmus amplitude, frequency, direction and waveform in nine positions of gaze [/fig_ref]. Interpreting some common clinical findings while examining nystagmus ## Infantile nystagmus syndrome (ins) INS is characterised by horizontal nystagmus, staying horizontal in vertical gaze, associated with null zones, dampening with convergence and made worse by visual attention and stress. It is rarely associated with underlying neuropathology but can be seen due to congenital visual loss of any cause. ## Fusion maldevelopment nystagmus syndrome (fmns, previously mln) FMNS is characterised by horizontal nystagmus which beats in the direction of the viewing eye, worsening in abduction and improving in adduction of the viewing eye. It is commonly seen with strabismus without neuropathology and is thought to be due to maldevelopment of fusion. ## Periodic alternating nystagmus (pan) PAN may be congenital (isolated or commonly seen in albinism) or related to identifiable lesions of the cerebellar nodulus/uvula. It alternates less regularly in congenital forms when it tends to be more asymmetrical and less predictable (asymmetrical periodic alternating nystagmus (APAN)). ## Vertical nystagmus - DBN is often more pronounced in downgaze but also in horizontal gaze. It can be accompanied by an alternating skew mimicking a superior oblique over-action. Some children adopt a resulting chin down posture which can mimic tonic upgaze. DBN is typically caused by lesions of the cerebellar flocculus bilaterally (such as in Arnold-Chiari malformations) and can also be found less commonly in 'idiopathic' patients and those with retinal dystrophy. - DBN may be responsive to treatment with aminopyridines and UBN and PAN also to Baclofen treatment. - Vertical and multidirectional nystagmus can be caused by intracranial lesions/metabolic disease but also retinal dystrophies. We would advocate electro-diagnostic testing (where available without significant delay) prior to neuroimaging for this reason in children with apparently isolated vertical nystagmus. - Up beat nystagmus (UBN) is usually due to lesions of the midbrain or medulla, e.g., tumours or multiple sclerosis in adults. - See-saw nystagmus is characterised by a cyclic movement of both eyes. In one half of the cycle, one eye will rise and intort and the other eye will fall and extort; then, in the next half cycle, the vertical and torsional components are reversed. It is most commonly caused by parasellar masses but has been described in many other conditions. It is rare in children. - Vertical nystagmus may be seen as a side effect from systemic medications, commonly antiepileptics, such as phenytoin. ## Vestibular nystagmus Alexander's law states that nystagmus intensity increases when the eyes are moved in the direction of the fast phase. Originally, described for peripheral vestibular nystagmus it also holds true for central vestibular nystagmus and possibly other forms. Torsional nystagmus is often vestibular and is rare in primary position when it is usually medullary in origin (Syringobulbia or Wallenberg syndrome). ## Some common clinical dilemmas In this section, we discuss some of the more common clinical dilemmas faced by clinicians. ## How to differentiate end-point from gen This is a common dilemma. The following features help the clinician to differentiate end-point nystagmus from GEN. In the authors' experience, using the following criteria, these patients rarely pose a significant diagnostic dilemma [fig_ref] Table 4: Differentiating end-point from gaze-evoked nystagmus End-point nystagmus Gaze-evoked nystagmus [/fig_ref]. ## How to differentiate fmns or mln from ins in a patient with early loss of fusion (such as strabismus or cataract) This is a frequent question for clinicians and many cases will have some features of FMNS and other features suggesting INS. However, the most clinically relevant distinction to make is between those cases with INS/FMNS and those with additional features suggesting a neurological cause, requiring additional investigation and management. - A full orthoptic examination looking for presence of early-onset manifest strabismus (which is often seen in FMNS) can provide a clue towards an FMNS diagnosis. How to differentiate opsoclonus/flutter and squarewave jerks from other eye movement conditions Opsoclonus/flutter can occasionally be confused with nystagmus especially in younger children. Making the distinction is important for clinical management and a few key differences exist: - Opsoclonus/flutter have characteristic, seemingly random, fast eye movements with no slow component (unlike nystagmus) and no inter-saccadic interval. When only horizontal they are described as flutter. - They are often intermittent (unlike nystagmus) and induced by changes in fixation or blinking. - Because opsoclonus/flutter is typically acquired and intermittent, children are often visibly troubled during periods of abnormal eye movement (unlike early-onset nystagmus). - Onset of abnormal eye movements can be noted at any age in opsoclonus/flutter; however, for most children with INS, the abnormal eye movements are noted between 3 and 6 months of age and worsen before stabilising. - Eye movement tics and voluntary nystagmus in older children has been confused with ocular flutter. However, as stated above, opsoclonus and ocular flutter are more common with changes in fixation or blinking and importantly, can be seen under closed eyelids which is rarely seen with tics and voluntary nystagmus. - Pathological square-wave jerks are rarely seen in children but have been described in association with various underlying pathologies and medications. The key distinction is that they comprise of only fast (saccadic) movements rather than the anomalous slow movement seen in nystagmus. When to request neuroimaging in a child with an apparent isolated supranuclear eye movement abnormality? For most clinicians, this is a major concern when faced with a child who has (often striking) abnormal eye movements. Practice varies widely and is often governed by access to clinical tools, equipment, necessity of general anaesthesia for brain imaging studies and varying opinion on risk of general anaesthesia in young children. The following is a guide based on the authors own experience and practice. - In most tertiary referral practice, children with clinical features consistent with INS (conjugate, clinically horizontal nystagmus, staying horizontal in vertical gaze, ±null zone, onset between 3 and 6 months of age, no other anomaly of VOR/SP/Vergence/vertical OKR and accelerating exponential slow phases on eye movement recordings if available), otherwise normal neurological development, normal posterior segment examination and ERG/VEP would not undergo neuroimaging in the first instance. Should subsequent examinations yield other eye movement findings, additional developmental issues or new ophthalmic findings (such as subtle optic nerve hypoplasia) neuroimaging would be sought. A similar approach would be taken in a child with typical FMNS (MLN) and early manifest strabismus or either INS or FMNS in a child with an underlying condition known to be associated with nystagmus such as Down's syndrome. - Where a clear underlying cause for the nystagmus is identified through clinical examination, OCT and ERG/ VEP, such as early-onset retinal dystrophy or features of albinism, neuroimaging would not be initially sought. - Unilateral nystagmus (or significant inter-ocular asymmetry) or supranuclear eye movement anomalies besides nystagmus would be joint managed with paediatric neurologists and neuroimaging would form a part of a broader set of urgent investigations in all cases. ## Summary Isolated abnormalities of specific supranuclear eye movements in children are rare. For most, a pattern will emerge from gaining some information about each of the systems described above, in addition to an orthoptic workup, refraction, good history, electro-diagnostic tests (where available), examination of the family and basic neurological examination. FMNS (MLN) is common, as is INS related to albinism or an eventual 'idiopathic' diagnosis. Additional information can be gleaned from eye movement recordings and hand-held OCT devices but in many cases the clinical diagnosis does not rely solely on these scarce resources. Similarly, the role of genetic testing in these patients is evolving but at present, hampered by the resources, financing and infrastructure required for sequencing and variant interpretation. It is likely that in coming years these technologies will become a part of routine clinical practice but even then, a methodical and detailed clinical examination will remain paramount in assessing and managing this complex group of patients. ## Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. [fig] Figure 1: The vestibulo-ocular reflex (VOR). LR lateral rectus; MR medial rectus; MLF medial longitudinal fasciculus; VI sixth nerve nucleus; VIII 8th nerve (vestibular) nuclei; III third nerve nucleus. This diagram represents a right face turn head movement with eye movement to the left [/fig] [fig] Figure 2: How to perform the doll's head manoeuvre on an infant in a clinical setting [/fig] [fig] Figure 3: Performing the spinning baby test in a clinical setting [/fig] [fig] Figure 4: Using an OKR Drum in a clinical setting [/fig] [fig] Figure 5: Saccades. LR lateral rectus; MR medial rectus; MLF medial longitudinal fosiculus; EBN excitory burst neurons; IBN inhibitory burst neurons; SC superior colliculus; PPRF pontine paramedian reticular formations. This diagram shows the pathway through the midbrain/pons of a saccade to the patient right [/fig] [fig] •: Observing suppression of post-rotational nystagmus after the spinning baby test. Observing suppression of VOR while spinning baby and encouraging fixation on examiners face. Observing suppression of VOR using a target which moves with the head and encouraging horizontal and vertical head movements. The target can be the patients finger held in front of the face or a target on a tongue depressor held in the patient's mouth.Interpreting some common findings while examining smooth pursuit Lesions of the flocculus or cerebellar pathways cause saccadic pursuit and loss of VOR suppression by visual fixation in addition to down beat nystagmus (DBN). Reduced smooth pursuit in all directions indicates a 'general' cerebellar flocculus disorder (drugs, alcohol, ataxias, etc.). Asymmetrical loss of smooth pursuit (i.e., reduced binocularly to a left vs. right moving target) suggests a structural lesion of the ipsilateral cortex or cerebellum. It may also indicate early-onset poor vision in one eye. [/fig] [fig] Figure 6: Recording nystagmus amplitude, frequency, direction and waveform in nine positions of gaze [/fig] [table] Table 2: Questions which can direct the clinician prior to examining a child with abnormal eye movements Pregnancy, maternal medication/drug use and birth history Maternal drug exposure and prematurity are associated with an array of eye movement abnormalities Family history of eye/neurological disease/systemic disease Many eye movement disorders have a hereditary component with different inheritance patterns indicating which genes may be [/table] [table] Table 4: Differentiating end-point from gaze-evoked nystagmus End-point nystagmus Gaze-evoked nystagmus (GEN) Unstained (dampens after a few beats) Sustained. Continues after 20 s of eccentric fixation attempt Delayed after the eccentric eye movement Immediate on eccentric fixation Usually only seen in extreme eccentric gaze Often seen in only mildly eccentric gaze No rebound nystagmus seen (nystagmus beating in the opposite direction once the eye has returned to its central position after 60 s eccentric gaze) Rebound often seen No other supranuclear eye movement abnormalities found. Very rarely seen without co-existing smooth pursuit abnormalities Typically horizontal nystagmus on side gazes only May be horizontal and/or vertical Null positions and head postures are frequent in INS and much less common in FMNS unless the child is crossfixating. However, some children with very asymmetrical visual acuity and FMNS may demonstrate a head posture to utilise adduction to dampen the FMNS in the seeing eye.INS onset is often earlier (<6-12 months) than FMNS. [/table]	None	https://www.nature.com/articles/s41433-018-0216-y.pdf	None
2558cb5baeda0c3139b5f4456a335ea3be40720d	pubmed	ASCO Resource-Stratified Guidelines: Methods and Opportunities	ASCO Resource-Stratified Guidelines: Methods and Opportunities # Introduction Cancer has become one of the leading causes of morbidity and mortality worldwide, with a disproportionately rising burden in low-and middleincome countries (LMICs), where 60% to 70% of the world's total new cancer cases are diagnosed, as well as 70% of cancer deaths.Worldwide, almost 70% of the annual total deaths are caused by noncommunicable diseases, principally from cardiovascular disease, diabetes, chronic respiratory disease, and cancer.In 2012, nearly 80% of all deaths from noncommunicable diseases occurred in LMICs, with cancer being the leading cause of death among those younger than 70 years.Globally, the economic toll from cancer is 19% higher than from cardiovascular disease, not considering direct medical costs and total number of years lost with subsequent impact on productivity. The latter makes cancer the largest single burden on total economy when compared with HIV and other infectious diseases.Health authorities, clinicians, policy makers, patients, and families in resource-constrained settings can experience a lack of expert guidance, as well as resources to address the cancer burden. Different international organizations and societies are working together to help improve access to cancer control worldwide. [bib_ref] Global health initiatives of the international oncology community, Al-Sukhun [/bib_ref] ASCO, recognizing its role as a leading oncology society, with one third of its 45,000 members from outside the United States/Canada, launched ASCO International on World Cancer Day 2013. ASCO International's volunteer programs include professional development, education, training, quality improvement, and support for and dissemination of research in LMICs. [bib_ref] The American Society of Clinical Oncology's efforts to support global cancer medicine, Hortobagyi [/bib_ref] "ASCO International connects the global community of cancer care providers through a large and expanding portfolio of international programs." 10 ASCO considered the reality that lack of resources (including infrastructure, personnel, and training) can make it difficult for some clinicians/institutions outside the United States to implement ASCO guidelines and thus began publishing Resource-Stratified Guidelines. This article aims to review the background, methods of development, and dissemination of ASCO Resource-Stratified Guidelines. Effective control of cancer requires integration of effective cancer prevention, early detection, and comprehensive therapeutic and palliative approaches. Because of competing priorities, as well as increased effective options for prevention and treatment, policy makers in LMICs and other resource-constrained settings are facing increasingly difficult decisions regarding budget priorities. Therefore, the difficulty of offering each service optimally is escalating. ASCO recognizes that human resources, poverty, human rights, education, medical system, and cultural and political issues are all influential in local medical and public health practices. ASCO has long-standing experience with developing evidence-based clinical practice guidelines, with a current portfolio of 85 guidelines, with 25 de novo guidelines and 15 guideline updates in development. ASCO started developing guidelines in 1995. Those guidelines provide detailed and medically sound compilations of updates, insights, advice, and recommendations in the areas of greatest clinical need and uncertainty to ensure that patients get the best-quality medical care. However, they were developed in the context of maximal resources being available and are not likely to be applicable within other resource settings. ASCO became interested in leveraging the expertise of its international membership and its expertise in clinical practice guideline development to increase guidance on cancer prevention and care around the world by addressing variations in the availability of resources. The guidelines are intended to complement-but not replace-local guidelines, because local guidelines can better reflect local situations, whereas ASCO guidelines take a more globally applicable perspective. The Breast Health Global Initiative (BHGI), of which ASCO was a supporter, developed evidence-based, economically feasible, and culturally appropriate guidelines for nations with limited health care resources to improve breast cancer outcomes.ASCO has adapted BHGI's four-tier resource-stratification levels. BHGI resource definitions were later adopted by many oncology societies in an attempt to help physicians deliver the best possible care in limited-resource settings, by efficiently allocating resources. Other groups producing recommendations for resource-stratified settings include the Asian Oncology Summit, [bib_ref] Cancer prevention in Asia: Resource-stratified guidelines from the Asian Oncology Summit, Lertkhachonsuk [/bib_ref] Disease Control Priorities (DCP3),National Comprehensive Cancer Network, 13 and WHO, 14 among others. ## Asco's international affairs and clinical practice Guidelines Committees proposed a resourcestratified approach using ASCO's well-known, high-quality guideline development to the ASCO Board of Directors with the goal of creating flexible, resource-stratified methods to practice guidelines, where clinicians and health authorities can identify how existing resources can be optimally applied to improve cancer outcomes, and to provide a bridge for improving cancer care in various health systems. After the Board approved the proposal, ASCO initiated a pilot effort to develop Resource-Stratified Guidelines for prevention of cervical cancer and treatment of women with cervical cancer, a globally high-incidence cancer, and to use the lessons learned from that initiative to inform a structured approach for all common cancers. The resource-stratified cervical cancer guidelines addressed primary prevention, secondary prevention/screening, work-up, and treatment. [bib_ref] Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Clinical Practice Guideline, Jeronimo [/bib_ref] [bib_ref] Primary Prevention of Cervical Cancer, Arrossi [/bib_ref] [bib_ref] Management and Care of Women With Invasive Cervical Cancer: American Society of..., Chuang [/bib_ref] Under the leadership of a Resource-Stratified Guidelines Advisory Group, ASCO expanded this suite of products into a planned series of Resource-Stratified Guidelines continuing with palliative care and colorectal cancer, with more topics to be determined over time. [bib_ref] Palliative Care in the Global Setting: ASCO Resource-Stratified Practice Guideline Summary, Osman [/bib_ref] Those topics were suggested and prioritized by the Resource-Stratified Guidelines Advisory Group, which included members from the International Affairs and Clinical Practice Guidelines Committees, representing members from all resource settings. # Methods The target audiences for the guidelines are clinicians, program planners, public health providers, health/public health authorities, policy makers, patients, and caregivers. The ASCO guidelines program began developing Resource-Stratified Guidelines using methods adapted from other established methodologies, including ASCO's systematic review techniques and consensus methodology, and the ADAPTE methodology. [bib_ref] Innovations in American Society of Clinical Oncology Practice Guideline Development, Somerfield [/bib_ref] ASCO began developing these guidelines to provide expert guidance for situations in which maximal resources are not available. ## Overview ASCO sets a high priority on assembling multidisciplinary Expert Panels with members from multiple resource settings. Members represent geographic, northern/southern hemisphere, sex, discipline (and so on) diversity; most members are from (or have extensive experience in) basicand limited-(indeed, from all four settings) resource settings. All Expert Panels include patient advocates and/or patients and, inspired by BHGI, each Panel meeting starts with the advocate's presentation. When available, health economists with expertise in these settings are included throughout ASCO's Resource-Stratified Guidelines initiative. Participation in Expert Panels is not limited to ASCO members, which results in the participation of public health, health economics, and other experts in the ASCO Expert Panels. ASCO has long-established guideline development procedures, including systematic reviews and formal consensus using a modified Delphi strategy and has now used these and other validated methods for some of the recommendations to develop Resource-Stratified Guidelines. These methods have included a modified ADAPTE method, elements of ASCO's endorsement processes, and, due to the paucity of evidence from some of these settings, formal consensus. 21 ## Systematic review All ASCO guidelines begin with a systematic review of the evidence, including a literature search with prespecified elements including inclusion/exclusion criteria. This includes looking for existing guidelines to adapt (part of ADAPTE). Searches are conducted in PubMed and related databases, such as the Guidelines International Network, and relevant Web sites for published high-quality guidelines, especially those published by established developers, preferably professional societies and/or national/international authorities that used high-quality/standardized methods in guideline development (eg, Centers for Disease Control and Prevention, WHO). ## Modified adapte process If relevant guidelines are identified, the ADAPTE process 20 involves content review by volunteer experts and methodology review by ASCO staff. One to two Panel members review each guideline for content using the ASCO Endorsement Form [fig_ref] Fig 1: ASCO Guideline Endorsement Content Review Form [/fig_ref] and one to two staff members use the Appraisal of Guidelines for Research and Development II (AGREE II) instrument, Rigor of Development subscale [fig_ref] Table 1: Rigor of Development Subscale of the Appraisal of Guidelines for Research and... [/fig_ref] 22,23 to assess methodological rigor. ## Recommendations development Recommendations are initially developed by the Panel co-chairs and/or Steering Group and then shared with the full Panel or, alternatively, the recommendations are drafted by the full Panel. Primarily done in person, recommendation development uses standard ASCO guideline recommendation syntax. The guideline recommendations are crafted, in part, using the GuideLines Into Decision Support (GLIDES) methodology. [bib_ref] Building better guidelines with BRIDGE-Wiz: Development and evaluation of a software assistant..., Shiffman [/bib_ref] This method helps Guideline Expert Panels systematically develop clear, translatable, and implementable recommendations using natural language, based on the evidence and assessment of its quality, and incorporates distilling the actions involved, identifying implementers (to whom and under what circumstances), and clarifying if and how end users can carry out the actions consistently. ## Formal consensus When the Expert Panel deems the available literature insufficient to inform an evidence-based recommendation to guide clinical practice, a formal consensus process is used to develop recommendations, which are considered the best current guidance for practice. [bib_ref] of Clinical Oncology Clinical Practice Guidelines: Formal systematic review-based consensus methodology, Loblaw [/bib_ref] The Panel is then supplemented by additional experts (ie, a Consensus Ratings Panel) to independently rate levels of agreement with the recommendations. The levels of agreement must collectively meet a prespecified threshold (eg, ≥ 75%) that the experts must have rated "agree" or "strongly agree" for each recommendation. The results are reported either in the guideline or its supplement. More details on ASCO methodologies are available in the ASCO Methodology Manual, including a description of formal consensus, systematic review, literature search terms, Appraisal of Guidelines for Research and Development II (AGREE II), and more. Dr. David Kerr was the founding editor-in-chief and Dr. Gilberto Lopes is the current editor-inchief. Resource-Stratified Guidelines are also included in ASCO's guidelines app, and ASCO leverages its social media and other communications mechanisms (eg, Pocket Cards; www. asco.org/practice-guidelines/quality-guidelines/ guidelines/guideline-pocket-cards) to disseminate the guidelines. In addition, ASCO University has produced a new, case-based course series designed to provide further essential guideline information to both US-and international-based ASCO members. Resource-Stratified Guidelines are also freely available through ASCO Web sites (www.asco.org, www.cancer.net) and in the app. To assist dissemination in Spanish-speaking areas, ASCO has translated the summaries of the first three Resource-Stratified Guidelines into Spanish. ## Implementation The guidelines have also been disseminated through the ASCO International programs in LMICs. ASCO's Cancer Control for Primary Care course trains primary care providers on cancer prevention, cancer screening, and referral systems to oncology specialists; the Guidelines have been shared in support of the cervical cancer training of this course. In a collaboration with Health Volunteers Overseas, ASCO is assisting hospitals in LMICs to improve the quality of care provided to patients with cancer, and the Guidelines have been incorporated into that assistance. The ASCO/Conquer Cancer International Development and Education Award assists early career oncologists in LMICs, and today there are more than 300 recipients of this award in more Reviewer Name: Background and Instructions. ASCO considers clinical practice guidelines developed by other professional organizations for endorsement. This is done by ASCO most often in lieu of undertaking its own guideline on the same topic. You have been asked to provide a content review of a guideline that is under consideration for endorsement by ASCO. Please check the box that best applies for each of the following items. ## Strongly agree Agree Neither Agree or Disagree Disagree Strongly Disagree ## Unsure The results of the studies described in this guideline are interpreted according to my understanding of the data. The recommendations in this report are clear. I agree with the recommendations as stated in the guideline. The recommendations are suitable for the patients for whom they are intended. The recommendations are too rigid to apply to individual patients. When applied, the recommendations will produce more benefits for patients than harms. The guideline presents options that will be acceptable to patients. The guideline should be endorsed by ASCO. , and ASCO has worked with these and other groups to disseminate/link to the guidelines. Clinicians in several countries/regions are implementing and/ or adapting the guidelines, including in Uganda, Turkey, Lebanon, Central America, and Myanmar. ASCO will continue to work with local oncology societies on disseminating the guidelines. # Discussion The dramatic increase in the toll of cancer in LMICs mandates effective interventions at all levels of cancer care. Considering the rising costs of cancer care globally, optimal use of resources to optimize outcome becomes essential. ASCO guidelines offer trustworthy, unbiased, and effective recommended care options that can be used to help plan treatment and management, but do not replace clinician judgement based on the individual circumstances. Resource-Stratified Guidelines give individual clinicians a practical framework for management of each patient, based on the level of health care resources available in the country, region, or practice area where care is being given. Resource-Stratified Guidelines also give policy makers insight into how to plan resource-appropriate cancer control. They are meant to complement local guidelinesnot to replace them-and, importantly, provide aspirational and objective criteria to lobby for, or otherwise implement, new resources for existing care and prevention options to reach the next resource stratum. They aim to establish consistent guidance for a minimum primary base of cancer prevention and care and to promote greater resource use and implementation, while realistically accounting for differences in resource levels and health care and public health systems around the world. # Limitations A major limitation of developing Resource-Stratified Guidelines is that the vast complexity and variety of existing health settings make it impossible to provide recommendations using a uniform approach. Rather, the guidelines are intended to provide objectives to help planners reach the next stratum of services while working within the settings of local health situations. We hope that the guidelines can be used as a resource toward local implementation; however, we recognize that much work needs to be done in this area to make implementation a reality. The development of Resource-Stratified Guidelines is also challenged by limited evidence from the settings where the guidelines are intended to be applied. The limited evidence is partially attributed to a lack of resources needed to conduct research, although this may be changing. Through Conquer Cancer, The ASCO Foundation, ASCO offers International Innovation Grants, which fund research in LMICs. Several of the Innovation Grants have been awarded to principal investigators in LMICs who are conducting research on cervical cancer. The systematic reviews for the guidelines enable the developers to identify gaps in research. Each guideline ## Rigor of development subscale item Systematic methods were used to search for evidence. The criteria for selecting the evidence are clearly described. The strengths and limitations of the body of evidence are clearly described. The methods used for formulating the recommendations are clearly described. The health benefits, side effects, and risks have been considered in formulating the recommendations. There is an explicit link between the recommendations and the supporting evidence. The guideline has been externally reviewed by experts prior to its publication. A procedure for updating the guideline is provided. NOTE. Each subscale item is rated on a seven-point scale from 1 (strongly disagree) to 7 (strongly agree). The score for the Rigor of Development domain is calculated by summing the scores across individual items in the domain and across all raters, subtracting the lowest possible score for that domain (1 × no. of items × no. of raters), and then standardizing the total score as a proportion of the maximum possible score (7 × no. of items × no. of raters) minus the lowest possible score. contains specific suggestions for future research (eg, setting-specific research on a given intervention). Another challenge is the paucity of implementation of science research in LMICs. In general, research on guideline implementation has found no single effective method, but rather suggests that a combination of methods may be necessary. These methods may include audit and feedback strategies, creating measures, and working with key opinion leaders. [bib_ref] Implementation strategies for health systems in low-income countries, Pantoja [/bib_ref] Therefore, ASCO will develop an implementation framework for the purposes of knowledge transfer while continuing its environmental scoping of other such guidelines. ## Opportunities As mentioned earlier, ASCO International organizes live, in-country training courses in LMICs on a range of cancer control topics, and the guidelines have been featured in the "Cancer Control for Primary Care" course. To take this further, ASCO is developing a course on the prevention and management of cervical cancer in LMICs, which will directly draw on the guidelines and facilitate their implementation in these settings. ASCO also anticipates that this course will provide a feedback loop on opportunities and challenges with applying the guidelines under real-world conditions that course participants face. In addition, planning of an evaluation of ASCO Resource-Stratified Guidelines by end users is underway, as well as exploring how to stimulate research to inform updates of the Resource-Stratified Guidelines. ASCO is contemplating piloting efforts to facilitate guideline implementation on a national level in some LMICs. ASCO continues to develop Resource-Stratified Guidelines as it deepens relationships with its international membership and other stakeholders in standing against cancer worldwide. It is the view of ASCO that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. [fig] Fig 1: ASCO Guideline Endorsement Content Review Form. (*) This form was adapted from the Cancer Care Ontario Program in Evidence-Based Care Practitioner Feedback instrument. This form was used for ASCO's Resource-Stratified Guidelines published 2016 to 2018. ASCO may change its Guideline Endorsement Content Review Form in the future; please visit https://www.asco.org/practice-guidelines/ quality-guidelines/guidelines-tools-resources/guidelines-development for the most current versions. Gynecologic Cancer Society (endorsement of Secondary Prevention [SP]), American College of Obstetrics and Gynecology (support of Primary Prevention and SP), American Society for Colposcopy and Cervical Pathology (endorsement of SP), and Gynecologic Cancer Intergroup (endorsement of Treatment guideline) [/fig] [table] Table 1: Rigor of Development Subscale of the Appraisal of Guidelines for Research and Evaluation II Instrument [/table]	None	https://ascopubs.org/doi/pdfdirect/10.1200/JGO.18.00113	The objectives of this article are to describe the ASCO Resource-Stratified Guidelines and to provide background within the context of ASCO Guidelines and efforts to address the global cancer burden.

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